Current laboratory values:

• Serum calcium concentration 7.8 mg/dL (reference range 8.5–10.5)
• Phosphorus 6.4 mg/dL (2.5–4.5)
• Corrected calcium-phosphorus product 55
• Parathyroid hormone 275 pg/mL (10–60)
• 25-hydroxyvitamin D 7.4 ng/mL (31–80).

Q: Given the patient’s history, which of the following does her skin lesion likely represent?

• Necrotizing fasciitis
• Calciphylaxis
• Disseminated intravascular coagulation
• Anticoagulant-induced skin necrosis

A: Calciphylaxis, or calcific uremic arteriolopathy, is the most likely. It is rare in people with normal renal function, and still rare but somewhat less so in end-stage renal disease patients undergoing chronic hemodialysis.

WHAT CAUSED IT IN OUR PATIENT?

The cause of calciphylaxis is unknown. Theories have focused on protein C and parathyroid hormone. Putative precipitating factors include acute tubular necrosis, albumin infusion with paracentesis, deficiency of protein C or S, hyperparathyroidism, hyperphosphatemia, hypercalcemia, vitamin D supplementation, steroids, trauma, and warfarin use.

Our patient had a history of hypothyroidism, ulcerative colitis, and end-stage liver disease due to primary sclerosing cholangitis, but no previous history of renal disease.

At the time of her acute renal failure, her calcium-phosphorus level was 55, parathyroid hormone level 274 pg/mL (normal 10–60), and protein C level 26% (normal 76%–147%). At the time the skin lesions were discovered, her protein C level had dropped to 14%; her parathyroid level had returned to normal.

Her home medications included furosemide (Lasix), levothyroxine (Synthroid), mesalamine (Pentasa), azathioprine (Imuran), ursodiol (Actigall), spironolactone (Aldactone), and omeprazole (Prilosec).

NONHEALING LESIONS

The skin lesions of calciphylaxis usually occur in areas of increased adipose tissue. The lesions may not manifest until several weeks after the initial insult (ie, the elevated calcium-phosphate level). Skin biopsy is recommended if a necrotic skin lesion is identified in a patient with an elevated calcium-phosphate level or in a patient with risk factors for renal, liver, or parathyroid disease.

PROGNOSIS IS POOR

Treatment is supportive. Intensive wound care (with surgical evaluation for skin grafting), hyperbaric oxygen, and possibly tissue plasminogen activator (if there is evidence of a hypercoagulable state and occlusive vasculopathy) may be the most beneficial. Identifying the underlying cause and regulating the calcium-phosphorus product level with diet, phosphate binders, bisphosphonates, and sodium thiosulfate are also important in wound healing. Cinacalcet (Sensipar) and parathyroidectomy should be considered in cases of secondary hyperparathyroidism.

Calciphylaxis is important to recognize early in its course and may require a multidisciplinary approach to treatment. Its prognosis is poor, with death rates ranging from 40% to 60%.

Our patient developed recurrent hepatorenal syndrome and sepsis and eventually died of septic shock.

Current laboratory values:

• Serum calcium concentration 7.8 mg/dL (reference range 8.5–10.5)
• Phosphorus 6.4 mg/dL (2.5–4.5)
• Corrected calcium-phosphorus product 55
• Parathyroid hormone 275 pg/mL (10–60)
• 25-hydroxyvitamin D 7.4 ng/mL (31–80).

Q: Given the patient’s history, which of the following does her skin lesion likely represent?

• Necrotizing fasciitis
• Calciphylaxis
• Disseminated intravascular coagulation
• Anticoagulant-induced skin necrosis

A: Calciphylaxis, or calcific uremic arteriolopathy, is the most likely. It is rare in people with normal renal function, and still rare but somewhat less so in end-stage renal disease patients undergoing chronic hemodialysis.

WHAT CAUSED IT IN OUR PATIENT?

The cause of calciphylaxis is unknown. Theories have focused on protein C and parathyroid hormone. Putative precipitating factors include acute tubular necrosis, albumin infusion with paracentesis, deficiency of protein C or S, hyperparathyroidism, hyperphosphatemia, hypercalcemia, vitamin D supplementation, steroids, trauma, and warfarin use.

Our patient had a history of hypothyroidism, ulcerative colitis, and end-stage liver disease due to primary sclerosing cholangitis, but no previous history of renal disease.

At the time of her acute renal failure, her calcium-phosphorus level was 55, parathyroid hormone level 274 pg/mL (normal 10–60), and protein C level 26% (normal 76%–147%). At the time the skin lesions were discovered, her protein C level had dropped to 14%; her parathyroid level had returned to normal.

Her home medications included furosemide (Lasix), levothyroxine (Synthroid), mesalamine (Pentasa), azathioprine (Imuran), ursodiol (Actigall), spironolactone (Aldactone), and omeprazole (Prilosec).

NONHEALING LESIONS

The skin lesions of calciphylaxis usually occur in areas of increased adipose tissue. The lesions may not manifest until several weeks after the initial insult (ie, the elevated calcium-phosphate level). Skin biopsy is recommended if a necrotic skin lesion is identified in a patient with an elevated calcium-phosphate level or in a patient with risk factors for renal, liver, or parathyroid disease.

PROGNOSIS IS POOR

Treatment is supportive. Intensive wound care (with surgical evaluation for skin grafting), hyperbaric oxygen, and possibly tissue plasminogen activator (if there is evidence of a hypercoagulable state and occlusive vasculopathy) may be the most beneficial. Identifying the underlying cause and regulating the calcium-phosphorus product level with diet, phosphate binders, bisphosphonates, and sodium thiosulfate are also important in wound healing. Cinacalcet (Sensipar) and parathyroidectomy should be considered in cases of secondary hyperparathyroidism.

Calciphylaxis is important to recognize early in its course and may require a multidisciplinary approach to treatment. Its prognosis is poor, with death rates ranging from 40% to 60%.

Our patient developed recurrent hepatorenal syndrome and sepsis and eventually died of septic shock.

Current laboratory values:

• Serum calcium concentration 7.8 mg/dL (reference range 8.5–10.5)
• Phosphorus 6.4 mg/dL (2.5–4.5)
• Corrected calcium-phosphorus product 55
• Parathyroid hormone 275 pg/mL (10–60)
• 25-hydroxyvitamin D 7.4 ng/mL (31–80).

Q: Given the patient’s history, which of the following does her skin lesion likely represent?

• Necrotizing fasciitis
• Calciphylaxis
• Disseminated intravascular coagulation
• Anticoagulant-induced skin necrosis

A: Calciphylaxis, or calcific uremic arteriolopathy, is the most likely. It is rare in people with normal renal function, and still rare but somewhat less so in end-stage renal disease patients undergoing chronic hemodialysis.

WHAT CAUSED IT IN OUR PATIENT?

The cause of calciphylaxis is unknown. Theories have focused on protein C and parathyroid hormone. Putative precipitating factors include acute tubular necrosis, albumin infusion with paracentesis, deficiency of protein C or S, hyperparathyroidism, hyperphosphatemia, hypercalcemia, vitamin D supplementation, steroids, trauma, and warfarin use.

Our patient had a history of hypothyroidism, ulcerative colitis, and end-stage liver disease due to primary sclerosing cholangitis, but no previous history of renal disease.

At the time of her acute renal failure, her calcium-phosphorus level was 55, parathyroid hormone level 274 pg/mL (normal 10–60), and protein C level 26% (normal 76%–147%). At the time the skin lesions were discovered, her protein C level had dropped to 14%; her parathyroid level had returned to normal.

Her home medications included furosemide (Lasix), levothyroxine (Synthroid), mesalamine (Pentasa), azathioprine (Imuran), ursodiol (Actigall), spironolactone (Aldactone), and omeprazole (Prilosec).

NONHEALING LESIONS

The skin lesions of calciphylaxis usually occur in areas of increased adipose tissue. The lesions may not manifest until several weeks after the initial insult (ie, the elevated calcium-phosphate level). Skin biopsy is recommended if a necrotic skin lesion is identified in a patient with an elevated calcium-phosphate level or in a patient with risk factors for renal, liver, or parathyroid disease.

PROGNOSIS IS POOR

Treatment is supportive. Intensive wound care (with surgical evaluation for skin grafting), hyperbaric oxygen, and possibly tissue plasminogen activator (if there is evidence of a hypercoagulable state and occlusive vasculopathy) may be the most beneficial. Identifying the underlying cause and regulating the calcium-phosphorus product level with diet, phosphate binders, bisphosphonates, and sodium thiosulfate are also important in wound healing. Cinacalcet (Sensipar) and parathyroidectomy should be considered in cases of secondary hyperparathyroidism.

Calciphylaxis is important to recognize early in its course and may require a multidisciplinary approach to treatment. Its prognosis is poor, with death rates ranging from 40% to 60%.

Our patient developed recurrent hepatorenal syndrome and sepsis and eventually died of septic shock.

Dr. Alan C. Braverman, in this issue of the Journal, discusses thoracic aortic dissection. To most of us who do not routinely treat aortic disease, it may not seem that much has changed since that Thanksgiving in Philadelphia. Atherosclerosis is still a common risk, surgery is the treatment for ascending dissection, beta-blockers are useful for chronic descending dissections, and the mortality rate is enormously high when dissections bleed.

As internists, we consider the possibility of genetic disorders in patients with a family history of dissection or aneurysm, but we don’t really expect to find many, and most of us don’t often track advances in the understanding of these disorders at the molecular level. At the time I was working in that emergency room, Marfan syndrome was viewed as a connective tissue disorder, with a structurally weak aortic wall and variable other morphologic features. When the molecular defect was defined as fibrillin-1 deficiency, I didn’t think much more than that the weak link of the aorta’s fibrous belt was identified.

But it turns out that fibrillin is not just an aortic girdle; fibrillin lowers the concentration of the cytokine transforming growth factor (TGF)-beta in the aorta (and other organs) by promoting its sequestration in the extracellular matrix. Absence of fibrillin enhances TGF-beta activity, and excess TGF-beta can produce Marfan syndrome in young mice. In maybe the most striking consequence of this line of research, Dietz and colleagues¹ have demonstrated that the specific antagonism of the angiotensin II type 1 receptor by the drug losartan (Cozaar) also blocks the effects of TGF-beta and consequently blocks the development of murine Marfan syndrome. And in a preliminary study, it slowed aneurysm progression in a small group of children with Marfan syndrome.

This does not imply that the same pathophysiology is at play in all aortic aneurysms. But at a time of new guidelines for screening for abdominal aneurysm, these observations offer a novel paradigm for developing drug therapies as an alternative to the mad rush for the vascular operating suite.

Dr. Alan C. Braverman, in this issue of the Journal, discusses thoracic aortic dissection. To most of us who do not routinely treat aortic disease, it may not seem that much has changed since that Thanksgiving in Philadelphia. Atherosclerosis is still a common risk, surgery is the treatment for ascending dissection, beta-blockers are useful for chronic descending dissections, and the mortality rate is enormously high when dissections bleed.

As internists, we consider the possibility of genetic disorders in patients with a family history of dissection or aneurysm, but we don’t really expect to find many, and most of us don’t often track advances in the understanding of these disorders at the molecular level. At the time I was working in that emergency room, Marfan syndrome was viewed as a connective tissue disorder, with a structurally weak aortic wall and variable other morphologic features. When the molecular defect was defined as fibrillin-1 deficiency, I didn’t think much more than that the weak link of the aorta’s fibrous belt was identified.

But it turns out that fibrillin is not just an aortic girdle; fibrillin lowers the concentration of the cytokine transforming growth factor (TGF)-beta in the aorta (and other organs) by promoting its sequestration in the extracellular matrix. Absence of fibrillin enhances TGF-beta activity, and excess TGF-beta can produce Marfan syndrome in young mice. In maybe the most striking consequence of this line of research, Dietz and colleagues¹ have demonstrated that the specific antagonism of the angiotensin II type 1 receptor by the drug losartan (Cozaar) also blocks the effects of TGF-beta and consequently blocks the development of murine Marfan syndrome. And in a preliminary study, it slowed aneurysm progression in a small group of children with Marfan syndrome.

This does not imply that the same pathophysiology is at play in all aortic aneurysms. But at a time of new guidelines for screening for abdominal aneurysm, these observations offer a novel paradigm for developing drug therapies as an alternative to the mad rush for the vascular operating suite.

Dr. Alan C. Braverman, in this issue of the Journal, discusses thoracic aortic dissection. To most of us who do not routinely treat aortic disease, it may not seem that much has changed since that Thanksgiving in Philadelphia. Atherosclerosis is still a common risk, surgery is the treatment for ascending dissection, beta-blockers are useful for chronic descending dissections, and the mortality rate is enormously high when dissections bleed.

As internists, we consider the possibility of genetic disorders in patients with a family history of dissection or aneurysm, but we don’t really expect to find many, and most of us don’t often track advances in the understanding of these disorders at the molecular level. At the time I was working in that emergency room, Marfan syndrome was viewed as a connective tissue disorder, with a structurally weak aortic wall and variable other morphologic features. When the molecular defect was defined as fibrillin-1 deficiency, I didn’t think much more than that the weak link of the aorta’s fibrous belt was identified.

But it turns out that fibrillin is not just an aortic girdle; fibrillin lowers the concentration of the cytokine transforming growth factor (TGF)-beta in the aorta (and other organs) by promoting its sequestration in the extracellular matrix. Absence of fibrillin enhances TGF-beta activity, and excess TGF-beta can produce Marfan syndrome in young mice. In maybe the most striking consequence of this line of research, Dietz and colleagues¹ have demonstrated that the specific antagonism of the angiotensin II type 1 receptor by the drug losartan (Cozaar) also blocks the effects of TGF-beta and consequently blocks the development of murine Marfan syndrome. And in a preliminary study, it slowed aneurysm progression in a small group of children with Marfan syndrome.

This does not imply that the same pathophysiology is at play in all aortic aneurysms. But at a time of new guidelines for screening for abdominal aneurysm, these observations offer a novel paradigm for developing drug therapies as an alternative to the mad rush for the vascular operating suite.

A 50-year-old man developed severe chest pain and collapsed to the floor. The pain was sudden in onset, was burning in quality, and was located in the center of his chest. Emergency medical services arrived a few minutes later and found the patient diaphoretic and cyanotic, with an initial blood pressure of 74/54 mm Hg and a heart rate of 125 beats per minute. He was rushed to the hospital.

His medical history was unremarkable. He smoked one pack of cigarettes per day for 20 years. His father died of a “heart attack” at age 52.

In the emergency department he underwent echocardiography with a portable handheld unit, which showed a pericardial effusion and cardiac tamponade. He was sent for emergency computed tomography of the chest, which revealed an aneurysm of the aortic root and acute type A (Stanford classification) aortic dissection with hemopericardium.

He underwent emergency cardiac surgery. At the time of surgery, he was in cardiogenic shock from aortic dissection complicated by severe aortic regurgitation and cardiac tamponade with hemopericardium. The aortic valve was trileaflet. A 27-mm St. Jude composite valve graft root replacement was performed.

The patient did well and was discharged home 7 days after surgery. Pathologic study of the aorta revealed cystic medial degeneration. He did not have any features of Marfan syndrome or Loeys-Dietz syndrome. His three children underwent evaluation, and each had a normal physical examination and echocardiographic test results.

A HIGH INDEX OF SUSPICION IS CRITICAL

Acute aortic dissection is the most common aortic catastrophe, with an incidence estimated at 5 to 30 per 1 million people per year, amounting to nearly 10,000 cases per year in the United States.^1–4

The diagnosis of acute aortic dissection has many potential pitfalls.^2,3 Aortic dissection may mimic other more common conditions, such as coronary ischemia, pleurisy, heart failure, stroke, and acute abdominal illness. Because acute aortic dissection may be rapidly fatal, one must maintain a high index of suspicion.^2,3 Prompt diagnosis and emergency treatment are critical.

WHAT CAUSES AORTIC DISSECTION?

One hypothesis is that acute aortic dissection is caused by a primary tear in the aortic intima, with blood from the aortic lumen penetrating into the diseased media leading to dissection and creating a true and false lumen.² Another is that rupture of the vasa vasorum leads to hemorrhage in the aortic wall with subsequent intimal disruption, creating the intimal tear and aortic dissection.

Once a dissection starts, pulsatile flow of blood within the aortic wall causes it to extend. The dissection flap may be localized, but it often spirals the entire length of the aorta. Distention of the false lumen with blood may cause the intimal flap to compress the true lumen and potentially lead to malperfusion syndromes.

CLASSIFIED ACCORDING TO LOCATION

It is important to recognize the location of the dissection, as the prognosis and treatment depend on whether the ascending aorta is involved.^2,3 For classification purposes, the ascending aorta is the portion proximal to the brachiocephalic artery, while the descending aorta is the portion distal to the left subclavian artery.³

The DeBakey classification defines a type I aortic dissection as one that begins in the ascending aorta and extends at least to the aortic arch or beyond. Type II dissections involve the ascending aorta only, while type III dissections begin in the descending aorta, most often just distal to the left subclavian artery.

The Stanford classification scheme divides dissections into type A and type B. Type A dissections involve the ascending aorta, while type B dissections do not involve the ascending aorta.

Which classification scheme is used is not important. However, identifying patients with dissection of the ascending aorta (DeBakey type I or type II or Stanford type A) is critical, as emergency cardiac surgery is recommended for this type of dissection.^2,3 For the purposes of this paper, the Stanford classification scheme will be used.

Dissection that involves the ascending aorta most commonly occurs in people ages 50 to 60, whereas acute dissection of the descending aorta typically occurs in people 10 years older.^1,2

An acute aortic dissection is one that has occurred within 2 weeks of symptom onset. A chronic dissection is one that occurred more than 2 weeks after symptoms began.

DISEASES AND CONDITIONS ASSOCIATED WITH AORTIC DISSECTION

Hypertension and disorders leading to disruption of the normal structure and function of the aortic wall. About 75% of patients with acute aortic dissection have underlying hypertension.^1–3

Cystic medial degeneration is a common pathologic feature in many cases of aortic dissection.

Cocaine use and intense weight-lifting increase the shear stresses on the aorta.^2,3

Inflammatory aortic diseases such as giant cell arteritis.

Pregnancy can be complicated by aortic dissection, usually in the setting of an underlying aortopathy.⁵

Iatrogenic aortic dissection accounts for about 4% of cases, as a result of cardiac surgery, catheterization, stenting, or use of an intra-aortic balloon pump.¹

Aortic aneurysm. Patients with thoracic aortic aneurysm are at higher risk of aortic dissection, and the larger the aortic diameter, the higher the risk.^2,3,6 In the International Registry of Acute Aortic Dissection (IRAD), the average size of the aorta was about 5.3 cm at the time of acute dissection. Importantly, about 40% of acute dissections of the ascending aorta occur in patients with ascending aortic diameters less than 5.0 cm.^7,8

Thus, many factors are associated with acute dissection, and specific reasons leading to an individual’s susceptibility to sudden dissection are poorly understood.

