Emergency Medicine

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.

A 46-year-old man presented to a hospital emergency department (ED) with a four-day history of right ear pain. He described the pain as a constant, dull, burning pain radiating to the neck and face, associated with a feeling of congestion. The patient also stated that the right side of his face had felt numb for about one day.

Three days earlier, the man had been seen by his primary health care provider, who told him that his ear looked normal and free of infection. The day before his current presentation to the ED, however, he noticed what he described as an “acne-like” rash on his ear lobe. Shortly before coming to the ED, the patient also developed numbness over his right upper lip, which he likened to the effects of procaine during a dental visit. He reported drooling from the right side of his mouth while drinking water and difficulty blinking his right eye. 

He denied any tinnitus, fever, headache, or change in hearing. A review of symptoms was positive only for mild dizziness during the previous two to three days.

The patient was a well-appearing white man. He was alert and oriented to identity, time, and place. His skin was warm, dry, and intact. The examiner noticed a small area of erythematous rash with vesicles on the man’s right ear lobe. The external auditory canals appeared within normal limits, with no erythema or edema, and were nontender bilaterally. The tympanic membranes were normal bilaterally, without bulging or discernible fluid levels.

The ocular exam was normal with no visual acuity changes and no fluorescein uptake; external ocular movements were intact. A slight droop was noted in the right eyelid, but there was no droop on the contralateral side of his face. When asked to puff up his cheeks, the patient found it difficult to do so on the right side of his mouth without releasing air from his lips.

The remainder of the cranial nerves were intact. Muscle strength was 5/5 in all extremities and equal bilaterally. The man’s gait was within normal limits, and the remaining findings in the physical exam were normal.

The initial diagnosis considered in the differential was otitis externa, because it is a common explanation for ear pain in patients who present to the ED.^1,2 Also, in otitis, pain is characteristically present in the affected ear, and erythema is often found in the external auditory canal.³ However, this diagnosis was deemed unlikely because otitis externa would not explain the neurologic findings or the vesicular rash.¹

Bell’s palsy was next in the differential, as it was considered consistent with the patient’s unilateral neurologic deficits.⁴ In addition to weakness or palsy of the facial nerve, many patients with Bell’s palsy complain of mastoid pain, which can be confused with a complaint of ear pain.⁵ However, patients with Bell’s palsy have no rash, and this diagnosis was considered unlikely.

The painful, burning rash on the patient’s face was characteristic of herpes zoster (shingles), which was next in the differential. Infrequently, shingles can also cause weakness in the nerve it affects. In the case patient, weakness that was evident in the affected nerve resembled that seen in Bell’s palsy. This combination of symptoms is referred to as Ramsay Hunt syndrome—which in this case was decided to be the correct diagnosis.

DISCUSSION
Ramsay Hunt syndrome (RHS, also known as geniculate herpes^5,6) is caused by the varicella-zoster virus, most commonly known as the cause of chickenpox. In the United States, RHS is believed to affect only about one in 1,500 persons, although 20% to 30% of persons experience herpes zoster infection at some time.⁷

Soon after a chickenpox infection subsides, the virus spreads along the sensory nerve fibers of the peripheral and cranial nerves. The virus then becomes dormant in the dorsal root ganglion, where in some patients it later reactivates in the form of shingles.⁸

In RHS, the ganglia of cranial nerve VII (CN VII, the facial nerve, which innervates the facial muscles) are infected; for this reason, the condition is also referred to as zoster oticus.⁹ Because of the involvement and weakening of the facial nerve, the presentation of RHS often resembles that of Bell’s palsy or facial nerve palsy.

While most cases of Bell’s palsy are idiopathic,^10,11 RHS can usually be attributed to viral infection—most commonly, infection with herpes simplex virus type 1 (HSV-1).¹² RHS can be differentiated from Bell’s palsy by the presence of a rash on the ipsilateral side. The rash appears in the form of inflamed vesicles on an erythematous base and may be present around the ear (see figure), the eardrum, the hard and soft palate, or the tongue.⁶ When the rash is painful, it is often described as a burning pain. Loss of taste may occur in the anterior portion of the tongue.^9,12

Unlike shingles, which usually manifests as a sensory neuropathy, RHS is distinguished by motor neuropathy.⁷ The patient usually reports weakness in the facial muscles on one side, leading to difficulty drinking water or puffing out the cheek and to drooling on one side of the face. A complaint of dryness in the ipsilateral eye may result from weakness or an inability to close the eyelid.

It is important to note that as in Bell’s palsy, RHS can be differentiated from stroke by the patient’s inability to wrinkle the forehead. The motor muscles of the forehead are innervated by both sides of the brain; in the case of stroke, only one side of the brain is affected, and movement of the forehead remains possible on the contralateral side. In facial nerve palsy, the nerve itself is affected; thus, no movement of the forehead is possible.¹³ Other common complaints in patients with facial nerve palsy include vertigo, hearing loss, and changes in facial sensation.