CLINICAL FEATURES OF ACUTE AORTIC DISSECTION

Because the symptoms of acute dissection may mimic other, more common conditions, one of the most important factors in the diagnosis of aortic dissection is a high clinical suspicion.^1–3

What is the pretest risk of disease?

Recently, the American College of Cardiology (ACC) and the American Heart Association (AHA) released joint guidelines on thoracic aortic disease.³ These guidelines provide an approach to patients who have complaints that may represent acute thoracic aortic dissection, the intent being to establish a pretest risk of disease to be used to guide decision-making.³

The focused evaluation includes specific questions about underlying conditions, symptoms, and findings on examination that may greatly increase the likelihood of acute dissection. These include:

• High-risk conditions and historical features associated with aortic dissection, such as Marfan syndrome and other genetic disorders (Table 2), bicuspid aortic valve, family history of thoracic aortic aneurysm or dissection, known thoracic aortic aneurysm, and recent aortic manipulation
• Pain in the chest, back, or abdomen with high-risk features (eg, abrupt onset, severe intensity, or a ripping or tearing quality)
• High-risk findings on examination (eg, pulse deficits, new aortic regurgitation, hypotension, shock, or systolic blood pressure differences).

Using this information, expedited aortic imaging and treatment algorithms have been devised to improve the diagnosis.³

Using the IRAD database of more than 2,500 acute dissections, the diagnostic algorithm proposed in the ACC/AHA guidelines was shown to be highly sensitive (about 95%) for detecting acute aortic dissection.⁴ In addition, using this score may expedite evaluation by classifying certain patients as being at high risk of acute dissection.^3,4

Important to recognize is that almost two-thirds of patients who suffered dissection in this large database did not have one of the “high-risk conditions” associated with dissection.⁴ Additionally, the specificity of the ACC/AHA algorithm is unknown, and further testing is necessary.⁴

Acute onset of severe pain

More than 90% of acute dissections present with acute pain in the chest or the back, or both.^1–3 The pain is usually severe, of sudden onset, and often described as sharp or, occasionally, tearing, ripping, or stabbing. The pain usually differs from that of coronary ischemia, being most severe at its onset as opposed to the less intense, crescendo-like pain of angina or myocardial infarction. The pain may migrate as the dissection progresses along the length of the aorta or to branch vessels. It may abate, leading to a false sense of security in the patient and the physician.³ “Painless” dissection occurs in a minority, usually in those with syncope, neurologic symptoms, or heart failure.^1–3

The patient with acute dissection may be anxious and may feel a sense of doom.

Acute heart failure, related to severe aortic regurgitation, may be a predominant symptom in dissection of the ascending aorta.

Syncope may occur as a result of aortic rupture, hemopericardium with cardiac tamponade, or acute neurologic complications.

Vascular insufficiency may occur in any branch vessel, leading to clinical syndromes that include acute myocardial infarction, stroke, paraplegia, paraparesis, mesenteric ischemia, and limb ischemia.

PHYSICAL FINDINGS CAN VARY WIDELY

Findings on physical examination in acute aortic dissection vary widely depending on underlying conditions and on the specific complications of the dissection.

Although the classic presentation is acute, severe pain in the chest or back in a severely hypertensive patient with aortic regurgitation and pulse deficits, most patients do not have all these characteristics.⁴ Most patients with type B dissection are hypertensive on presentation, but many with type A dissection present with normal blood pressure or hypotension.¹ Pulse deficits (unequal or absent pulses) are reported in 10% to 30% of acute dissections and may be intermittent as the dynamic movement of the dissection flap interferes with branch vessel perfusion.^1–3

• Aortic leaflet prolapse or distortion of the leaflet alignment
• Malcoaptation of the aortic leaflets from dilation of the aortic root and annulus
• Prolapse of the intimal flap across the aortic valve, interfering with valve function
• Preexisting aortic regurgitation from underlying aortic root aneurysm or primary aortic valve disease (such as a bicuspid aortic valve).

Neurologic manifestations are most common in dissection of the ascending aorta and are particularly important to recognize, as they may dominate the clinical presentation and lead to delay in the diagnosis of dissection.^2,3 Neurologic syndromes include:

• Persistent or transient ischemic stroke
• Spinal cord ischemia
• Ischemic neuropathy
• Hypoxic encephalopathy.

These manifestations are related to malperfusion to branches supplying the brain, spinal cord, or peripheral nerves.⁹

Syncope is relatively common in aortic dissection and may be related to acute hypotension caused by cardiac tamponade or aortic rupture, cerebral vessel obstruction, or activation of cerebral baroreceptors.^2,9 It is important to consider aortic dissection in the differential diagnosis in cases of unexplained syncope.³

Aortic dissections may extend into the abdominal aorta, leading to vascular complications involving one or more branch vessels.¹⁰ The renal artery is involved in at least 5% to 10% of cases and may lead to renal ischemia, infarction, renal insufficiency, or refractory hypertension.²Mesenteric ischemia or infarction occurs in about 5% of dissections, may be difficult to diagnose, and is particularly dangerous.^2,8 Aortic dissection may extend into the iliac arteries and may cause acute lower extremity ischemia.

Acute myocardial infarction due to involvement of the dissection flap causing malperfusion of a coronary artery occurs in 1% to 7% of acute type A aortic dissections.^1–3 The right coronary artery (Figure 2) is most commonly involved, leading to acute inferior myocardial infarction. Acute myocardial ischemia and infarction in the setting of dissection may lead to a delay in the diagnosis of dissection and to bleeding complications from antiplatelet and anticoagulant drugs given to treat the acute coronary syndrome.

Cardiac tamponade, occurring in about 10% of acute type A dissections, portends a higher risk of death.^2,3

Additional clinical features of aortic dissection include a left-sided pleural effusion, usually related to an inflammatory response. An acute hemothorax may occur from rupture or leaking of a descending aortic dissection.

FINDINGS ON RADIOGRAPHY AND ELECTROCARDIOGRAPHY

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald's Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

Electrocardiography usually has normal or nonspecific findings, unless acute myocardial infarction complicates the dissection.

D-DIMER LEVELS

Biomarkers for the diagnosis of acute aortic dissection are of great interest.

D-dimer levels rise in acute aortic dissection as they do in pulmonary embolism.¹¹ A D-dimer level greater than 1,600 ng/mL within the first 6 hours has a very high positive likelihood ratio for dissection, so this test may be useful in identifying patients with a high probability for dissection. In the first 24 hours after symptom onset, a D-dimer level of less than 500 ng/mL has a negative predictive value of 95%. Thus, elevations in D-dimer may help decide which imaging to perform in a patient presenting with chest pain or suspicion of dissection.¹¹

However, D-dimer levels may not be elevated in dissection variants, such as aortic intramural hematoma or penetrating aortic ulcer. Additionally, once 24 hours have elapsed since the dissection started, D-dimer levels may no longer be elevated. The current ACC/AHA guidelines on thoracic aortic disease concluded that the D-dimer level cannot be used to rule out aortic dissection in high-risk individuals.³

Additional studies may clarify the appropriate role of the D-dimer assay in diagnosing aortic dissection.

DEFINITIVE IMAGING STUDIES: CT, MRI, TEE

Contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI), and transesophageal echocardiography (TEE) all have very high sensitivity and specificity for the diagnosis of aortic dissection.^2,3 The choice of imaging study often depends on the availability of these studies, with CT and TEE being the most commonly performed initial studies.

MRI is outstanding for detecting and following aortic dissection, but it is usually not the initial study performed because of the time required for image acquisition and because it is generally not available on an emergency basis.

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald's Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

While transthoracic echocardiography (TTE) can detect aortic dissection, its sensitivity is much lower than that of other imaging tests.^2,3 Therefore, negative findings on TTE do not exclude aortic dissection.

MANAGEMENT OF AORTIC DISSECTION

When acute aortic dissection is diagnosed, multidisciplinary evaluation and treatment are necessary. Time is of the essence, as the death rate in acute dissection may be as high as 1% per hour during the first 24 hours.^1–3 All patients with acute aortic dissection, whether type A or type B, should be transferred to a tertiary care center with a staff experienced in managing aortic dissection and its complications.³ Emergency surgery is recommended for type A aortic dissection, whereas type B dissection is generally treated medically unless complications occur.^2,3

The cornerstone of drug therapy is the prompt reduction in blood pressure with a beta-blocker to reduce shear stresses on the aorta. Intravenous agents such as esmolol (Brevibloc) or labetalol (Normodyne) are usually chosen. Sodium nitroprusside may be added to beta-blocker therapy for rapid blood pressure control in appropriate patients. The patient may require multiple antihypertensive medications. If hypertension is refractory, one must consider renal artery hypertension due to the dissection causing renal malperfusion.² Acute pain may also worsen hypertension, and appropriate analgesia should be used.

Definitive therapy in acute dissection

Patients with acute type A dissection require emergency surgery,^2,3 as they are at risk for life-threatening complications including cardiac tamponade from hemopericardium, aortic rupture, stroke, visceral ischemia, and heart failure due to severe aortic regurgitation. When aortic regurgitation complicates acute type A dissection, some patients are adequately treated by resuspension of the aortic valve leaflets, while others require valve-sparing root replacement or prosthetic aortic valve replacement.

Surgical therapy is associated with a survival benefit compared with medical therapy in acute type A dissection.¹ The 14-day mortality rate for acute type A dissection treated surgically is about 25%.¹ Patients with high-risk features such as heart failure, shock, tamponade, and mesenteric ischemia have a worse prognosis compared with those without these features.^2,12,13

Acute type B aortic dissection carries a lower rate of death than type A dissection.^1–3 In the IRAD cohort, the early mortality rate in those with type B dissection treated medically was about 10%.¹ However, when complications such as malperfusion, shock, or requirement for surgery occur in type B dissection, the mortality rate is much higher,^2,14 with rates of 25% to 50% reported.²

Thus, initial medical therapy is the preferred approach to acute type B dissection, and surgery or endovascular therapy is reserved for patients with acute complications.^2,3 Typical indications for surgery or endovascular therapy in type B dissection include visceral or limb ischemia, aortic rupture, refractory pain, and aneurysmal dilation (Table 3).²

Endovascular therapy in aortic dissection

The high mortality rate with open surgery in acute type B dissection has spurred tremendous interest in endovascular treatments for complications involving the descending aorta and branch vessels.²

Fenestration of the aorta and stenting of branch vessels were the earliest techniques used in complicated type B dissection. By fenestrating (ie, opening) the intimal flap, blood can flow from the false lumen into the true lumen, decompressing the distended false lumen.

Endovascular stenting is used for acute aortic rupture, for malperfusion syndromes, and for rapidly enlarging false lumens. Endovascular grafts may cover the area of a primary intimal tear and thus eliminate the flow into the false channel and promote false-lumen thrombosis. Many patients with complicated type B dissection are treated with a hybrid approach, in which one segment of the aorta, such as the aortic arch, is treated surgically, while the descending aorta receives an endovascular graft.²

Patients with a type B dissection treated medically are at risk for late complications, including aneurysmal enlargement and subsequent aortic rupture. The Investigation of Stent Grafts in Aortic Dissection (INSTEAD) trial included 140 patients with uncomplicated type B dissection and compared drug therapy with endovascular stent grafting.¹⁵ After 2 years of follow-up, there was no difference in the rate of death between the two treatment groups. Patients receiving endovascular grafts had a higher rate of false-lumen thrombosis.

More studies are under way to examine the role of endovascular therapy in uncomplicated type B dissection.

AORTIC DISSECTION VARIANTS

Aortic intramural hematoma

Aortic intramural hematoma is a form of acute aortic syndrome in which a hematoma develops in the aortic media and no intimal flap is visualized either by imaging or at surgery.^2,3,16 It is important to recognize this clinical entity in a patient presenting with acute chest or back pain, as sometimes it is mistaken for a “thrombus in a nonaneurysmal aorta.” Intramural hematoma accounts for 5% to 25% of acute aortic syndromes, depending on the study population (it is more common in Asian studies).^2,3,17 It may present with symptoms similar to classic aortic dissection and is classified as type A or type B, depending on whether the ascending aorta is involved.

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald's Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

Patients with an intramural hematoma may progress to having complications such as hemopericardium, classic aortic dissection, aortic rupture, or aneurysmal dilation.^2,3 However, many cases of type B aortic intramural hematoma result in complete resorption of the hematoma over time. In general, like classic aortic dissection, type A intramural hematoma is treated with emergency surgery and type B with initial medical therapy.^2,3

There are reports from Southeast Asia of successful initial medical therapy for type A intramural hematoma, with surgery used for acute complications.¹⁸ In the Western literature, improved outcomes are reported with initial surgical therapy.¹⁷ Given the unpredictable nature of type A intramural hematoma, most experts recommend surgical therapy for appropriate candidates with acute type A intramural hematoma.^2,3,19

Penetrating atherosclerotic ulcer of the aorta

Penetrating atherosclerotic ulcer of the aorta, another acute aortic syndrome, results from acute penetration of an atherosclerotic aortic lesion through the internal elastic lamina into the media.^2,3,20 It is often associated with bleeding into the media, or intramural hematoma. While the ulcer may be found incidentally on imaging studies, especially in patients with severe aortic atherosclerosis, the typical presentation is acute, severe chest or back pain. It occurs most often in the descending aorta and the abdominal aorta.

Penetrating atherosclerotic ulcer may lead to pseudoaneurysm formation, focal aortic dissection, aortic rupture, or late aortic aneurysm.²

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald's Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

LONG-TERM MANAGEMENT AFTER AORTIC DISSECTION

After hospital discharge, patients with aortic dissection require lifelong management. This includes blood pressure control, lifestyle modification, serial imaging of the aorta with CT or MRI, patient education about the condition, and, when appropriate, screening of family members for aortic disease.^5,21

Reported survival rates after hospitalization for type A dissection are 52% to 94% at 1 year and 45% to 88% at 5 years.^2,22 The 10-year actuarial survival rate for those with acute dissection who survive the acute hospitalization is reported as 30% to 60%. Long-term survival rates after acute type B dissection have been reported at 56% to 92% at 1 year and 48% to 82% at 5 years.²³ Survival rates depend on many factors, including the underlying condition, the age of the patient, and comorbidities.

It is important to treat hypertension after aortic dissection, with a goal blood pressure of 120/80 mm Hg or less for most patients. Older studies found higher mortality rates with poorly controlled hypertension. Beta-blockers are the drugs of first choice. Even in the absence of hypertension, long-term beta-blocker therapy should be used to lessen the aortic stress and force of ventricular contraction.

Genetically triggered causes of aortic dissection should be considered. In many circumstances, referral to a medical geneticist or other practitioner knowledgeable in these conditions is important when these disorders are being evaluated (Table 2).

Many of these disorders have an autosomal dominant inheritance, and the patient should be asked about a family history of aortic disease, aortic dissection, or unexplained sudden death. Features of Marfan syndrome, Loeys-Dietz syndrome, and familial thoracic aortic aneurysm syndromes should be sought. Through comprehensive family studies, it is now recognized that up to 20% of patients with thoracic aortic disease (such as aneurysm or dissection) have another first-degree relative with thoracic aortic disease.^2,3,24 Thus, first-degree relatives of patients with aortic aneurysm or dissection should be screened for thoracic aortic aneurysm disease.

Research into molecular genetics is providing a better understanding of the genetics of aortic dissection.³ New mutations associated with aortic dissection are being discovered in signaling pathways as well as elements critical for the integrity of the vascular wall.^2,3 However, at present, most patients with aortic dissection will not have a specific identifiable genetic defect.

Not only does genetic testing enable the accurate diagnosis of the affected individual, but also treatments are often based on this diagnosis.³ Importantly, the identification of a specific gene mutation (ie, in TGFBR1 or 2, FBN1, ACTA2, MYH11, and COL3A1) in an affected individual has the potential to identify other family members at risk.³

Follow-up imaging

It is important to continue to image the aorta after aortic dissection. Patients may develop progressive dilation or aneurysm formation of the dissected aorta, pseudoaneurysm formation after repair, or recurrent dissection. Many patients require additional surgery on the aorta because of late aneurysm formation.

CT or MRI is usually performed at least every 6 months in the first 2 years after dissection and at least annually thereafter. More centers are choosing MRI for long-term follow-up to avoid the repeated radiation exposure with serial CT.

Patient education

Besides receiving medical therapy and undergoing imaging, patients with aortic dissection should be educated about this condition.^5,21 The patient should be aware of symptoms suggesting dissection and should be instructed to seek attention for any concerning symptoms.

Lifestyle modifications are also important. The patient should be educated about safe activity levels and to avoid heavy isometric exercise, such as weight-lifting. Some patients will have to cease their current occupation because of activity restrictions.

A 50-year-old man developed severe chest pain and collapsed to the floor. The pain was sudden in onset, was burning in quality, and was located in the center of his chest. Emergency medical services arrived a few minutes later and found the patient diaphoretic and cyanotic, with an initial blood pressure of 74/54 mm Hg and a heart rate of 125 beats per minute. He was rushed to the hospital.

His medical history was unremarkable. He smoked one pack of cigarettes per day for 20 years. His father died of a “heart attack” at age 52.

In the emergency department he underwent echocardiography with a portable handheld unit, which showed a pericardial effusion and cardiac tamponade. He was sent for emergency computed tomography of the chest, which revealed an aneurysm of the aortic root and acute type A (Stanford classification) aortic dissection with hemopericardium.

He underwent emergency cardiac surgery. At the time of surgery, he was in cardiogenic shock from aortic dissection complicated by severe aortic regurgitation and cardiac tamponade with hemopericardium. The aortic valve was trileaflet. A 27-mm St. Jude composite valve graft root replacement was performed.

The patient did well and was discharged home 7 days after surgery. Pathologic study of the aorta revealed cystic medial degeneration. He did not have any features of Marfan syndrome or Loeys-Dietz syndrome. His three children underwent evaluation, and each had a normal physical examination and echocardiographic test results.

A HIGH INDEX OF SUSPICION IS CRITICAL

Acute aortic dissection is the most common aortic catastrophe, with an incidence estimated at 5 to 30 per 1 million people per year, amounting to nearly 10,000 cases per year in the United States.^1–4

The diagnosis of acute aortic dissection has many potential pitfalls.^2,3 Aortic dissection may mimic other more common conditions, such as coronary ischemia, pleurisy, heart failure, stroke, and acute abdominal illness. Because acute aortic dissection may be rapidly fatal, one must maintain a high index of suspicion.^2,3 Prompt diagnosis and emergency treatment are critical.

WHAT CAUSES AORTIC DISSECTION?

One hypothesis is that acute aortic dissection is caused by a primary tear in the aortic intima, with blood from the aortic lumen penetrating into the diseased media leading to dissection and creating a true and false lumen.² Another is that rupture of the vasa vasorum leads to hemorrhage in the aortic wall with subsequent intimal disruption, creating the intimal tear and aortic dissection.

Once a dissection starts, pulsatile flow of blood within the aortic wall causes it to extend. The dissection flap may be localized, but it often spirals the entire length of the aorta. Distention of the false lumen with blood may cause the intimal flap to compress the true lumen and potentially lead to malperfusion syndromes.

CLASSIFIED ACCORDING TO LOCATION

It is important to recognize the location of the dissection, as the prognosis and treatment depend on whether the ascending aorta is involved.^2,3 For classification purposes, the ascending aorta is the portion proximal to the brachiocephalic artery, while the descending aorta is the portion distal to the left subclavian artery.³

The DeBakey classification defines a type I aortic dissection as one that begins in the ascending aorta and extends at least to the aortic arch or beyond. Type II dissections involve the ascending aorta only, while type III dissections begin in the descending aorta, most often just distal to the left subclavian artery.

The Stanford classification scheme divides dissections into type A and type B. Type A dissections involve the ascending aorta, while type B dissections do not involve the ascending aorta.

Which classification scheme is used is not important. However, identifying patients with dissection of the ascending aorta (DeBakey type I or type II or Stanford type A) is critical, as emergency cardiac surgery is recommended for this type of dissection.^2,3 For the purposes of this paper, the Stanford classification scheme will be used.

Dissection that involves the ascending aorta most commonly occurs in people ages 50 to 60, whereas acute dissection of the descending aorta typically occurs in people 10 years older.^1,2

An acute aortic dissection is one that has occurred within 2 weeks of symptom onset. A chronic dissection is one that occurred more than 2 weeks after symptoms began.

DISEASES AND CONDITIONS ASSOCIATED WITH AORTIC DISSECTION

Hypertension and disorders leading to disruption of the normal structure and function of the aortic wall. About 75% of patients with acute aortic dissection have underlying hypertension.^1–3

Cystic medial degeneration is a common pathologic feature in many cases of aortic dissection.

Cocaine use and intense weight-lifting increase the shear stresses on the aorta.^2,3

Inflammatory aortic diseases such as giant cell arteritis.

Pregnancy can be complicated by aortic dissection, usually in the setting of an underlying aortopathy.⁵

Iatrogenic aortic dissection accounts for about 4% of cases, as a result of cardiac surgery, catheterization, stenting, or use of an intra-aortic balloon pump.¹

Aortic aneurysm. Patients with thoracic aortic aneurysm are at higher risk of aortic dissection, and the larger the aortic diameter, the higher the risk.^2,3,6 In the International Registry of Acute Aortic Dissection (IRAD), the average size of the aorta was about 5.3 cm at the time of acute dissection. Importantly, about 40% of acute dissections of the ascending aorta occur in patients with ascending aortic diameters less than 5.0 cm.^7,8

Thus, many factors are associated with acute dissection, and specific reasons leading to an individual’s susceptibility to sudden dissection are poorly understood.

CLINICAL FEATURES OF ACUTE AORTIC DISSECTION

Because the symptoms of acute dissection may mimic other, more common conditions, one of the most important factors in the diagnosis of aortic dissection is a high clinical suspicion.^1–3

What is the pretest risk of disease?

Recently, the American College of Cardiology (ACC) and the American Heart Association (AHA) released joint guidelines on thoracic aortic disease.³ These guidelines provide an approach to patients who have complaints that may represent acute thoracic aortic dissection, the intent being to establish a pretest risk of disease to be used to guide decision-making.³

The focused evaluation includes specific questions about underlying conditions, symptoms, and findings on examination that may greatly increase the likelihood of acute dissection. These include:

• High-risk conditions and historical features associated with aortic dissection, such as Marfan syndrome and other genetic disorders (Table 2), bicuspid aortic valve, family history of thoracic aortic aneurysm or dissection, known thoracic aortic aneurysm, and recent aortic manipulation
• Pain in the chest, back, or abdomen with high-risk features (eg, abrupt onset, severe intensity, or a ripping or tearing quality)
• High-risk findings on examination (eg, pulse deficits, new aortic regurgitation, hypotension, shock, or systolic blood pressure differences).

Using this information, expedited aortic imaging and treatment algorithms have been devised to improve the diagnosis.³

Using the IRAD database of more than 2,500 acute dissections, the diagnostic algorithm proposed in the ACC/AHA guidelines was shown to be highly sensitive (about 95%) for detecting acute aortic dissection.⁴ In addition, using this score may expedite evaluation by classifying certain patients as being at high risk of acute dissection.^3,4

Important to recognize is that almost two-thirds of patients who suffered dissection in this large database did not have one of the “high-risk conditions” associated with dissection.⁴ Additionally, the specificity of the ACC/AHA algorithm is unknown, and further testing is necessary.⁴

Acute onset of severe pain

More than 90% of acute dissections present with acute pain in the chest or the back, or both.^1–3 The pain is usually severe, of sudden onset, and often described as sharp or, occasionally, tearing, ripping, or stabbing. The pain usually differs from that of coronary ischemia, being most severe at its onset as opposed to the less intense, crescendo-like pain of angina or myocardial infarction. The pain may migrate as the dissection progresses along the length of the aorta or to branch vessels. It may abate, leading to a false sense of security in the patient and the physician.³ “Painless” dissection occurs in a minority, usually in those with syncope, neurologic symptoms, or heart failure.^1–3

The patient with acute dissection may be anxious and may feel a sense of doom.

Acute heart failure, related to severe aortic regurgitation, may be a predominant symptom in dissection of the ascending aorta.

Syncope may occur as a result of aortic rupture, hemopericardium with cardiac tamponade, or acute neurologic complications.

Vascular insufficiency may occur in any branch vessel, leading to clinical syndromes that include acute myocardial infarction, stroke, paraplegia, paraparesis, mesenteric ischemia, and limb ischemia.

PHYSICAL FINDINGS CAN VARY WIDELY

Findings on physical examination in acute aortic dissection vary widely depending on underlying conditions and on the specific complications of the dissection.

Although the classic presentation is acute, severe pain in the chest or back in a severely hypertensive patient with aortic regurgitation and pulse deficits, most patients do not have all these characteristics.⁴ Most patients with type B dissection are hypertensive on presentation, but many with type A dissection present with normal blood pressure or hypotension.¹ Pulse deficits (unequal or absent pulses) are reported in 10% to 30% of acute dissections and may be intermittent as the dynamic movement of the dissection flap interferes with branch vessel perfusion.^1–3

• Aortic leaflet prolapse or distortion of the leaflet alignment
• Malcoaptation of the aortic leaflets from dilation of the aortic root and annulus
• Prolapse of the intimal flap across the aortic valve, interfering with valve function
• Preexisting aortic regurgitation from underlying aortic root aneurysm or primary aortic valve disease (such as a bicuspid aortic valve).

Neurologic manifestations are most common in dissection of the ascending aorta and are particularly important to recognize, as they may dominate the clinical presentation and lead to delay in the diagnosis of dissection.^2,3 Neurologic syndromes include:

• Persistent or transient ischemic stroke
• Spinal cord ischemia
• Ischemic neuropathy
• Hypoxic encephalopathy.

These manifestations are related to malperfusion to branches supplying the brain, spinal cord, or peripheral nerves.⁹

Syncope is relatively common in aortic dissection and may be related to acute hypotension caused by cardiac tamponade or aortic rupture, cerebral vessel obstruction, or activation of cerebral baroreceptors.^2,9 It is important to consider aortic dissection in the differential diagnosis in cases of unexplained syncope.³

Aortic dissections may extend into the abdominal aorta, leading to vascular complications involving one or more branch vessels.¹⁰ The renal artery is involved in at least 5% to 10% of cases and may lead to renal ischemia, infarction, renal insufficiency, or refractory hypertension.²Mesenteric ischemia or infarction occurs in about 5% of dissections, may be difficult to diagnose, and is particularly dangerous.^2,8 Aortic dissection may extend into the iliac arteries and may cause acute lower extremity ischemia.

Acute myocardial infarction due to involvement of the dissection flap causing malperfusion of a coronary artery occurs in 1% to 7% of acute type A aortic dissections.^1–3 The right coronary artery (Figure 2) is most commonly involved, leading to acute inferior myocardial infarction. Acute myocardial ischemia and infarction in the setting of dissection may lead to a delay in the diagnosis of dissection and to bleeding complications from antiplatelet and anticoagulant drugs given to treat the acute coronary syndrome.

Cardiac tamponade, occurring in about 10% of acute type A dissections, portends a higher risk of death.^2,3

Additional clinical features of aortic dissection include a left-sided pleural effusion, usually related to an inflammatory response. An acute hemothorax may occur from rupture or leaking of a descending aortic dissection.

FINDINGS ON RADIOGRAPHY AND ELECTROCARDIOGRAPHY

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald's Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

Electrocardiography usually has normal or nonspecific findings, unless acute myocardial infarction complicates the dissection.

D-DIMER LEVELS

Biomarkers for the diagnosis of acute aortic dissection are of great interest.

D-dimer levels rise in acute aortic dissection as they do in pulmonary embolism.¹¹ A D-dimer level greater than 1,600 ng/mL within the first 6 hours has a very high positive likelihood ratio for dissection, so this test may be useful in identifying patients with a high probability for dissection. In the first 24 hours after symptom onset, a D-dimer level of less than 500 ng/mL has a negative predictive value of 95%. Thus, elevations in D-dimer may help decide which imaging to perform in a patient presenting with chest pain or suspicion of dissection.¹¹

However, D-dimer levels may not be elevated in dissection variants, such as aortic intramural hematoma or penetrating aortic ulcer. Additionally, once 24 hours have elapsed since the dissection started, D-dimer levels may no longer be elevated. The current ACC/AHA guidelines on thoracic aortic disease concluded that the D-dimer level cannot be used to rule out aortic dissection in high-risk individuals.³

Additional studies may clarify the appropriate role of the D-dimer assay in diagnosing aortic dissection.

DEFINITIVE IMAGING STUDIES: CT, MRI, TEE

Contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI), and transesophageal echocardiography (TEE) all have very high sensitivity and specificity for the diagnosis of aortic dissection.^2,3 The choice of imaging study often depends on the availability of these studies, with CT and TEE being the most commonly performed initial studies.

MRI is outstanding for detecting and following aortic dissection, but it is usually not the initial study performed because of the time required for image acquisition and because it is generally not available on an emergency basis.

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald's Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

While transthoracic echocardiography (TTE) can detect aortic dissection, its sensitivity is much lower than that of other imaging tests.^2,3 Therefore, negative findings on TTE do not exclude aortic dissection.

MANAGEMENT OF AORTIC DISSECTION

When acute aortic dissection is diagnosed, multidisciplinary evaluation and treatment are necessary. Time is of the essence, as the death rate in acute dissection may be as high as 1% per hour during the first 24 hours.^1–3 All patients with acute aortic dissection, whether type A or type B, should be transferred to a tertiary care center with a staff experienced in managing aortic dissection and its complications.³ Emergency surgery is recommended for type A aortic dissection, whereas type B dissection is generally treated medically unless complications occur.^2,3

The cornerstone of drug therapy is the prompt reduction in blood pressure with a beta-blocker to reduce shear stresses on the aorta. Intravenous agents such as esmolol (Brevibloc) or labetalol (Normodyne) are usually chosen. Sodium nitroprusside may be added to beta-blocker therapy for rapid blood pressure control in appropriate patients. The patient may require multiple antihypertensive medications. If hypertension is refractory, one must consider renal artery hypertension due to the dissection causing renal malperfusion.² Acute pain may also worsen hypertension, and appropriate analgesia should be used.

Definitive therapy in acute dissection

Patients with acute type A dissection require emergency surgery,^2,3 as they are at risk for life-threatening complications including cardiac tamponade from hemopericardium, aortic rupture, stroke, visceral ischemia, and heart failure due to severe aortic regurgitation. When aortic regurgitation complicates acute type A dissection, some patients are adequately treated by resuspension of the aortic valve leaflets, while others require valve-sparing root replacement or prosthetic aortic valve replacement.

Surgical therapy is associated with a survival benefit compared with medical therapy in acute type A dissection.¹ The 14-day mortality rate for acute type A dissection treated surgically is about 25%.¹ Patients with high-risk features such as heart failure, shock, tamponade, and mesenteric ischemia have a worse prognosis compared with those without these features.^2,12,13

Acute type B aortic dissection carries a lower rate of death than type A dissection.^1–3 In the IRAD cohort, the early mortality rate in those with type B dissection treated medically was about 10%.¹ However, when complications such as malperfusion, shock, or requirement for surgery occur in type B dissection, the mortality rate is much higher,^2,14 with rates of 25% to 50% reported.²

Thus, initial medical therapy is the preferred approach to acute type B dissection, and surgery or endovascular therapy is reserved for patients with acute complications.^2,3 Typical indications for surgery or endovascular therapy in type B dissection include visceral or limb ischemia, aortic rupture, refractory pain, and aneurysmal dilation (Table 3).²

Endovascular therapy in aortic dissection

The high mortality rate with open surgery in acute type B dissection has spurred tremendous interest in endovascular treatments for complications involving the descending aorta and branch vessels.²

Fenestration of the aorta and stenting of branch vessels were the earliest techniques used in complicated type B dissection. By fenestrating (ie, opening) the intimal flap, blood can flow from the false lumen into the true lumen, decompressing the distended false lumen.

Endovascular stenting is used for acute aortic rupture, for malperfusion syndromes, and for rapidly enlarging false lumens. Endovascular grafts may cover the area of a primary intimal tear and thus eliminate the flow into the false channel and promote false-lumen thrombosis. Many patients with complicated type B dissection are treated with a hybrid approach, in which one segment of the aorta, such as the aortic arch, is treated surgically, while the descending aorta receives an endovascular graft.²

Patients with a type B dissection treated medically are at risk for late complications, including aneurysmal enlargement and subsequent aortic rupture. The Investigation of Stent Grafts in Aortic Dissection (INSTEAD) trial included 140 patients with uncomplicated type B dissection and compared drug therapy with endovascular stent grafting.¹⁵ After 2 years of follow-up, there was no difference in the rate of death between the two treatment groups. Patients receiving endovascular grafts had a higher rate of false-lumen thrombosis.

More studies are under way to examine the role of endovascular therapy in uncomplicated type B dissection.

AORTIC DISSECTION VARIANTS

Aortic intramural hematoma

Aortic intramural hematoma is a form of acute aortic syndrome in which a hematoma develops in the aortic media and no intimal flap is visualized either by imaging or at surgery.^2,3,16 It is important to recognize this clinical entity in a patient presenting with acute chest or back pain, as sometimes it is mistaken for a “thrombus in a nonaneurysmal aorta.” Intramural hematoma accounts for 5% to 25% of acute aortic syndromes, depending on the study population (it is more common in Asian studies).^2,3,17 It may present with symptoms similar to classic aortic dissection and is classified as type A or type B, depending on whether the ascending aorta is involved.

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald's Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

Patients with an intramural hematoma may progress to having complications such as hemopericardium, classic aortic dissection, aortic rupture, or aneurysmal dilation.^2,3 However, many cases of type B aortic intramural hematoma result in complete resorption of the hematoma over time. In general, like classic aortic dissection, type A intramural hematoma is treated with emergency surgery and type B with initial medical therapy.^2,3

There are reports from Southeast Asia of successful initial medical therapy for type A intramural hematoma, with surgery used for acute complications.¹⁸ In the Western literature, improved outcomes are reported with initial surgical therapy.¹⁷ Given the unpredictable nature of type A intramural hematoma, most experts recommend surgical therapy for appropriate candidates with acute type A intramural hematoma.^2,3,19

Penetrating atherosclerotic ulcer of the aorta

Penetrating atherosclerotic ulcer of the aorta, another acute aortic syndrome, results from acute penetration of an atherosclerotic aortic lesion through the internal elastic lamina into the media.^2,3,20 It is often associated with bleeding into the media, or intramural hematoma. While the ulcer may be found incidentally on imaging studies, especially in patients with severe aortic atherosclerosis, the typical presentation is acute, severe chest or back pain. It occurs most often in the descending aorta and the abdominal aorta.

Penetrating atherosclerotic ulcer may lead to pseudoaneurysm formation, focal aortic dissection, aortic rupture, or late aortic aneurysm.²

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald's Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

LONG-TERM MANAGEMENT AFTER AORTIC DISSECTION

After hospital discharge, patients with aortic dissection require lifelong management. This includes blood pressure control, lifestyle modification, serial imaging of the aorta with CT or MRI, patient education about the condition, and, when appropriate, screening of family members for aortic disease.^5,21

Reported survival rates after hospitalization for type A dissection are 52% to 94% at 1 year and 45% to 88% at 5 years.^2,22 The 10-year actuarial survival rate for those with acute dissection who survive the acute hospitalization is reported as 30% to 60%. Long-term survival rates after acute type B dissection have been reported at 56% to 92% at 1 year and 48% to 82% at 5 years.²³ Survival rates depend on many factors, including the underlying condition, the age of the patient, and comorbidities.

It is important to treat hypertension after aortic dissection, with a goal blood pressure of 120/80 mm Hg or less for most patients. Older studies found higher mortality rates with poorly controlled hypertension. Beta-blockers are the drugs of first choice. Even in the absence of hypertension, long-term beta-blocker therapy should be used to lessen the aortic stress and force of ventricular contraction.

Genetically triggered causes of aortic dissection should be considered. In many circumstances, referral to a medical geneticist or other practitioner knowledgeable in these conditions is important when these disorders are being evaluated (Table 2).

Many of these disorders have an autosomal dominant inheritance, and the patient should be asked about a family history of aortic disease, aortic dissection, or unexplained sudden death. Features of Marfan syndrome, Loeys-Dietz syndrome, and familial thoracic aortic aneurysm syndromes should be sought. Through comprehensive family studies, it is now recognized that up to 20% of patients with thoracic aortic disease (such as aneurysm or dissection) have another first-degree relative with thoracic aortic disease.^2,3,24 Thus, first-degree relatives of patients with aortic aneurysm or dissection should be screened for thoracic aortic aneurysm disease.

Research into molecular genetics is providing a better understanding of the genetics of aortic dissection.³ New mutations associated with aortic dissection are being discovered in signaling pathways as well as elements critical for the integrity of the vascular wall.^2,3 However, at present, most patients with aortic dissection will not have a specific identifiable genetic defect.

Not only does genetic testing enable the accurate diagnosis of the affected individual, but also treatments are often based on this diagnosis.³ Importantly, the identification of a specific gene mutation (ie, in TGFBR1 or 2, FBN1, ACTA2, MYH11, and COL3A1) in an affected individual has the potential to identify other family members at risk.³

Follow-up imaging

It is important to continue to image the aorta after aortic dissection. Patients may develop progressive dilation or aneurysm formation of the dissected aorta, pseudoaneurysm formation after repair, or recurrent dissection. Many patients require additional surgery on the aorta because of late aneurysm formation.

CT or MRI is usually performed at least every 6 months in the first 2 years after dissection and at least annually thereafter. More centers are choosing MRI for long-term follow-up to avoid the repeated radiation exposure with serial CT.

Patient education

Besides receiving medical therapy and undergoing imaging, patients with aortic dissection should be educated about this condition.^5,21 The patient should be aware of symptoms suggesting dissection and should be instructed to seek attention for any concerning symptoms.

Lifestyle modifications are also important. The patient should be educated about safe activity levels and to avoid heavy isometric exercise, such as weight-lifting. Some patients will have to cease their current occupation because of activity restrictions.

A 50-year-old man developed severe chest pain and collapsed to the floor. The pain was sudden in onset, was burning in quality, and was located in the center of his chest. Emergency medical services arrived a few minutes later and found the patient diaphoretic and cyanotic, with an initial blood pressure of 74/54 mm Hg and a heart rate of 125 beats per minute. He was rushed to the hospital.

His medical history was unremarkable. He smoked one pack of cigarettes per day for 20 years. His father died of a “heart attack” at age 52.

In the emergency department he underwent echocardiography with a portable handheld unit, which showed a pericardial effusion and cardiac tamponade. He was sent for emergency computed tomography of the chest, which revealed an aneurysm of the aortic root and acute type A (Stanford classification) aortic dissection with hemopericardium.

He underwent emergency cardiac surgery. At the time of surgery, he was in cardiogenic shock from aortic dissection complicated by severe aortic regurgitation and cardiac tamponade with hemopericardium. The aortic valve was trileaflet. A 27-mm St. Jude composite valve graft root replacement was performed.

The patient did well and was discharged home 7 days after surgery. Pathologic study of the aorta revealed cystic medial degeneration. He did not have any features of Marfan syndrome or Loeys-Dietz syndrome. His three children underwent evaluation, and each had a normal physical examination and echocardiographic test results.

A HIGH INDEX OF SUSPICION IS CRITICAL

Acute aortic dissection is the most common aortic catastrophe, with an incidence estimated at 5 to 30 per 1 million people per year, amounting to nearly 10,000 cases per year in the United States.^1–4

The diagnosis of acute aortic dissection has many potential pitfalls.^2,3 Aortic dissection may mimic other more common conditions, such as coronary ischemia, pleurisy, heart failure, stroke, and acute abdominal illness. Because acute aortic dissection may be rapidly fatal, one must maintain a high index of suspicion.^2,3 Prompt diagnosis and emergency treatment are critical.

WHAT CAUSES AORTIC DISSECTION?

One hypothesis is that acute aortic dissection is caused by a primary tear in the aortic intima, with blood from the aortic lumen penetrating into the diseased media leading to dissection and creating a true and false lumen.² Another is that rupture of the vasa vasorum leads to hemorrhage in the aortic wall with subsequent intimal disruption, creating the intimal tear and aortic dissection.

Once a dissection starts, pulsatile flow of blood within the aortic wall causes it to extend. The dissection flap may be localized, but it often spirals the entire length of the aorta. Distention of the false lumen with blood may cause the intimal flap to compress the true lumen and potentially lead to malperfusion syndromes.

CLASSIFIED ACCORDING TO LOCATION

It is important to recognize the location of the dissection, as the prognosis and treatment depend on whether the ascending aorta is involved.^2,3 For classification purposes, the ascending aorta is the portion proximal to the brachiocephalic artery, while the descending aorta is the portion distal to the left subclavian artery.³

The DeBakey classification defines a type I aortic dissection as one that begins in the ascending aorta and extends at least to the aortic arch or beyond. Type II dissections involve the ascending aorta only, while type III dissections begin in the descending aorta, most often just distal to the left subclavian artery.

The Stanford classification scheme divides dissections into type A and type B. Type A dissections involve the ascending aorta, while type B dissections do not involve the ascending aorta.

Which classification scheme is used is not important. However, identifying patients with dissection of the ascending aorta (DeBakey type I or type II or Stanford type A) is critical, as emergency cardiac surgery is recommended for this type of dissection.^2,3 For the purposes of this paper, the Stanford classification scheme will be used.

Dissection that involves the ascending aorta most commonly occurs in people ages 50 to 60, whereas acute dissection of the descending aorta typically occurs in people 10 years older.^1,2

An acute aortic dissection is one that has occurred within 2 weeks of symptom onset. A chronic dissection is one that occurred more than 2 weeks after symptoms began.

DISEASES AND CONDITIONS ASSOCIATED WITH AORTIC DISSECTION

Hypertension and disorders leading to disruption of the normal structure and function of the aortic wall. About 75% of patients with acute aortic dissection have underlying hypertension.^1–3

Cystic medial degeneration is a common pathologic feature in many cases of aortic dissection.

Cocaine use and intense weight-lifting increase the shear stresses on the aorta.^2,3

Inflammatory aortic diseases such as giant cell arteritis.

Pregnancy can be complicated by aortic dissection, usually in the setting of an underlying aortopathy.⁵

Iatrogenic aortic dissection accounts for about 4% of cases, as a result of cardiac surgery, catheterization, stenting, or use of an intra-aortic balloon pump.¹

Aortic aneurysm. Patients with thoracic aortic aneurysm are at higher risk of aortic dissection, and the larger the aortic diameter, the higher the risk.^2,3,6 In the International Registry of Acute Aortic Dissection (IRAD), the average size of the aorta was about 5.3 cm at the time of acute dissection. Importantly, about 40% of acute dissections of the ascending aorta occur in patients with ascending aortic diameters less than 5.0 cm.^7,8

Thus, many factors are associated with acute dissection, and specific reasons leading to an individual’s susceptibility to sudden dissection are poorly understood.

CLINICAL FEATURES OF ACUTE AORTIC DISSECTION

Because the symptoms of acute dissection may mimic other, more common conditions, one of the most important factors in the diagnosis of aortic dissection is a high clinical suspicion.^1–3

What is the pretest risk of disease?

Recently, the American College of Cardiology (ACC) and the American Heart Association (AHA) released joint guidelines on thoracic aortic disease.³ These guidelines provide an approach to patients who have complaints that may represent acute thoracic aortic dissection, the intent being to establish a pretest risk of disease to be used to guide decision-making.³

The focused evaluation includes specific questions about underlying conditions, symptoms, and findings on examination that may greatly increase the likelihood of acute dissection. These include:

• High-risk conditions and historical features associated with aortic dissection, such as Marfan syndrome and other genetic disorders (Table 2), bicuspid aortic valve, family history of thoracic aortic aneurysm or dissection, known thoracic aortic aneurysm, and recent aortic manipulation
• Pain in the chest, back, or abdomen with high-risk features (eg, abrupt onset, severe intensity, or a ripping or tearing quality)
• High-risk findings on examination (eg, pulse deficits, new aortic regurgitation, hypotension, shock, or systolic blood pressure differences).

Using this information, expedited aortic imaging and treatment algorithms have been devised to improve the diagnosis.³

Using the IRAD database of more than 2,500 acute dissections, the diagnostic algorithm proposed in the ACC/AHA guidelines was shown to be highly sensitive (about 95%) for detecting acute aortic dissection.⁴ In addition, using this score may expedite evaluation by classifying certain patients as being at high risk of acute dissection.^3,4

Important to recognize is that almost two-thirds of patients who suffered dissection in this large database did not have one of the “high-risk conditions” associated with dissection.⁴ Additionally, the specificity of the ACC/AHA algorithm is unknown, and further testing is necessary.⁴

Acute onset of severe pain

More than 90% of acute dissections present with acute pain in the chest or the back, or both.^1–3 The pain is usually severe, of sudden onset, and often described as sharp or, occasionally, tearing, ripping, or stabbing. The pain usually differs from that of coronary ischemia, being most severe at its onset as opposed to the less intense, crescendo-like pain of angina or myocardial infarction. The pain may migrate as the dissection progresses along the length of the aorta or to branch vessels. It may abate, leading to a false sense of security in the patient and the physician.³ “Painless” dissection occurs in a minority, usually in those with syncope, neurologic symptoms, or heart failure.^1–3

The patient with acute dissection may be anxious and may feel a sense of doom.

Acute heart failure, related to severe aortic regurgitation, may be a predominant symptom in dissection of the ascending aorta.

Syncope may occur as a result of aortic rupture, hemopericardium with cardiac tamponade, or acute neurologic complications.

Vascular insufficiency may occur in any branch vessel, leading to clinical syndromes that include acute myocardial infarction, stroke, paraplegia, paraparesis, mesenteric ischemia, and limb ischemia.

PHYSICAL FINDINGS CAN VARY WIDELY

Findings on physical examination in acute aortic dissection vary widely depending on underlying conditions and on the specific complications of the dissection.

Although the classic presentation is acute, severe pain in the chest or back in a severely hypertensive patient with aortic regurgitation and pulse deficits, most patients do not have all these characteristics.⁴ Most patients with type B dissection are hypertensive on presentation, but many with type A dissection present with normal blood pressure or hypotension.¹ Pulse deficits (unequal or absent pulses) are reported in 10% to 30% of acute dissections and may be intermittent as the dynamic movement of the dissection flap interferes with branch vessel perfusion.^1–3

• Aortic leaflet prolapse or distortion of the leaflet alignment
• Malcoaptation of the aortic leaflets from dilation of the aortic root and annulus
• Prolapse of the intimal flap across the aortic valve, interfering with valve function
• Preexisting aortic regurgitation from underlying aortic root aneurysm or primary aortic valve disease (such as a bicuspid aortic valve).

Neurologic manifestations are most common in dissection of the ascending aorta and are particularly important to recognize, as they may dominate the clinical presentation and lead to delay in the diagnosis of dissection.^2,3 Neurologic syndromes include:

• Persistent or transient ischemic stroke
• Spinal cord ischemia
• Ischemic neuropathy
• Hypoxic encephalopathy.

These manifestations are related to malperfusion to branches supplying the brain, spinal cord, or peripheral nerves.⁹

Syncope is relatively common in aortic dissection and may be related to acute hypotension caused by cardiac tamponade or aortic rupture, cerebral vessel obstruction, or activation of cerebral baroreceptors.^2,9 It is important to consider aortic dissection in the differential diagnosis in cases of unexplained syncope.³

Aortic dissections may extend into the abdominal aorta, leading to vascular complications involving one or more branch vessels.¹⁰ The renal artery is involved in at least 5% to 10% of cases and may lead to renal ischemia, infarction, renal insufficiency, or refractory hypertension.²Mesenteric ischemia or infarction occurs in about 5% of dissections, may be difficult to diagnose, and is particularly dangerous.^2,8 Aortic dissection may extend into the iliac arteries and may cause acute lower extremity ischemia.

Acute myocardial infarction due to involvement of the dissection flap causing malperfusion of a coronary artery occurs in 1% to 7% of acute type A aortic dissections.^1–3 The right coronary artery (Figure 2) is most commonly involved, leading to acute inferior myocardial infarction. Acute myocardial ischemia and infarction in the setting of dissection may lead to a delay in the diagnosis of dissection and to bleeding complications from antiplatelet and anticoagulant drugs given to treat the acute coronary syndrome.

Cardiac tamponade, occurring in about 10% of acute type A dissections, portends a higher risk of death.^2,3

Additional clinical features of aortic dissection include a left-sided pleural effusion, usually related to an inflammatory response. An acute hemothorax may occur from rupture or leaking of a descending aortic dissection.

FINDINGS ON RADIOGRAPHY AND ELECTROCARDIOGRAPHY

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald's Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

Electrocardiography usually has normal or nonspecific findings, unless acute myocardial infarction complicates the dissection.

D-DIMER LEVELS

Biomarkers for the diagnosis of acute aortic dissection are of great interest.

D-dimer levels rise in acute aortic dissection as they do in pulmonary embolism.¹¹ A D-dimer level greater than 1,600 ng/mL within the first 6 hours has a very high positive likelihood ratio for dissection, so this test may be useful in identifying patients with a high probability for dissection. In the first 24 hours after symptom onset, a D-dimer level of less than 500 ng/mL has a negative predictive value of 95%. Thus, elevations in D-dimer may help decide which imaging to perform in a patient presenting with chest pain or suspicion of dissection.¹¹

However, D-dimer levels may not be elevated in dissection variants, such as aortic intramural hematoma or penetrating aortic ulcer. Additionally, once 24 hours have elapsed since the dissection started, D-dimer levels may no longer be elevated. The current ACC/AHA guidelines on thoracic aortic disease concluded that the D-dimer level cannot be used to rule out aortic dissection in high-risk individuals.³

Additional studies may clarify the appropriate role of the D-dimer assay in diagnosing aortic dissection.

DEFINITIVE IMAGING STUDIES: CT, MRI, TEE

Contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI), and transesophageal echocardiography (TEE) all have very high sensitivity and specificity for the diagnosis of aortic dissection.^2,3 The choice of imaging study often depends on the availability of these studies, with CT and TEE being the most commonly performed initial studies.

MRI is outstanding for detecting and following aortic dissection, but it is usually not the initial study performed because of the time required for image acquisition and because it is generally not available on an emergency basis.

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald's Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

While transthoracic echocardiography (TTE) can detect aortic dissection, its sensitivity is much lower than that of other imaging tests.^2,3 Therefore, negative findings on TTE do not exclude aortic dissection.

MANAGEMENT OF AORTIC DISSECTION

When acute aortic dissection is diagnosed, multidisciplinary evaluation and treatment are necessary. Time is of the essence, as the death rate in acute dissection may be as high as 1% per hour during the first 24 hours.^1–3 All patients with acute aortic dissection, whether type A or type B, should be transferred to a tertiary care center with a staff experienced in managing aortic dissection and its complications.³ Emergency surgery is recommended for type A aortic dissection, whereas type B dissection is generally treated medically unless complications occur.^2,3

The cornerstone of drug therapy is the prompt reduction in blood pressure with a beta-blocker to reduce shear stresses on the aorta. Intravenous agents such as esmolol (Brevibloc) or labetalol (Normodyne) are usually chosen. Sodium nitroprusside may be added to beta-blocker therapy for rapid blood pressure control in appropriate patients. The patient may require multiple antihypertensive medications. If hypertension is refractory, one must consider renal artery hypertension due to the dissection causing renal malperfusion.² Acute pain may also worsen hypertension, and appropriate analgesia should be used.

Definitive therapy in acute dissection

Patients with acute type A dissection require emergency surgery,^2,3 as they are at risk for life-threatening complications including cardiac tamponade from hemopericardium, aortic rupture, stroke, visceral ischemia, and heart failure due to severe aortic regurgitation. When aortic regurgitation complicates acute type A dissection, some patients are adequately treated by resuspension of the aortic valve leaflets, while others require valve-sparing root replacement or prosthetic aortic valve replacement.

Surgical therapy is associated with a survival benefit compared with medical therapy in acute type A dissection.¹ The 14-day mortality rate for acute type A dissection treated surgically is about 25%.¹ Patients with high-risk features such as heart failure, shock, tamponade, and mesenteric ischemia have a worse prognosis compared with those without these features.^2,12,13

Acute type B aortic dissection carries a lower rate of death than type A dissection.^1–3 In the IRAD cohort, the early mortality rate in those with type B dissection treated medically was about 10%.¹ However, when complications such as malperfusion, shock, or requirement for surgery occur in type B dissection, the mortality rate is much higher,^2,14 with rates of 25% to 50% reported.²

Thus, initial medical therapy is the preferred approach to acute type B dissection, and surgery or endovascular therapy is reserved for patients with acute complications.^2,3 Typical indications for surgery or endovascular therapy in type B dissection include visceral or limb ischemia, aortic rupture, refractory pain, and aneurysmal dilation (Table 3).²

Endovascular therapy in aortic dissection

The high mortality rate with open surgery in acute type B dissection has spurred tremendous interest in endovascular treatments for complications involving the descending aorta and branch vessels.²

Fenestration of the aorta and stenting of branch vessels were the earliest techniques used in complicated type B dissection. By fenestrating (ie, opening) the intimal flap, blood can flow from the false lumen into the true lumen, decompressing the distended false lumen.

Endovascular stenting is used for acute aortic rupture, for malperfusion syndromes, and for rapidly enlarging false lumens. Endovascular grafts may cover the area of a primary intimal tear and thus eliminate the flow into the false channel and promote false-lumen thrombosis. Many patients with complicated type B dissection are treated with a hybrid approach, in which one segment of the aorta, such as the aortic arch, is treated surgically, while the descending aorta receives an endovascular graft.²

Patients with a type B dissection treated medically are at risk for late complications, including aneurysmal enlargement and subsequent aortic rupture. The Investigation of Stent Grafts in Aortic Dissection (INSTEAD) trial included 140 patients with uncomplicated type B dissection and compared drug therapy with endovascular stent grafting.¹⁵ After 2 years of follow-up, there was no difference in the rate of death between the two treatment groups. Patients receiving endovascular grafts had a higher rate of false-lumen thrombosis.

More studies are under way to examine the role of endovascular therapy in uncomplicated type B dissection.

AORTIC DISSECTION VARIANTS

Aortic intramural hematoma

Aortic intramural hematoma is a form of acute aortic syndrome in which a hematoma develops in the aortic media and no intimal flap is visualized either by imaging or at surgery.^2,3,16 It is important to recognize this clinical entity in a patient presenting with acute chest or back pain, as sometimes it is mistaken for a “thrombus in a nonaneurysmal aorta.” Intramural hematoma accounts for 5% to 25% of acute aortic syndromes, depending on the study population (it is more common in Asian studies).^2,3,17 It may present with symptoms similar to classic aortic dissection and is classified as type A or type B, depending on whether the ascending aorta is involved.

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald's Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

Patients with an intramural hematoma may progress to having complications such as hemopericardium, classic aortic dissection, aortic rupture, or aneurysmal dilation.^2,3 However, many cases of type B aortic intramural hematoma result in complete resorption of the hematoma over time. In general, like classic aortic dissection, type A intramural hematoma is treated with emergency surgery and type B with initial medical therapy.^2,3

There are reports from Southeast Asia of successful initial medical therapy for type A intramural hematoma, with surgery used for acute complications.¹⁸ In the Western literature, improved outcomes are reported with initial surgical therapy.¹⁷ Given the unpredictable nature of type A intramural hematoma, most experts recommend surgical therapy for appropriate candidates with acute type A intramural hematoma.^2,3,19

Penetrating atherosclerotic ulcer of the aorta

Penetrating atherosclerotic ulcer of the aorta, another acute aortic syndrome, results from acute penetration of an atherosclerotic aortic lesion through the internal elastic lamina into the media.^2,3,20 It is often associated with bleeding into the media, or intramural hematoma. While the ulcer may be found incidentally on imaging studies, especially in patients with severe aortic atherosclerosis, the typical presentation is acute, severe chest or back pain. It occurs most often in the descending aorta and the abdominal aorta.

Penetrating atherosclerotic ulcer may lead to pseudoaneurysm formation, focal aortic dissection, aortic rupture, or late aortic aneurysm.²

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald's Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

LONG-TERM MANAGEMENT AFTER AORTIC DISSECTION

After hospital discharge, patients with aortic dissection require lifelong management. This includes blood pressure control, lifestyle modification, serial imaging of the aorta with CT or MRI, patient education about the condition, and, when appropriate, screening of family members for aortic disease.^5,21

Reported survival rates after hospitalization for type A dissection are 52% to 94% at 1 year and 45% to 88% at 5 years.^2,22 The 10-year actuarial survival rate for those with acute dissection who survive the acute hospitalization is reported as 30% to 60%. Long-term survival rates after acute type B dissection have been reported at 56% to 92% at 1 year and 48% to 82% at 5 years.²³ Survival rates depend on many factors, including the underlying condition, the age of the patient, and comorbidities.

It is important to treat hypertension after aortic dissection, with a goal blood pressure of 120/80 mm Hg or less for most patients. Older studies found higher mortality rates with poorly controlled hypertension. Beta-blockers are the drugs of first choice. Even in the absence of hypertension, long-term beta-blocker therapy should be used to lessen the aortic stress and force of ventricular contraction.

Genetically triggered causes of aortic dissection should be considered. In many circumstances, referral to a medical geneticist or other practitioner knowledgeable in these conditions is important when these disorders are being evaluated (Table 2).

Many of these disorders have an autosomal dominant inheritance, and the patient should be asked about a family history of aortic disease, aortic dissection, or unexplained sudden death. Features of Marfan syndrome, Loeys-Dietz syndrome, and familial thoracic aortic aneurysm syndromes should be sought. Through comprehensive family studies, it is now recognized that up to 20% of patients with thoracic aortic disease (such as aneurysm or dissection) have another first-degree relative with thoracic aortic disease.^2,3,24 Thus, first-degree relatives of patients with aortic aneurysm or dissection should be screened for thoracic aortic aneurysm disease.

Research into molecular genetics is providing a better understanding of the genetics of aortic dissection.³ New mutations associated with aortic dissection are being discovered in signaling pathways as well as elements critical for the integrity of the vascular wall.^2,3 However, at present, most patients with aortic dissection will not have a specific identifiable genetic defect.

Not only does genetic testing enable the accurate diagnosis of the affected individual, but also treatments are often based on this diagnosis.³ Importantly, the identification of a specific gene mutation (ie, in TGFBR1 or 2, FBN1, ACTA2, MYH11, and COL3A1) in an affected individual has the potential to identify other family members at risk.³

Follow-up imaging

It is important to continue to image the aorta after aortic dissection. Patients may develop progressive dilation or aneurysm formation of the dissected aorta, pseudoaneurysm formation after repair, or recurrent dissection. Many patients require additional surgery on the aorta because of late aneurysm formation.

CT or MRI is usually performed at least every 6 months in the first 2 years after dissection and at least annually thereafter. More centers are choosing MRI for long-term follow-up to avoid the repeated radiation exposure with serial CT.

Patient education

Besides receiving medical therapy and undergoing imaging, patients with aortic dissection should be educated about this condition.^5,21 The patient should be aware of symptoms suggesting dissection and should be instructed to seek attention for any concerning symptoms.

Lifestyle modifications are also important. The patient should be educated about safe activity levels and to avoid heavy isometric exercise, such as weight-lifting. Some patients will have to cease their current occupation because of activity restrictions.

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Mr. N, age 29, presents to the emergency department at the urging of his family because of poor self-care, bizarre behavior, and disturbed sleep. He first experienced psychiatric symptoms 10 years ago after his mother died. He became dysphoric and paranoid, displaying bizarre responses and behaviors with poor self-care and a gradual functional decline. He has been taking sertraline, 100 mg/d, for 10 years.

Upon arrival at the hospital’s inpatient unit, Mr. N is unkempt, oddly related, and paranoid. His affect is constricted. Mr. N displays thought blocking and possibly is responding to internal stimuli. Sertraline is continued and haloperidol, 1 mg/d, is initiated. For the next 2 weeks, Mr. N continues to be oddly related, irritable, and paranoid, and experiences disturbed sleep and thought blocking. After an episode of impulsive aggression, the treatment team initiates aripiprazole, which is titrated to 30 mg/d for 1 week. Mr. N’s clinical status worsens; he is menacing toward other patients and his thinking is more disorganized, with loose associations and ideas of reference. He requires 4 injections of IM haloperidol, 5 mg, and several visits to the seclusion room over the next week. Haloperidol is increased to 30 mg/d over the next 10 days, then aripiprazole is discontinued because of a putative drug interaction with haloperidol. Following the medication changes Mr. N demonstrates better behavioral control, but still is grossly psychotic. While awaiting transfer to a state hospital, Mr. N receives a trial of olanzapine, 20 to 40 mg/d, for 2 weeks without significant benefit.

Several clinical trials demonstrate a significant reduction in intensity of psychotic symptoms with aripiprazole, which has a unique mechanism of action.¹ However, since its FDA approval in 2002, several case reports have described treatment-emergent psychotic symptoms associated with aripiprazole initiation. Over the past 40 years, reports of worsening psychosis associated with antipsychotics have been limited to patients with schizophrenia who were taking high dosages or who had high plasma concentrations, when anticholinergic delirium may have explained increased psychotic symptoms.^2-4

How can a drug effectively treat psychotic symptoms and occasionally worsen them? In this article, we discuss the relevant pharmacology and clinical literature on aripiprazole and try to make sense of this apparent paradox.

Unique pharmacologic profile

Antipsychotics have been reported to be either neutral antagonists or inverse agonists at the D2 receptor, based on in vitro data.⁵ Aripiprazole and its main metabolite, dehydroaripiprazole, originally were described as partial agonists at D2 dopamine receptors.^6,7 However, it appears aripiprazole’s pharmacologic action is better explained by the concept of functional selectivity. Aripiprazole may interact preferentially with distinct conformations of the D2 receptor, leading to a spectrum of pharmacologic effects, including acting as a full agonist, partial agonist, or antagonistic.⁵

Researchers have hypothesized that the pathophysiology of schizophrenia may, in part, be caused by dysfunction of mesocorticolimbic dopaminergic neurons characterized by an enhanced sensitivity of postsynaptic D2 receptors and increased sensitivity to dopaminergic drugs.^8,9 In addition, chronic treatment with a D2 receptor antagonist is associated with increases in postsynaptic dopamine receptor density (ie, an increase in receptor reserve).^10,11 Upregulation of D2 receptors may explain several features seen in patients chronically treated with antipsychotics, including tardive dyskinesia¹² and rapid psychotic relapse after discontinuing an antipsychotic (supersensitivity psychosis).¹³ Because chronic antipsychotic treatment leads to high postsynaptic receptor reserve, aripiprazole initiation may produce overactivation of D2 receptors, which might worsen a patient’s condition.¹⁴ In vitro data^15-18 and clinical observations indicate that aripiprazole has intrinsic efficacy at D2 receptors, as do clinical observations, such as:

• its propensity to reduce serum prolactin¹⁹
• a decreased likelihood of producing extrapyramidal side effects despite >80% occupancy of D2 receptors⁶
• case reports documenting aripiprazole-associated mania,²⁰ improvement of risperidone-associated cognitive impairment,²¹ and pathologic gambling.²²

Emergence or worsening of psychotic symptoms or a marginal antipsychotic effect may occur if aripiprazole is indeed a postsynaptic D2 receptor agonist. An individual patient’s outcome likely would depend on his or her sensitivity to psychosis and concurrent or previous exposure to a D2 receptor antagonist. For example, stimulation of postsynaptic D2 receptors may be further augmented if the dosage of the previous antipsychotic was reduced or withdrawn before initiating aripiprazole because additional receptors would be available for interaction with aripiprazole.

Case reports

A literature review revealed 23 reports of treatment-emergent psychosis associated with aripiprazole initiation (Table). The mean age of the patients was 47 (range: 17 to 69) and 57% were men. Most patients (87%) were diagnosed with a schizophrenia-spectrum illness before aripiprazole initiation. Most (57%) had mild, stable, or no psychotic symptoms before aripiprazole initiation. Most were receiving relatively high doses of antipsychotics (average chlorpromazine equivalents [CPZE]: 648 mg/d) before aripiprazole initiation. This medication was either decreased or discontinued in 70% of patients.

Emergence or worsening of psychotic symptoms included agitation, aggressive behavior, and increased psychomotor activity. However, akathisia evaluation was described in only 2 reports: 1 author identified akathisia symptoms, but attributed them to a concomitant antipsychotic (fluphenazine)²³ and the other report specifically excluded the possibility of akathisia.²⁴ Two systematic studies have attempted to establish risk factors for aripiprazole-associated worsening psychosis (Box).^14,25

In our literature review, the mean final dose of aripiprazole was 21.5 mg/d (range: 2 to 60 mg/d). In the cases describing subsequent treatment, all but 1 patient were switched to another antipsychotic, including 2 whose psychotic symptoms stabilized with continuation of aripiprazole and addition of a second antipsychotic. Interestingly, in the case reported by Adan-Manes et al,²⁶ initial treatment with aripiprazole monotherapy was efficacious, but a subsequent trial of adjunctive aripiprazole resulted in worsening psychosis.

Table

Case reports: Treatment-emergent psychosis associated with aripiprazole

Other potential explanations

Aripiprazole’s manufacturer reported the incidence of psychosis-related adverse events in an analysis of 9 randomized schizophrenia trials.²⁷ The rates of psychosis-related adverse events ranged from 0.6% to 18%, but there was no apparent relationship to study design or method of transitioning to aripiprazole. Rates of psychosis-related adverse events were similar between aripiprazole and the control group (placebo in 3 studies, another antipsychotic in 2 studies).

Emergence or worsening of psychotic symptoms temporally associated with aripiprazole initiation does not necessarily imply causation. As in Mr. N’s case, it is not always possible to determine whether worsening psychosis is the natural disease course or a treatment effect. In addition, it is not possible to differentiate lack of efficacy from a true propensity for aripiprazole to worsen psychosis.

It also is conceivable discontinuation or dosage reduction of a previous antipsychotic would worsen psychotic symptoms or cause side effects. When significant changes in psychopathology or side effects develop during the transition from 1 antipsychotic to another, it is difficult to determine etiology. Specifically, rapid transition from a medication with significant anticholinergic and antihistaminic properties—such as quetiapine or olanzapine—to 1 without these properties—such as aripiprazole—may result in symptoms of activation, including restlessness, insomnia, and anxiety. Consequently, these symptoms could be mistaken for worsening psychosis.²⁸ Only 1 patient in this series was reported to abruptly discontinue an antipsychotic with significant anticholinergic properties (clozapine) before initiating aripiprazole.²⁴ Studies by Takeuchi et al¹⁴ and Pae et al²⁵ did not report the relative baseline use of antipsychotic medication with anticholinergic properties.

In a pooled analysis of treatment-emergent adverse events in 5 randomized clinical trials of patients receiving aripiprazole for acute relapse of schizophrenia, the incidence of akathisia was 10%, although it is not clear if this is a dose-related adverse effect.²⁹ Because akathisia may be confused for worsening psychosis,³⁰ it is possible akathisia was mistakenly identified as worsening psychotic symptoms in Mr. N’s case, as well as several reports from our literature review.

Covert akathisia is unlikely to explain worsening psychopathology observed in all patients in our literature review because confusion of akathisia and worsening psychosis is not a widespread phenomenon. In a post hoc analysis of pooled safety data from aripiprazole trials, Kane et al³¹ did not find a correlation between presence of akathisia and aripiprazole efficacy as measured by the Positive and Negative Syndrome Scale (PANSS) total, PANSS positive, PANSS negative, Clinical Global Impressions-Severity, Clinical Global Impressions-Improvement, and percentage of responders. Pae et al²⁵ also noted there was no correlation between scores on the Barnes Akathisia Rating Scale and worsening psychopathology in patients switched to aripiprazole.

An antagonist always is an antagonist and clinicians have appreciated this concept since the days of chlorpromazine. The activity of aripiprazole, however, is on a pharmacologic continuum between a neutral antagonist and full agonist and currently there is no way to precisely determine the level of D2 receptor agonist action in a patient.

Although it is interesting to speculate that aripiprazole’s D2 receptor agonist action may contribute to worsening psychosis,^32-34 there are other plausible explanations to consider. Rapid transition from a drug with significant anticholinergic properties and aripiprazole-associated akathisia may contribute to worsening psychopathology in patients starting aripiprazole. Because covert side effects may be incorrectly identified as psychotic agitation, we cannot exclude this as a possible etiologic factor in Mr. N’s case as well as the cases in our literature review.

Related Resource

• Abilify [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2011.

Drug Brand Names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Benztropine • Cogentin
• Biperiden • Akineton
• Carbamazepine • Tegretol
• Chlorpromazine • Thorazine
• Clonazepam • Klonopin
• Clozapine • Clozaril
• Divalproex • Depakote
• Duloxetine • Cymbalta
• Fluphenazine • Permitil, Prolixin
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Lithium • Eskalith, Lithobid
• Lorazepam • Ativan
• Nortriptyline • Aventyl, Pamelor
• Methylphenidate • Concerta
• Molindone • Moban
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Propranolol • Inderal
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Thioridazine • Mellaril
• Thyroxine • Synthroid
• Valproic acid • Depakene
• Ziprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Mr. N, age 29, presents to the emergency department at the urging of his family because of poor self-care, bizarre behavior, and disturbed sleep. He first experienced psychiatric symptoms 10 years ago after his mother died. He became dysphoric and paranoid, displaying bizarre responses and behaviors with poor self-care and a gradual functional decline. He has been taking sertraline, 100 mg/d, for 10 years.

Upon arrival at the hospital’s inpatient unit, Mr. N is unkempt, oddly related, and paranoid. His affect is constricted. Mr. N displays thought blocking and possibly is responding to internal stimuli. Sertraline is continued and haloperidol, 1 mg/d, is initiated. For the next 2 weeks, Mr. N continues to be oddly related, irritable, and paranoid, and experiences disturbed sleep and thought blocking. After an episode of impulsive aggression, the treatment team initiates aripiprazole, which is titrated to 30 mg/d for 1 week. Mr. N’s clinical status worsens; he is menacing toward other patients and his thinking is more disorganized, with loose associations and ideas of reference. He requires 4 injections of IM haloperidol, 5 mg, and several visits to the seclusion room over the next week. Haloperidol is increased to 30 mg/d over the next 10 days, then aripiprazole is discontinued because of a putative drug interaction with haloperidol. Following the medication changes Mr. N demonstrates better behavioral control, but still is grossly psychotic. While awaiting transfer to a state hospital, Mr. N receives a trial of olanzapine, 20 to 40 mg/d, for 2 weeks without significant benefit.

Several clinical trials demonstrate a significant reduction in intensity of psychotic symptoms with aripiprazole, which has a unique mechanism of action.¹ However, since its FDA approval in 2002, several case reports have described treatment-emergent psychotic symptoms associated with aripiprazole initiation. Over the past 40 years, reports of worsening psychosis associated with antipsychotics have been limited to patients with schizophrenia who were taking high dosages or who had high plasma concentrations, when anticholinergic delirium may have explained increased psychotic symptoms.^2-4

How can a drug effectively treat psychotic symptoms and occasionally worsen them? In this article, we discuss the relevant pharmacology and clinical literature on aripiprazole and try to make sense of this apparent paradox.

Unique pharmacologic profile

Antipsychotics have been reported to be either neutral antagonists or inverse agonists at the D2 receptor, based on in vitro data.⁵ Aripiprazole and its main metabolite, dehydroaripiprazole, originally were described as partial agonists at D2 dopamine receptors.^6,7 However, it appears aripiprazole’s pharmacologic action is better explained by the concept of functional selectivity. Aripiprazole may interact preferentially with distinct conformations of the D2 receptor, leading to a spectrum of pharmacologic effects, including acting as a full agonist, partial agonist, or antagonistic.⁵

Researchers have hypothesized that the pathophysiology of schizophrenia may, in part, be caused by dysfunction of mesocorticolimbic dopaminergic neurons characterized by an enhanced sensitivity of postsynaptic D2 receptors and increased sensitivity to dopaminergic drugs.^8,9 In addition, chronic treatment with a D2 receptor antagonist is associated with increases in postsynaptic dopamine receptor density (ie, an increase in receptor reserve).^10,11 Upregulation of D2 receptors may explain several features seen in patients chronically treated with antipsychotics, including tardive dyskinesia¹² and rapid psychotic relapse after discontinuing an antipsychotic (supersensitivity psychosis).¹³ Because chronic antipsychotic treatment leads to high postsynaptic receptor reserve, aripiprazole initiation may produce overactivation of D2 receptors, which might worsen a patient’s condition.¹⁴ In vitro data^15-18 and clinical observations indicate that aripiprazole has intrinsic efficacy at D2 receptors, as do clinical observations, such as:

• its propensity to reduce serum prolactin¹⁹
• a decreased likelihood of producing extrapyramidal side effects despite >80% occupancy of D2 receptors⁶
• case reports documenting aripiprazole-associated mania,²⁰ improvement of risperidone-associated cognitive impairment,²¹ and pathologic gambling.²²

Emergence or worsening of psychotic symptoms or a marginal antipsychotic effect may occur if aripiprazole is indeed a postsynaptic D2 receptor agonist. An individual patient’s outcome likely would depend on his or her sensitivity to psychosis and concurrent or previous exposure to a D2 receptor antagonist. For example, stimulation of postsynaptic D2 receptors may be further augmented if the dosage of the previous antipsychotic was reduced or withdrawn before initiating aripiprazole because additional receptors would be available for interaction with aripiprazole.

Case reports

A literature review revealed 23 reports of treatment-emergent psychosis associated with aripiprazole initiation (Table). The mean age of the patients was 47 (range: 17 to 69) and 57% were men. Most patients (87%) were diagnosed with a schizophrenia-spectrum illness before aripiprazole initiation. Most (57%) had mild, stable, or no psychotic symptoms before aripiprazole initiation. Most were receiving relatively high doses of antipsychotics (average chlorpromazine equivalents [CPZE]: 648 mg/d) before aripiprazole initiation. This medication was either decreased or discontinued in 70% of patients.

Emergence or worsening of psychotic symptoms included agitation, aggressive behavior, and increased psychomotor activity. However, akathisia evaluation was described in only 2 reports: 1 author identified akathisia symptoms, but attributed them to a concomitant antipsychotic (fluphenazine)²³ and the other report specifically excluded the possibility of akathisia.²⁴ Two systematic studies have attempted to establish risk factors for aripiprazole-associated worsening psychosis (Box).^14,25

In our literature review, the mean final dose of aripiprazole was 21.5 mg/d (range: 2 to 60 mg/d). In the cases describing subsequent treatment, all but 1 patient were switched to another antipsychotic, including 2 whose psychotic symptoms stabilized with continuation of aripiprazole and addition of a second antipsychotic. Interestingly, in the case reported by Adan-Manes et al,²⁶ initial treatment with aripiprazole monotherapy was efficacious, but a subsequent trial of adjunctive aripiprazole resulted in worsening psychosis.

Table

Case reports: Treatment-emergent psychosis associated with aripiprazole

Other potential explanations

Aripiprazole’s manufacturer reported the incidence of psychosis-related adverse events in an analysis of 9 randomized schizophrenia trials.²⁷ The rates of psychosis-related adverse events ranged from 0.6% to 18%, but there was no apparent relationship to study design or method of transitioning to aripiprazole. Rates of psychosis-related adverse events were similar between aripiprazole and the control group (placebo in 3 studies, another antipsychotic in 2 studies).

Emergence or worsening of psychotic symptoms temporally associated with aripiprazole initiation does not necessarily imply causation. As in Mr. N’s case, it is not always possible to determine whether worsening psychosis is the natural disease course or a treatment effect. In addition, it is not possible to differentiate lack of efficacy from a true propensity for aripiprazole to worsen psychosis.

It also is conceivable discontinuation or dosage reduction of a previous antipsychotic would worsen psychotic symptoms or cause side effects. When significant changes in psychopathology or side effects develop during the transition from 1 antipsychotic to another, it is difficult to determine etiology. Specifically, rapid transition from a medication with significant anticholinergic and antihistaminic properties—such as quetiapine or olanzapine—to 1 without these properties—such as aripiprazole—may result in symptoms of activation, including restlessness, insomnia, and anxiety. Consequently, these symptoms could be mistaken for worsening psychosis.²⁸ Only 1 patient in this series was reported to abruptly discontinue an antipsychotic with significant anticholinergic properties (clozapine) before initiating aripiprazole.²⁴ Studies by Takeuchi et al¹⁴ and Pae et al²⁵ did not report the relative baseline use of antipsychotic medication with anticholinergic properties.

In a pooled analysis of treatment-emergent adverse events in 5 randomized clinical trials of patients receiving aripiprazole for acute relapse of schizophrenia, the incidence of akathisia was 10%, although it is not clear if this is a dose-related adverse effect.²⁹ Because akathisia may be confused for worsening psychosis,³⁰ it is possible akathisia was mistakenly identified as worsening psychotic symptoms in Mr. N’s case, as well as several reports from our literature review.

Covert akathisia is unlikely to explain worsening psychopathology observed in all patients in our literature review because confusion of akathisia and worsening psychosis is not a widespread phenomenon. In a post hoc analysis of pooled safety data from aripiprazole trials, Kane et al³¹ did not find a correlation between presence of akathisia and aripiprazole efficacy as measured by the Positive and Negative Syndrome Scale (PANSS) total, PANSS positive, PANSS negative, Clinical Global Impressions-Severity, Clinical Global Impressions-Improvement, and percentage of responders. Pae et al²⁵ also noted there was no correlation between scores on the Barnes Akathisia Rating Scale and worsening psychopathology in patients switched to aripiprazole.

An antagonist always is an antagonist and clinicians have appreciated this concept since the days of chlorpromazine. The activity of aripiprazole, however, is on a pharmacologic continuum between a neutral antagonist and full agonist and currently there is no way to precisely determine the level of D2 receptor agonist action in a patient.

Although it is interesting to speculate that aripiprazole’s D2 receptor agonist action may contribute to worsening psychosis,^32-34 there are other plausible explanations to consider. Rapid transition from a drug with significant anticholinergic properties and aripiprazole-associated akathisia may contribute to worsening psychopathology in patients starting aripiprazole. Because covert side effects may be incorrectly identified as psychotic agitation, we cannot exclude this as a possible etiologic factor in Mr. N’s case as well as the cases in our literature review.

Related Resource

• Abilify [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2011.

Drug Brand Names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Benztropine • Cogentin
• Biperiden • Akineton
• Carbamazepine • Tegretol
• Chlorpromazine • Thorazine
• Clonazepam • Klonopin
• Clozapine • Clozaril
• Divalproex • Depakote
• Duloxetine • Cymbalta
• Fluphenazine • Permitil, Prolixin
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Lithium • Eskalith, Lithobid
• Lorazepam • Ativan
• Nortriptyline • Aventyl, Pamelor
• Methylphenidate • Concerta
• Molindone • Moban
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Propranolol • Inderal
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Thioridazine • Mellaril
• Thyroxine • Synthroid
• Valproic acid • Depakene
• Ziprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Mr. N, age 29, presents to the emergency department at the urging of his family because of poor self-care, bizarre behavior, and disturbed sleep. He first experienced psychiatric symptoms 10 years ago after his mother died. He became dysphoric and paranoid, displaying bizarre responses and behaviors with poor self-care and a gradual functional decline. He has been taking sertraline, 100 mg/d, for 10 years.

Upon arrival at the hospital’s inpatient unit, Mr. N is unkempt, oddly related, and paranoid. His affect is constricted. Mr. N displays thought blocking and possibly is responding to internal stimuli. Sertraline is continued and haloperidol, 1 mg/d, is initiated. For the next 2 weeks, Mr. N continues to be oddly related, irritable, and paranoid, and experiences disturbed sleep and thought blocking. After an episode of impulsive aggression, the treatment team initiates aripiprazole, which is titrated to 30 mg/d for 1 week. Mr. N’s clinical status worsens; he is menacing toward other patients and his thinking is more disorganized, with loose associations and ideas of reference. He requires 4 injections of IM haloperidol, 5 mg, and several visits to the seclusion room over the next week. Haloperidol is increased to 30 mg/d over the next 10 days, then aripiprazole is discontinued because of a putative drug interaction with haloperidol. Following the medication changes Mr. N demonstrates better behavioral control, but still is grossly psychotic. While awaiting transfer to a state hospital, Mr. N receives a trial of olanzapine, 20 to 40 mg/d, for 2 weeks without significant benefit.

Several clinical trials demonstrate a significant reduction in intensity of psychotic symptoms with aripiprazole, which has a unique mechanism of action.¹ However, since its FDA approval in 2002, several case reports have described treatment-emergent psychotic symptoms associated with aripiprazole initiation. Over the past 40 years, reports of worsening psychosis associated with antipsychotics have been limited to patients with schizophrenia who were taking high dosages or who had high plasma concentrations, when anticholinergic delirium may have explained increased psychotic symptoms.^2-4

How can a drug effectively treat psychotic symptoms and occasionally worsen them? In this article, we discuss the relevant pharmacology and clinical literature on aripiprazole and try to make sense of this apparent paradox.

Unique pharmacologic profile

Antipsychotics have been reported to be either neutral antagonists or inverse agonists at the D2 receptor, based on in vitro data.⁵ Aripiprazole and its main metabolite, dehydroaripiprazole, originally were described as partial agonists at D2 dopamine receptors.^6,7 However, it appears aripiprazole’s pharmacologic action is better explained by the concept of functional selectivity. Aripiprazole may interact preferentially with distinct conformations of the D2 receptor, leading to a spectrum of pharmacologic effects, including acting as a full agonist, partial agonist, or antagonistic.⁵

Researchers have hypothesized that the pathophysiology of schizophrenia may, in part, be caused by dysfunction of mesocorticolimbic dopaminergic neurons characterized by an enhanced sensitivity of postsynaptic D2 receptors and increased sensitivity to dopaminergic drugs.^8,9 In addition, chronic treatment with a D2 receptor antagonist is associated with increases in postsynaptic dopamine receptor density (ie, an increase in receptor reserve).^10,11 Upregulation of D2 receptors may explain several features seen in patients chronically treated with antipsychotics, including tardive dyskinesia¹² and rapid psychotic relapse after discontinuing an antipsychotic (supersensitivity psychosis).¹³ Because chronic antipsychotic treatment leads to high postsynaptic receptor reserve, aripiprazole initiation may produce overactivation of D2 receptors, which might worsen a patient’s condition.¹⁴ In vitro data^15-18 and clinical observations indicate that aripiprazole has intrinsic efficacy at D2 receptors, as do clinical observations, such as:

• its propensity to reduce serum prolactin¹⁹
• a decreased likelihood of producing extrapyramidal side effects despite >80% occupancy of D2 receptors⁶
• case reports documenting aripiprazole-associated mania,²⁰ improvement of risperidone-associated cognitive impairment,²¹ and pathologic gambling.²²

Emergence or worsening of psychotic symptoms or a marginal antipsychotic effect may occur if aripiprazole is indeed a postsynaptic D2 receptor agonist. An individual patient’s outcome likely would depend on his or her sensitivity to psychosis and concurrent or previous exposure to a D2 receptor antagonist. For example, stimulation of postsynaptic D2 receptors may be further augmented if the dosage of the previous antipsychotic was reduced or withdrawn before initiating aripiprazole because additional receptors would be available for interaction with aripiprazole.

Case reports

A literature review revealed 23 reports of treatment-emergent psychosis associated with aripiprazole initiation (Table). The mean age of the patients was 47 (range: 17 to 69) and 57% were men. Most patients (87%) were diagnosed with a schizophrenia-spectrum illness before aripiprazole initiation. Most (57%) had mild, stable, or no psychotic symptoms before aripiprazole initiation. Most were receiving relatively high doses of antipsychotics (average chlorpromazine equivalents [CPZE]: 648 mg/d) before aripiprazole initiation. This medication was either decreased or discontinued in 70% of patients.

Emergence or worsening of psychotic symptoms included agitation, aggressive behavior, and increased psychomotor activity. However, akathisia evaluation was described in only 2 reports: 1 author identified akathisia symptoms, but attributed them to a concomitant antipsychotic (fluphenazine)²³ and the other report specifically excluded the possibility of akathisia.²⁴ Two systematic studies have attempted to establish risk factors for aripiprazole-associated worsening psychosis (Box).^14,25

In our literature review, the mean final dose of aripiprazole was 21.5 mg/d (range: 2 to 60 mg/d). In the cases describing subsequent treatment, all but 1 patient were switched to another antipsychotic, including 2 whose psychotic symptoms stabilized with continuation of aripiprazole and addition of a second antipsychotic. Interestingly, in the case reported by Adan-Manes et al,²⁶ initial treatment with aripiprazole monotherapy was efficacious, but a subsequent trial of adjunctive aripiprazole resulted in worsening psychosis.

Table

Case reports: Treatment-emergent psychosis associated with aripiprazole

Other potential explanations

Aripiprazole’s manufacturer reported the incidence of psychosis-related adverse events in an analysis of 9 randomized schizophrenia trials.²⁷ The rates of psychosis-related adverse events ranged from 0.6% to 18%, but there was no apparent relationship to study design or method of transitioning to aripiprazole. Rates of psychosis-related adverse events were similar between aripiprazole and the control group (placebo in 3 studies, another antipsychotic in 2 studies).

Emergence or worsening of psychotic symptoms temporally associated with aripiprazole initiation does not necessarily imply causation. As in Mr. N’s case, it is not always possible to determine whether worsening psychosis is the natural disease course or a treatment effect. In addition, it is not possible to differentiate lack of efficacy from a true propensity for aripiprazole to worsen psychosis.

It also is conceivable discontinuation or dosage reduction of a previous antipsychotic would worsen psychotic symptoms or cause side effects. When significant changes in psychopathology or side effects develop during the transition from 1 antipsychotic to another, it is difficult to determine etiology. Specifically, rapid transition from a medication with significant anticholinergic and antihistaminic properties—such as quetiapine or olanzapine—to 1 without these properties—such as aripiprazole—may result in symptoms of activation, including restlessness, insomnia, and anxiety. Consequently, these symptoms could be mistaken for worsening psychosis.²⁸ Only 1 patient in this series was reported to abruptly discontinue an antipsychotic with significant anticholinergic properties (clozapine) before initiating aripiprazole.²⁴ Studies by Takeuchi et al¹⁴ and Pae et al²⁵ did not report the relative baseline use of antipsychotic medication with anticholinergic properties.

In a pooled analysis of treatment-emergent adverse events in 5 randomized clinical trials of patients receiving aripiprazole for acute relapse of schizophrenia, the incidence of akathisia was 10%, although it is not clear if this is a dose-related adverse effect.²⁹ Because akathisia may be confused for worsening psychosis,³⁰ it is possible akathisia was mistakenly identified as worsening psychotic symptoms in Mr. N’s case, as well as several reports from our literature review.

Covert akathisia is unlikely to explain worsening psychopathology observed in all patients in our literature review because confusion of akathisia and worsening psychosis is not a widespread phenomenon. In a post hoc analysis of pooled safety data from aripiprazole trials, Kane et al³¹ did not find a correlation between presence of akathisia and aripiprazole efficacy as measured by the Positive and Negative Syndrome Scale (PANSS) total, PANSS positive, PANSS negative, Clinical Global Impressions-Severity, Clinical Global Impressions-Improvement, and percentage of responders. Pae et al²⁵ also noted there was no correlation between scores on the Barnes Akathisia Rating Scale and worsening psychopathology in patients switched to aripiprazole.

An antagonist always is an antagonist and clinicians have appreciated this concept since the days of chlorpromazine. The activity of aripiprazole, however, is on a pharmacologic continuum between a neutral antagonist and full agonist and currently there is no way to precisely determine the level of D2 receptor agonist action in a patient.

Although it is interesting to speculate that aripiprazole’s D2 receptor agonist action may contribute to worsening psychosis,^32-34 there are other plausible explanations to consider. Rapid transition from a drug with significant anticholinergic properties and aripiprazole-associated akathisia may contribute to worsening psychopathology in patients starting aripiprazole. Because covert side effects may be incorrectly identified as psychotic agitation, we cannot exclude this as a possible etiologic factor in Mr. N’s case as well as the cases in our literature review.

Related Resource

• Abilify [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2011.

Drug Brand Names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Benztropine • Cogentin
• Biperiden • Akineton
• Carbamazepine • Tegretol
• Chlorpromazine • Thorazine
• Clonazepam • Klonopin
• Clozapine • Clozaril
• Divalproex • Depakote
• Duloxetine • Cymbalta
• Fluphenazine • Permitil, Prolixin
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Lithium • Eskalith, Lithobid
• Lorazepam • Ativan
• Nortriptyline • Aventyl, Pamelor
• Methylphenidate • Concerta
• Molindone • Moban
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Propranolol • Inderal
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Thioridazine • Mellaril
• Thyroxine • Synthroid
• Valproic acid • Depakene
• Ziprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Vague symptoms. Unexpected flares. Inconsistent manifestations. These characteristics can make diagnosis and treatment of chronic pelvic pain frustrating for both patient and physician. Most patients undergo myriad tests and studies to uncover the source of their pain—but a targeted pelvic exam may be all that is necessary to identify a prevalent but commonly overlooked cause of pelvic pain. Levator myalgia, myofascial pelvic pain syndrome, and pelvic floor spasm are all terms that describe a condition that may affect as many as 78% of women who are given a diagnosis of chronic pelvic pain.¹ This syndrome may be represented by an array of symptoms, including pelvic pressure, dyspareunia, rectal discomfort, and irritative urinary symptoms such as spasms, frequency, and urgency. It is characterized by the presence of tight, band-like pelvic muscles that reproduce the patient’s pain when palpated.²

Diagnosis of this syndrome often surprises the patient. Although the concept of a muscle spasm is not foreign, the location is unexpected. Patients and physicians alike may forget that there is a large complex of muscles that completely lines the pelvic girdle. To complicate matters, the patient often associates the onset of her symptoms with an acute event such as a “bad” urinary tract infection or pelvic or vaginal surgery, which may divert attention from the musculature. Although a muscle spasm may be the cause of the patient’s pain, it’s important to realize that an underlying process may have triggered the original spasm. To provide effective treatment of pain, therefore, you must identify the fundamental cause, assuming that it is reversible, rather than focus exclusively on symptoms.

Although there are many therapeutic options for levator myalgia, an appraisal of the extensive literature on these medications is beyond the scope of this article. Rather, we will review alternative treatment modalities and summarize the results of five trials that explored physical therapy, trigger-point or chemodenervation injection, and neuromodulation (TABLE).

Weighing the nonpharmaceutical options for treatment
of myofascial pelvic pain

Pelvic myofascial therapy offers relief—but qualified therapists may be scarce

FitzGerald MP, Anderson RU, Potts J, et al; Urological Pelvic Pain Collaborative Research Network. Randomized multicenter feasibility trial of myofascial physical therapy for the treatment of urological chronic pelvic pain syndromes. J Urology. 2009;182(2):570–580.

Physical therapy of the pelvic floor—otherwise known as pelvic myofascial therapy—requires a therapist who is highly trained and specialized in this technique. It is more invasive than other forms of rehabilitative therapy because of the need to perform transvaginal maneuvers (FIGURE 1).

This pilot study by the Urological Pelvic Pain Collaborative Research Network evaluated the ability of patients to adhere to pelvic myofascial therapy, the response of their pain to therapy, and adverse events associated with manual therapy. It found that patients were willing to undergo the therapy, despite the invasive nature of the maneuvers, because it was significantly effective.

Details of the study

Patients (both men and women) were randomized to myofascial physical therapy or global therapeutic massage. Myofascial therapy consisted of internal or vaginal manipulation of the trigger-point muscle bundles and tissues of the pelvic floor. It also focused on muscles of the hip girdle and abdomen. The comparison group underwent traditional Western full-body massage. In both groups, treatment lasted 1 hour every week, and participants agreed to 10 full treatments.

Patients were eligible for the study if they experienced pelvic pain, urinary frequency, or bladder discomfort in the previous 6 months. In addition, an examiner must have been able to elicit tenderness upon palpation of the pelvic floor during examination. Patients were excluded if they showed signs of urinary tract infection or dysmenorrhea.

A total of 47 patients were randomized—24 to global massage and 23 to myofascial physical therapy. Overall, the myofascial group experienced a significantly higher rate of improvement in the global response at 12 weeks than did patients in the global-massage group (57% vs 21%; P=.03). Patients were willing to engage in myofascial pelvic therapy, and adverse events were minor.

FIGURE 1 Transvaginal myofascial therapy
Physical therapy of the pelvic floor is more invasive than other forms of rehabilitative therapy because of the need to perform transvaginal maneuvers.

Need for specialized training may limit number of therapists

The randomized controlled study design renders these findings fairly reliable. Therapists were unmasked and aware of the treatment arms but were trained to make the different therapy sessions appear as similar as possible.

Although investigators were enthusiastic about their initial findings, additional studies are needed to validate the results. Moreover, these findings may be difficult to generalize because women who volunteer to participate in such a study may differ from the general population.

Nevertheless, patients who suffer from chronic pelvic pain may take heart that there is a nonpharmaceutical alternative to manage their symptoms, although availability is likely limited in many areas. Given the nature of the physical therapy required for this particular location of myofascial pain, specialized training is necessary for therapists. Despite motivated patients and well-informed providers, it may be difficult to find specialized therapists within local vicinities. Referrals to centers where this type of therapy is offered may be necessary.

The ideal agent for trigger-point injections remains a mystery

Langford CF, Udvari Nagy S, Ghoniem G M. Levator ani trigger point injections: An underutilized treatment for chronic pelvic pain. Neurourol Urodyn. 2007;26(1):59–62.

Abbott JA, Jarvis SK, Lyons SD, Thomson A, Vancaille TG. Botulinum toxin type A for chronic pain and pelvic floor spasm in women: a randomized controlled trial. Obstet Gynecol. 2006;108(4):915–923.

Trigger points are discrete, tender areas within a ridge of contracted muscle. These points may cause focal pain or referred pain upon irritation of the muscle.² Trigger-point injection therapy aims to anesthetize or relax these points by infiltrating the muscle with medications.

These two studies evaluated the value of trigger-point injections in the treatment of pelvic myofascial pain; they found that the injections provide relief, although the mechanism of action and the ideal agent remain to be determined.

Langford et al: Details of the study

In this prospective study, 18 women who had pelvic pain of at least 6 months’ duration and confirmed trigger points on examination underwent transvaginal injection of a solution of bupivacaine, lidocaine, and triamcinolone. They were assessed by questionnaire at baseline and 3 months after injection. Assessment included a visual analog scale for pain severity. Investigators defined success as a decrease in pain of 50% or more and global-satisfaction and global-cure visual scores of 60% or higher.

Thirteen of the 18 women (72.2%) improved after their first injection, with six women reporting a complete absence of pain. Overall, women reported significant decreases in pain and increases in the rates of satisfaction and cure, meeting the definition of success at 3 months after the injection.

Among the theories proposed to explain the mechanism of action of trigger-point injections are:

• disruption of reflex arcs within skeletal muscle
• release of endorphins
• mechanical changes in abnormally contracted muscle fibers.

This last theory highlights one of the limitations of this study—lack of a placebo arm. Could it be possible that the injection of any fluid produces the same effect?

This study was not designed to investigate the causal relationship between the injection of a particular solution and pain relief, but it does highlight the need for studies to clarify the mechanism of action, including use of a placebo. It also prompts questions about the duration of effect after a single injection.

Goal of chemodenervation is blocking of muscle activity

Botulinum toxin type A (Botox) blocks the release of acetylcholine from presynaptic neurons. The release of acetylcholine stimulates muscle contractions; therefore, blockage of its release reduces muscle activity. This type of chemodenervation has found widespread use, and botulinum toxin A now has approval from the Food and Drug Administration (FDA) for treatment of chronic migraine, limb spasticity, cervical dystonia, strabismus, hyperhidrosis, and facial cosmesis.³ Although it is not approved for pelvic floor levator spasm, its success in treating other myotonic disorders suggests that its application may be relevant.

Abbott et al: Details of the study

Abbott and colleagues performed a double-blind, randomized, controlled trial to compare injection of botulinum toxin A with injection of saline. They measured changes in the pain scale, quality of life, and vaginal pressure.

Women were eligible for the study if they had subjectively reported pelvic pain of more than 2 years’ duration and objective evidence of trigger points (on examination) and elevated vaginal resting pressure (by vaginal manometry). Neither the clinical research staff nor the patient knew the contents of the injections, but all women received a total of four—two at sites in the puborectalis muscle and two in the pubococcygeus muscle.

After periodic assessment by questionnaire and examination through 6 months after injection, no differences were found in the pain score or resting vaginal pressure between the group of women who received botulinum toxin A and the group who received placebo. However, each group experienced a significant reduction in pain and vaginal pressure, compared with baseline. And both groups reported improved quality of life, compared with baseline. Neither group reported voiding dysfunction.

Neuromodulation shows promise as treatment for pelvic myofascial pain

van Balken MR, Vandoninck V, Messelink, BJ, et al. Percutaneous tibial nerve stimulation as neuromodulative treatment of chronic pelvic pain. Eur Urol. 2003;43(2):158–163.

Zabihi N, Mourtzinos A, Maher MG, Raz S, Rodriguez LV. Short-term results of bilateral S2-S4 sacral neuromodulation for the treatment of refractory interstitial cystitis, painful bladder syndrome, and chronic pelvic pain. Int Urogynecol J Pelvic Floor Dysfunct. 2008;19(4):553–557.

Neuromodulation is the science of using electrical impulses to alter neuronal activities. The exact mechanisms of action are unclear, but the technology has been utilized to control symptoms of overactive bladder and urinary retention caused by poor relaxation of the urethral and pelvic floor muscles. While studying the effects of sacral nerve root neuromodulation on the bladder, investigators noted improvements in other symptoms, such as pelvic pain.

Neuromodulation of the sacral nerve roots may be achieved by direct conduction of electrical impulses from a lead implanted in the sacrum (sacral neuromodulation) or by the retrograde conduction of these impulses through the posterior tibial nerve (percutaneous tibial nerve stimulation, or PTNS) (FIGURE 2). The tibial nerve arises from sacral nerves L5 to S3 and is one of the larger branches of the sciatic nerve.

FIGURE 2 InterStim therapy
Stimulation of the sacral nerve has been used successfully to manage overactive bladder and urinary retention and may prove useful in the treatment of pelvic myofascial pain.

Van Balken et al: Details of the study

In this prospective observational study, 33 patients (both male and female) who had chronic pelvic pain by history and examination were treated with weekly, 30-minute outpatient sessions of PTNS for 12 weeks. Participants were asked to provide baseline pain scores and keep a diary of their pain. Quality-of-life questionnaires were also administered at baseline and at 12 weeks.

Investigators considered both subjective and objective success in their outcomes. If a patient elected to continue therapy, he or she was classified as a subjective success. Objective success required a decrease of at least 50% in the pain score. At the end of 12 weeks, although 33 patients (42%) wanted to continue therapy, only seven (21%) met the definition for objective success. Of those seven, six elected to continue therapy.

This study sheds light on a treatment modality that has not been studied adequately for the indication of pelvic pain but that may be promising in patients who have levator myalgia. Limitations of this study include the lack of a placebo arm, short-term outcome, and lack of localization of pain. Furthermore, although PTNS has FDA approval for treatment of urinary urgency, frequency, and urge incontinence, it is not approved for the treatment of pelvic pain. These preliminary findings demonstrate potential but, as with any new indication, long-term comparative studies are needed.

Zabihi et al: Details of the study

Patients in this retrospective study had a diagnosis of interstitial cystitis or chronic pelvic pain. Pelvic myofascial pain and trigger points were not required for eligibility. Thirty patients (21 women and nine men) had temporary placement of a lead containing four small electrodes along the S2 to S4 sacral nerve roots on both sides of the sacrum. They were then followed for a trial period of 2 to 4 weeks. To qualify for the final stage of the study, in which the leads were connected internally to a generator implanted in the buttocks, patients had to report improvement of at least 50% in their symptoms. If their improvement did not meet that threshold, the leads were removed.

Twenty-three patients (77%) met the criteria for permanent implantation. Of these patients, 42% reported improvement of more than 50% at 6 postoperative months. Quality-of-life scores also improved significantly.

Sacral neuromodulation is not FDA-approved for the treatment of chronic pelvic pain; further studies are needed before it can be recommended for this indication.

We want to hear from you! Tell us what you think.

Vague symptoms. Unexpected flares. Inconsistent manifestations. These characteristics can make diagnosis and treatment of chronic pelvic pain frustrating for both patient and physician. Most patients undergo myriad tests and studies to uncover the source of their pain—but a targeted pelvic exam may be all that is necessary to identify a prevalent but commonly overlooked cause of pelvic pain. Levator myalgia, myofascial pelvic pain syndrome, and pelvic floor spasm are all terms that describe a condition that may affect as many as 78% of women who are given a diagnosis of chronic pelvic pain.¹ This syndrome may be represented by an array of symptoms, including pelvic pressure, dyspareunia, rectal discomfort, and irritative urinary symptoms such as spasms, frequency, and urgency. It is characterized by the presence of tight, band-like pelvic muscles that reproduce the patient’s pain when palpated.²

Diagnosis of this syndrome often surprises the patient. Although the concept of a muscle spasm is not foreign, the location is unexpected. Patients and physicians alike may forget that there is a large complex of muscles that completely lines the pelvic girdle. To complicate matters, the patient often associates the onset of her symptoms with an acute event such as a “bad” urinary tract infection or pelvic or vaginal surgery, which may divert attention from the musculature. Although a muscle spasm may be the cause of the patient’s pain, it’s important to realize that an underlying process may have triggered the original spasm. To provide effective treatment of pain, therefore, you must identify the fundamental cause, assuming that it is reversible, rather than focus exclusively on symptoms.

Although there are many therapeutic options for levator myalgia, an appraisal of the extensive literature on these medications is beyond the scope of this article. Rather, we will review alternative treatment modalities and summarize the results of five trials that explored physical therapy, trigger-point or chemodenervation injection, and neuromodulation (TABLE).

Weighing the nonpharmaceutical options for treatment
of myofascial pelvic pain

Pelvic myofascial therapy offers relief—but qualified therapists may be scarce

FitzGerald MP, Anderson RU, Potts J, et al; Urological Pelvic Pain Collaborative Research Network. Randomized multicenter feasibility trial of myofascial physical therapy for the treatment of urological chronic pelvic pain syndromes. J Urology. 2009;182(2):570–580.

Physical therapy of the pelvic floor—otherwise known as pelvic myofascial therapy—requires a therapist who is highly trained and specialized in this technique. It is more invasive than other forms of rehabilitative therapy because of the need to perform transvaginal maneuvers (FIGURE 1).

This pilot study by the Urological Pelvic Pain Collaborative Research Network evaluated the ability of patients to adhere to pelvic myofascial therapy, the response of their pain to therapy, and adverse events associated with manual therapy. It found that patients were willing to undergo the therapy, despite the invasive nature of the maneuvers, because it was significantly effective.

Details of the study

Patients (both men and women) were randomized to myofascial physical therapy or global therapeutic massage. Myofascial therapy consisted of internal or vaginal manipulation of the trigger-point muscle bundles and tissues of the pelvic floor. It also focused on muscles of the hip girdle and abdomen. The comparison group underwent traditional Western full-body massage. In both groups, treatment lasted 1 hour every week, and participants agreed to 10 full treatments.

Patients were eligible for the study if they experienced pelvic pain, urinary frequency, or bladder discomfort in the previous 6 months. In addition, an examiner must have been able to elicit tenderness upon palpation of the pelvic floor during examination. Patients were excluded if they showed signs of urinary tract infection or dysmenorrhea.

A total of 47 patients were randomized—24 to global massage and 23 to myofascial physical therapy. Overall, the myofascial group experienced a significantly higher rate of improvement in the global response at 12 weeks than did patients in the global-massage group (57% vs 21%; P=.03). Patients were willing to engage in myofascial pelvic therapy, and adverse events were minor.

FIGURE 1 Transvaginal myofascial therapy
Physical therapy of the pelvic floor is more invasive than other forms of rehabilitative therapy because of the need to perform transvaginal maneuvers.

Need for specialized training may limit number of therapists

The randomized controlled study design renders these findings fairly reliable. Therapists were unmasked and aware of the treatment arms but were trained to make the different therapy sessions appear as similar as possible.

Although investigators were enthusiastic about their initial findings, additional studies are needed to validate the results. Moreover, these findings may be difficult to generalize because women who volunteer to participate in such a study may differ from the general population.

Nevertheless, patients who suffer from chronic pelvic pain may take heart that there is a nonpharmaceutical alternative to manage their symptoms, although availability is likely limited in many areas. Given the nature of the physical therapy required for this particular location of myofascial pain, specialized training is necessary for therapists. Despite motivated patients and well-informed providers, it may be difficult to find specialized therapists within local vicinities. Referrals to centers where this type of therapy is offered may be necessary.

The ideal agent for trigger-point injections remains a mystery

Langford CF, Udvari Nagy S, Ghoniem G M. Levator ani trigger point injections: An underutilized treatment for chronic pelvic pain. Neurourol Urodyn. 2007;26(1):59–62.

Abbott JA, Jarvis SK, Lyons SD, Thomson A, Vancaille TG. Botulinum toxin type A for chronic pain and pelvic floor spasm in women: a randomized controlled trial. Obstet Gynecol. 2006;108(4):915–923.

Trigger points are discrete, tender areas within a ridge of contracted muscle. These points may cause focal pain or referred pain upon irritation of the muscle.² Trigger-point injection therapy aims to anesthetize or relax these points by infiltrating the muscle with medications.

These two studies evaluated the value of trigger-point injections in the treatment of pelvic myofascial pain; they found that the injections provide relief, although the mechanism of action and the ideal agent remain to be determined.

Langford et al: Details of the study

In this prospective study, 18 women who had pelvic pain of at least 6 months’ duration and confirmed trigger points on examination underwent transvaginal injection of a solution of bupivacaine, lidocaine, and triamcinolone. They were assessed by questionnaire at baseline and 3 months after injection. Assessment included a visual analog scale for pain severity. Investigators defined success as a decrease in pain of 50% or more and global-satisfaction and global-cure visual scores of 60% or higher.

Thirteen of the 18 women (72.2%) improved after their first injection, with six women reporting a complete absence of pain. Overall, women reported significant decreases in pain and increases in the rates of satisfaction and cure, meeting the definition of success at 3 months after the injection.

Among the theories proposed to explain the mechanism of action of trigger-point injections are:

• disruption of reflex arcs within skeletal muscle
• release of endorphins
• mechanical changes in abnormally contracted muscle fibers.

This last theory highlights one of the limitations of this study—lack of a placebo arm. Could it be possible that the injection of any fluid produces the same effect?

This study was not designed to investigate the causal relationship between the injection of a particular solution and pain relief, but it does highlight the need for studies to clarify the mechanism of action, including use of a placebo. It also prompts questions about the duration of effect after a single injection.

Goal of chemodenervation is blocking of muscle activity

Botulinum toxin type A (Botox) blocks the release of acetylcholine from presynaptic neurons. The release of acetylcholine stimulates muscle contractions; therefore, blockage of its release reduces muscle activity. This type of chemodenervation has found widespread use, and botulinum toxin A now has approval from the Food and Drug Administration (FDA) for treatment of chronic migraine, limb spasticity, cervical dystonia, strabismus, hyperhidrosis, and facial cosmesis.³ Although it is not approved for pelvic floor levator spasm, its success in treating other myotonic disorders suggests that its application may be relevant.

Abbott et al: Details of the study

Abbott and colleagues performed a double-blind, randomized, controlled trial to compare injection of botulinum toxin A with injection of saline. They measured changes in the pain scale, quality of life, and vaginal pressure.

Women were eligible for the study if they had subjectively reported pelvic pain of more than 2 years’ duration and objective evidence of trigger points (on examination) and elevated vaginal resting pressure (by vaginal manometry). Neither the clinical research staff nor the patient knew the contents of the injections, but all women received a total of four—two at sites in the puborectalis muscle and two in the pubococcygeus muscle.

After periodic assessment by questionnaire and examination through 6 months after injection, no differences were found in the pain score or resting vaginal pressure between the group of women who received botulinum toxin A and the group who received placebo. However, each group experienced a significant reduction in pain and vaginal pressure, compared with baseline. And both groups reported improved quality of life, compared with baseline. Neither group reported voiding dysfunction.

Neuromodulation shows promise as treatment for pelvic myofascial pain

van Balken MR, Vandoninck V, Messelink, BJ, et al. Percutaneous tibial nerve stimulation as neuromodulative treatment of chronic pelvic pain. Eur Urol. 2003;43(2):158–163.

Zabihi N, Mourtzinos A, Maher MG, Raz S, Rodriguez LV. Short-term results of bilateral S2-S4 sacral neuromodulation for the treatment of refractory interstitial cystitis, painful bladder syndrome, and chronic pelvic pain. Int Urogynecol J Pelvic Floor Dysfunct. 2008;19(4):553–557.

Neuromodulation is the science of using electrical impulses to alter neuronal activities. The exact mechanisms of action are unclear, but the technology has been utilized to control symptoms of overactive bladder and urinary retention caused by poor relaxation of the urethral and pelvic floor muscles. While studying the effects of sacral nerve root neuromodulation on the bladder, investigators noted improvements in other symptoms, such as pelvic pain.

Neuromodulation of the sacral nerve roots may be achieved by direct conduction of electrical impulses from a lead implanted in the sacrum (sacral neuromodulation) or by the retrograde conduction of these impulses through the posterior tibial nerve (percutaneous tibial nerve stimulation, or PTNS) (FIGURE 2). The tibial nerve arises from sacral nerves L5 to S3 and is one of the larger branches of the sciatic nerve.

FIGURE 2 InterStim therapy
Stimulation of the sacral nerve has been used successfully to manage overactive bladder and urinary retention and may prove useful in the treatment of pelvic myofascial pain.

Van Balken et al: Details of the study

In this prospective observational study, 33 patients (both male and female) who had chronic pelvic pain by history and examination were treated with weekly, 30-minute outpatient sessions of PTNS for 12 weeks. Participants were asked to provide baseline pain scores and keep a diary of their pain. Quality-of-life questionnaires were also administered at baseline and at 12 weeks.

Investigators considered both subjective and objective success in their outcomes. If a patient elected to continue therapy, he or she was classified as a subjective success. Objective success required a decrease of at least 50% in the pain score. At the end of 12 weeks, although 33 patients (42%) wanted to continue therapy, only seven (21%) met the definition for objective success. Of those seven, six elected to continue therapy.

This study sheds light on a treatment modality that has not been studied adequately for the indication of pelvic pain but that may be promising in patients who have levator myalgia. Limitations of this study include the lack of a placebo arm, short-term outcome, and lack of localization of pain. Furthermore, although PTNS has FDA approval for treatment of urinary urgency, frequency, and urge incontinence, it is not approved for the treatment of pelvic pain. These preliminary findings demonstrate potential but, as with any new indication, long-term comparative studies are needed.

Zabihi et al: Details of the study

Patients in this retrospective study had a diagnosis of interstitial cystitis or chronic pelvic pain. Pelvic myofascial pain and trigger points were not required for eligibility. Thirty patients (21 women and nine men) had temporary placement of a lead containing four small electrodes along the S2 to S4 sacral nerve roots on both sides of the sacrum. They were then followed for a trial period of 2 to 4 weeks. To qualify for the final stage of the study, in which the leads were connected internally to a generator implanted in the buttocks, patients had to report improvement of at least 50% in their symptoms. If their improvement did not meet that threshold, the leads were removed.

Twenty-three patients (77%) met the criteria for permanent implantation. Of these patients, 42% reported improvement of more than 50% at 6 postoperative months. Quality-of-life scores also improved significantly.

Sacral neuromodulation is not FDA-approved for the treatment of chronic pelvic pain; further studies are needed before it can be recommended for this indication.

We want to hear from you! Tell us what you think.

Vague symptoms. Unexpected flares. Inconsistent manifestations. These characteristics can make diagnosis and treatment of chronic pelvic pain frustrating for both patient and physician. Most patients undergo myriad tests and studies to uncover the source of their pain—but a targeted pelvic exam may be all that is necessary to identify a prevalent but commonly overlooked cause of pelvic pain. Levator myalgia, myofascial pelvic pain syndrome, and pelvic floor spasm are all terms that describe a condition that may affect as many as 78% of women who are given a diagnosis of chronic pelvic pain.¹ This syndrome may be represented by an array of symptoms, including pelvic pressure, dyspareunia, rectal discomfort, and irritative urinary symptoms such as spasms, frequency, and urgency. It is characterized by the presence of tight, band-like pelvic muscles that reproduce the patient’s pain when palpated.²

Diagnosis of this syndrome often surprises the patient. Although the concept of a muscle spasm is not foreign, the location is unexpected. Patients and physicians alike may forget that there is a large complex of muscles that completely lines the pelvic girdle. To complicate matters, the patient often associates the onset of her symptoms with an acute event such as a “bad” urinary tract infection or pelvic or vaginal surgery, which may divert attention from the musculature. Although a muscle spasm may be the cause of the patient’s pain, it’s important to realize that an underlying process may have triggered the original spasm. To provide effective treatment of pain, therefore, you must identify the fundamental cause, assuming that it is reversible, rather than focus exclusively on symptoms.

Although there are many therapeutic options for levator myalgia, an appraisal of the extensive literature on these medications is beyond the scope of this article. Rather, we will review alternative treatment modalities and summarize the results of five trials that explored physical therapy, trigger-point or chemodenervation injection, and neuromodulation (TABLE).

Weighing the nonpharmaceutical options for treatment
of myofascial pelvic pain

Pelvic myofascial therapy offers relief—but qualified therapists may be scarce

FitzGerald MP, Anderson RU, Potts J, et al; Urological Pelvic Pain Collaborative Research Network. Randomized multicenter feasibility trial of myofascial physical therapy for the treatment of urological chronic pelvic pain syndromes. J Urology. 2009;182(2):570–580.

Physical therapy of the pelvic floor—otherwise known as pelvic myofascial therapy—requires a therapist who is highly trained and specialized in this technique. It is more invasive than other forms of rehabilitative therapy because of the need to perform transvaginal maneuvers (FIGURE 1).

This pilot study by the Urological Pelvic Pain Collaborative Research Network evaluated the ability of patients to adhere to pelvic myofascial therapy, the response of their pain to therapy, and adverse events associated with manual therapy. It found that patients were willing to undergo the therapy, despite the invasive nature of the maneuvers, because it was significantly effective.

Details of the study

Patients (both men and women) were randomized to myofascial physical therapy or global therapeutic massage. Myofascial therapy consisted of internal or vaginal manipulation of the trigger-point muscle bundles and tissues of the pelvic floor. It also focused on muscles of the hip girdle and abdomen. The comparison group underwent traditional Western full-body massage. In both groups, treatment lasted 1 hour every week, and participants agreed to 10 full treatments.

Patients were eligible for the study if they experienced pelvic pain, urinary frequency, or bladder discomfort in the previous 6 months. In addition, an examiner must have been able to elicit tenderness upon palpation of the pelvic floor during examination. Patients were excluded if they showed signs of urinary tract infection or dysmenorrhea.

A total of 47 patients were randomized—24 to global massage and 23 to myofascial physical therapy. Overall, the myofascial group experienced a significantly higher rate of improvement in the global response at 12 weeks than did patients in the global-massage group (57% vs 21%; P=.03). Patients were willing to engage in myofascial pelvic therapy, and adverse events were minor.

FIGURE 1 Transvaginal myofascial therapy
Physical therapy of the pelvic floor is more invasive than other forms of rehabilitative therapy because of the need to perform transvaginal maneuvers.

Need for specialized training may limit number of therapists

The randomized controlled study design renders these findings fairly reliable. Therapists were unmasked and aware of the treatment arms but were trained to make the different therapy sessions appear as similar as possible.

Although investigators were enthusiastic about their initial findings, additional studies are needed to validate the results. Moreover, these findings may be difficult to generalize because women who volunteer to participate in such a study may differ from the general population.

Nevertheless, patients who suffer from chronic pelvic pain may take heart that there is a nonpharmaceutical alternative to manage their symptoms, although availability is likely limited in many areas. Given the nature of the physical therapy required for this particular location of myofascial pain, specialized training is necessary for therapists. Despite motivated patients and well-informed providers, it may be difficult to find specialized therapists within local vicinities. Referrals to centers where this type of therapy is offered may be necessary.

The ideal agent for trigger-point injections remains a mystery

Langford CF, Udvari Nagy S, Ghoniem G M. Levator ani trigger point injections: An underutilized treatment for chronic pelvic pain. Neurourol Urodyn. 2007;26(1):59–62.

Abbott JA, Jarvis SK, Lyons SD, Thomson A, Vancaille TG. Botulinum toxin type A for chronic pain and pelvic floor spasm in women: a randomized controlled trial. Obstet Gynecol. 2006;108(4):915–923.

Trigger points are discrete, tender areas within a ridge of contracted muscle. These points may cause focal pain or referred pain upon irritation of the muscle.² Trigger-point injection therapy aims to anesthetize or relax these points by infiltrating the muscle with medications.

These two studies evaluated the value of trigger-point injections in the treatment of pelvic myofascial pain; they found that the injections provide relief, although the mechanism of action and the ideal agent remain to be determined.

Langford et al: Details of the study

In this prospective study, 18 women who had pelvic pain of at least 6 months’ duration and confirmed trigger points on examination underwent transvaginal injection of a solution of bupivacaine, lidocaine, and triamcinolone. They were assessed by questionnaire at baseline and 3 months after injection. Assessment included a visual analog scale for pain severity. Investigators defined success as a decrease in pain of 50% or more and global-satisfaction and global-cure visual scores of 60% or higher.

Thirteen of the 18 women (72.2%) improved after their first injection, with six women reporting a complete absence of pain. Overall, women reported significant decreases in pain and increases in the rates of satisfaction and cure, meeting the definition of success at 3 months after the injection.

Among the theories proposed to explain the mechanism of action of trigger-point injections are:

• disruption of reflex arcs within skeletal muscle
• release of endorphins
• mechanical changes in abnormally contracted muscle fibers.

This last theory highlights one of the limitations of this study—lack of a placebo arm. Could it be possible that the injection of any fluid produces the same effect?

This study was not designed to investigate the causal relationship between the injection of a particular solution and pain relief, but it does highlight the need for studies to clarify the mechanism of action, including use of a placebo. It also prompts questions about the duration of effect after a single injection.

Goal of chemodenervation is blocking of muscle activity

Botulinum toxin type A (Botox) blocks the release of acetylcholine from presynaptic neurons. The release of acetylcholine stimulates muscle contractions; therefore, blockage of its release reduces muscle activity. This type of chemodenervation has found widespread use, and botulinum toxin A now has approval from the Food and Drug Administration (FDA) for treatment of chronic migraine, limb spasticity, cervical dystonia, strabismus, hyperhidrosis, and facial cosmesis.³ Although it is not approved for pelvic floor levator spasm, its success in treating other myotonic disorders suggests that its application may be relevant.

Abbott et al: Details of the study

Abbott and colleagues performed a double-blind, randomized, controlled trial to compare injection of botulinum toxin A with injection of saline. They measured changes in the pain scale, quality of life, and vaginal pressure.

Women were eligible for the study if they had subjectively reported pelvic pain of more than 2 years’ duration and objective evidence of trigger points (on examination) and elevated vaginal resting pressure (by vaginal manometry). Neither the clinical research staff nor the patient knew the contents of the injections, but all women received a total of four—two at sites in the puborectalis muscle and two in the pubococcygeus muscle.

After periodic assessment by questionnaire and examination through 6 months after injection, no differences were found in the pain score or resting vaginal pressure between the group of women who received botulinum toxin A and the group who received placebo. However, each group experienced a significant reduction in pain and vaginal pressure, compared with baseline. And both groups reported improved quality of life, compared with baseline. Neither group reported voiding dysfunction.

Neuromodulation shows promise as treatment for pelvic myofascial pain

van Balken MR, Vandoninck V, Messelink, BJ, et al. Percutaneous tibial nerve stimulation as neuromodulative treatment of chronic pelvic pain. Eur Urol. 2003;43(2):158–163.

Zabihi N, Mourtzinos A, Maher MG, Raz S, Rodriguez LV. Short-term results of bilateral S2-S4 sacral neuromodulation for the treatment of refractory interstitial cystitis, painful bladder syndrome, and chronic pelvic pain. Int Urogynecol J Pelvic Floor Dysfunct. 2008;19(4):553–557.

Neuromodulation is the science of using electrical impulses to alter neuronal activities. The exact mechanisms of action are unclear, but the technology has been utilized to control symptoms of overactive bladder and urinary retention caused by poor relaxation of the urethral and pelvic floor muscles. While studying the effects of sacral nerve root neuromodulation on the bladder, investigators noted improvements in other symptoms, such as pelvic pain.

Neuromodulation of the sacral nerve roots may be achieved by direct conduction of electrical impulses from a lead implanted in the sacrum (sacral neuromodulation) or by the retrograde conduction of these impulses through the posterior tibial nerve (percutaneous tibial nerve stimulation, or PTNS) (FIGURE 2). The tibial nerve arises from sacral nerves L5 to S3 and is one of the larger branches of the sciatic nerve.

FIGURE 2 InterStim therapy
Stimulation of the sacral nerve has been used successfully to manage overactive bladder and urinary retention and may prove useful in the treatment of pelvic myofascial pain.

Van Balken et al: Details of the study

In this prospective observational study, 33 patients (both male and female) who had chronic pelvic pain by history and examination were treated with weekly, 30-minute outpatient sessions of PTNS for 12 weeks. Participants were asked to provide baseline pain scores and keep a diary of their pain. Quality-of-life questionnaires were also administered at baseline and at 12 weeks.

Investigators considered both subjective and objective success in their outcomes. If a patient elected to continue therapy, he or she was classified as a subjective success. Objective success required a decrease of at least 50% in the pain score. At the end of 12 weeks, although 33 patients (42%) wanted to continue therapy, only seven (21%) met the definition for objective success. Of those seven, six elected to continue therapy.

This study sheds light on a treatment modality that has not been studied adequately for the indication of pelvic pain but that may be promising in patients who have levator myalgia. Limitations of this study include the lack of a placebo arm, short-term outcome, and lack of localization of pain. Furthermore, although PTNS has FDA approval for treatment of urinary urgency, frequency, and urge incontinence, it is not approved for the treatment of pelvic pain. These preliminary findings demonstrate potential but, as with any new indication, long-term comparative studies are needed.

Zabihi et al: Details of the study

Patients in this retrospective study had a diagnosis of interstitial cystitis or chronic pelvic pain. Pelvic myofascial pain and trigger points were not required for eligibility. Thirty patients (21 women and nine men) had temporary placement of a lead containing four small electrodes along the S2 to S4 sacral nerve roots on both sides of the sacrum. They were then followed for a trial period of 2 to 4 weeks. To qualify for the final stage of the study, in which the leads were connected internally to a generator implanted in the buttocks, patients had to report improvement of at least 50% in their symptoms. If their improvement did not meet that threshold, the leads were removed.

Twenty-three patients (77%) met the criteria for permanent implantation. Of these patients, 42% reported improvement of more than 50% at 6 postoperative months. Quality-of-life scores also improved significantly.

Sacral neuromodulation is not FDA-approved for the treatment of chronic pelvic pain; further studies are needed before it can be recommended for this indication.

We want to hear from you! Tell us what you think.

As a scientist and certified colon therapist with a colon hydrotherapy practice, I was concerned by the lack of objectivity in your recent article, “The dangers of colon cleansing” (J Fam Pract. 2011;60:454-457). The authors cited literature describing adverse effects associated with common laxative preparations used prior to colonoscopy exams, such as oral sodium phosphate or polyethylene glycol, but neither one is generally used by patients looking to colon cleanse to “enhance their well-being.” Ironically, the use of colon hydrotherapy is growing in popularity as an alternative to these laxatives for colonoscopy prep,¹ yet the authors made no mention of this.

The article also contained jumps in logic that misrepresent colon cleansing in general, and colon hydrotherapy in particular. For example, the first case study involved a 31-year-old with Crohn’s disease—a specific contraindication for colon therapy. Therapists certified by the Global Professional Association for Colon Therapy (http://GPACT.org) are taught to give extensive health background questionnaires before administering colon hydrotherapy, so it is difficult to determine whether the therapist or the patient was at fault for failure to disclose her health status. Other case reports the authors cited described isolated events that either involved people who already had severe health problems or could not be attributed to colon hydrotherapy with certainty.

While there is no denying the paucity of studies on the potential benefits of colonic irrigation, it is unfortunate that the authors chose to omit the few studies that have been conducted. One study found that daily water irrigations in patients who underwent sigmoidostomies for rectal cancer were not associated with alterations in the colonic mucosa structure.² Others determined that colonic irrigation was an effective alternative for the treatment of persistent fecal incontinence after dynamic graciloplasty³ and low anterior resection for a rectal carcinoma.⁴ In addition, the potential benefits of colonic irrigation have been shown in rats following the induction of pancreatitis by intraduodenal injection of sodium taurocholate.⁵

There are inherent risks to most, if not all, medical treatments, whether given by an allopathic doctor or alternative health practitioner. However, the huge number of colon hydrotherapy sessions performed worldwide has resulted in a vast database of testimonials to the positive effects of this therapy.

Melisa Bunderson-Schelvan, PhD
Missoula, Mont

As a scientist and certified colon therapist with a colon hydrotherapy practice, I was concerned by the lack of objectivity in your recent article, “The dangers of colon cleansing” (J Fam Pract. 2011;60:454-457). The authors cited literature describing adverse effects associated with common laxative preparations used prior to colonoscopy exams, such as oral sodium phosphate or polyethylene glycol, but neither one is generally used by patients looking to colon cleanse to “enhance their well-being.” Ironically, the use of colon hydrotherapy is growing in popularity as an alternative to these laxatives for colonoscopy prep,¹ yet the authors made no mention of this.

The article also contained jumps in logic that misrepresent colon cleansing in general, and colon hydrotherapy in particular. For example, the first case study involved a 31-year-old with Crohn’s disease—a specific contraindication for colon therapy. Therapists certified by the Global Professional Association for Colon Therapy (http://GPACT.org) are taught to give extensive health background questionnaires before administering colon hydrotherapy, so it is difficult to determine whether the therapist or the patient was at fault for failure to disclose her health status. Other case reports the authors cited described isolated events that either involved people who already had severe health problems or could not be attributed to colon hydrotherapy with certainty.

While there is no denying the paucity of studies on the potential benefits of colonic irrigation, it is unfortunate that the authors chose to omit the few studies that have been conducted. One study found that daily water irrigations in patients who underwent sigmoidostomies for rectal cancer were not associated with alterations in the colonic mucosa structure.² Others determined that colonic irrigation was an effective alternative for the treatment of persistent fecal incontinence after dynamic graciloplasty³ and low anterior resection for a rectal carcinoma.⁴ In addition, the potential benefits of colonic irrigation have been shown in rats following the induction of pancreatitis by intraduodenal injection of sodium taurocholate.⁵

There are inherent risks to most, if not all, medical treatments, whether given by an allopathic doctor or alternative health practitioner. However, the huge number of colon hydrotherapy sessions performed worldwide has resulted in a vast database of testimonials to the positive effects of this therapy.

Melisa Bunderson-Schelvan, PhD
Missoula, Mont

As a scientist and certified colon therapist with a colon hydrotherapy practice, I was concerned by the lack of objectivity in your recent article, “The dangers of colon cleansing” (J Fam Pract. 2011;60:454-457). The authors cited literature describing adverse effects associated with common laxative preparations used prior to colonoscopy exams, such as oral sodium phosphate or polyethylene glycol, but neither one is generally used by patients looking to colon cleanse to “enhance their well-being.” Ironically, the use of colon hydrotherapy is growing in popularity as an alternative to these laxatives for colonoscopy prep,¹ yet the authors made no mention of this.

The article also contained jumps in logic that misrepresent colon cleansing in general, and colon hydrotherapy in particular. For example, the first case study involved a 31-year-old with Crohn’s disease—a specific contraindication for colon therapy. Therapists certified by the Global Professional Association for Colon Therapy (http://GPACT.org) are taught to give extensive health background questionnaires before administering colon hydrotherapy, so it is difficult to determine whether the therapist or the patient was at fault for failure to disclose her health status. Other case reports the authors cited described isolated events that either involved people who already had severe health problems or could not be attributed to colon hydrotherapy with certainty.

While there is no denying the paucity of studies on the potential benefits of colonic irrigation, it is unfortunate that the authors chose to omit the few studies that have been conducted. One study found that daily water irrigations in patients who underwent sigmoidostomies for rectal cancer were not associated with alterations in the colonic mucosa structure.² Others determined that colonic irrigation was an effective alternative for the treatment of persistent fecal incontinence after dynamic graciloplasty³ and low anterior resection for a rectal carcinoma.⁴ In addition, the potential benefits of colonic irrigation have been shown in rats following the induction of pancreatitis by intraduodenal injection of sodium taurocholate.⁵

There are inherent risks to most, if not all, medical treatments, whether given by an allopathic doctor or alternative health practitioner. However, the huge number of colon hydrotherapy sessions performed worldwide has resulted in a vast database of testimonials to the positive effects of this therapy.

Melisa Bunderson-Schelvan, PhD
Missoula, Mont