RHS was first described in 1907 as herpes zoster associated with Bell’s palsy by the neurologist J. Ramsay Hunt, for whom the condition is named.^9,14 RHS is more common in men than women. It occurs most commonly in adults and is rare in children younger than 6.^13,15

Diagnosis
In most cases, a diagnosis of RHS is made on a clinical basis.¹ However, a polymerase chain reaction (PCR) assay can be performed on samples of tear fluid or submandibular saliva to detect the zoster virus.^16,17 PCR can also be performed using exudates from the geniculate zone of the ear (a small area in the center of the auricle^6,14), which is more sensitive than tears or blood.^18,19 Findings from a complete blood count and the erythrocyte sedimentation rate can be used to differentiate between infectious and inflammatory causes.¹³

Head CT or MRI can be obtained to rule out any structural lesions. In one study, Kim et al²⁰ examined MRI changes in patients with either Bell’s palsy or RHS. In both conditions, researchers were able to identify swelling of the labyrinthine segment of the facial nerve on temporal MRI scans.²⁰ Although CT has not been shown to have any prognostic or diagnostic application, it can occasionally be used if decompression of the facial nerve is warranted.¹¹

Treatment
Data used to support the use of corticosteroids for treatment of Bell’s palsy^10,21,22 have been extrapolated to justify their use for treatment of RHS,²³ and prednisolone is the most common choice.¹⁰ Steroids reduce the associated inflammation, resulting in decreased pain and neurologic symptoms. A daily dose for one to two weeks, followed by a slow taper, is the preferred prescribing method.¹⁰

The addition of acyclovir has been recommended to inhibit viral DNA replication^9,23 (valacyclovir and famciclovir have also been mentioned^12,18). If started within three days of symptom onset, acyclovir can help reduce pain and hasten resolution of symptoms.

In a large retrospective study, it was demonstrated that patients treated with prednisone at 1.0 mg/kg/d for five days, followed by a 10-day taper, combined with acyclovir, showed long-term improvement that was statistically significant.²³ Complete facial recovery was reported in only 52% of patients, however. Risk factors for a poor prognosis include hypertension, diabetes mellitus, and advancing age.⁷

Artificial tears are also prescribed to keep the affected eye from becoming irritated and dry. The patient can be instructed to tape the eye closed at night.¹⁰

Early diagnosis and treatment (ie, within three days of symptom onset, and preferably with a combination of acyclovir and steroids²³) is an important factor in a good prognosis.^7,23 Because RHS-affected patients have only about a 50% chance of full recovery,²³ proper follow-up care is extremely important. Follow-up visits are recommended at two weeks, six weeks, and three months.¹³ For optimal outcomes in patients with this neurologic diagnosis, referral to a neurologist is recommended for ongoing management. This practitioner is likely to detect subtle changes in patient presentation and can perform follow-up testing as needed.

THE CASE PATIENT
One week after the patient’s visit to the ED, he was contacted by hospital staff for a standard satisfaction and quality control survey. The patient (who had been treated with steroids and acyclovir, ibuprofen, and artificial tears) reported almost complete resolution of his pain; any mild pain, he said, was easily tolerated or could be resolved with OTC medication. He reported only minimal persistent facial weakness, stating that he was able to eat, drink, and speak normally.

The patient had not been seen by any health care provider for follow-up, but he agreed to make an appointment as soon as possible.     

REFERENCES
1. Kim D, Bhimani M. Ramsay Hunt syndrome presenting as simple otitis externa. CJEM. 2008;10(3):247-250.

2. Agius AM, Pickles JM, Burch KL. A prospective study of otitis externa. Clin Otolaryngol. 1992;17(2):150-154.

3. Rosenfeld RM, Brown L, Cannon CR, et al; American Academy of Otolaryngology—Head and Neck Surgery Foundation. Clinical practice guideline: acute otitis externa. Otolaryngol Head Neck Surg. 2006;134(4 suppl):S4-S23.

4. Holland J, Bernstein J. Bell’s palsy. Clin Evid (Online). 2011 Mar 7;2011.pii:1204.

5. Jacewicz M. Bell’s palsy (2007). www.merckmanuals.com/professional/sec16/ch219/ch219i.html. Accessed May 26, 2011.

6. Harrison K. Discussion: the Ramsay Hunt Syndrome. Proc Royal Soc Med. 1953;47(371):11-24.

7. Bhupal HK. Ramsay Hunt syndrome presenting in primary care. Practitioner. 2010;254(1727):33-35.

8. Aizawa H, Ohtani F, Furuta Y, et al. Variable patterns of varicella-zoster virus reactivation in Ramsay Hunt syndrome. J Med Virol. 2004;74(2):355-360.

9. Gondivkar S, Parikh V, Parikh R. Herpes zoster oticus: a rare clinical entity. Contemp Clin Dent. 2010;1(2):127-129.

10. Sullivan FM, Swan IRC, Donnan PT, et al. Early treatment with prednisolone or acyclovir in Bell’s palsy. N Engl J Med. 2007;357(16):1598-1607.

11. Gilden DH. Bell’s palsy. N Engl J Med. 2004;351(13):1323-1331.

12. Diaz GA, Rakita RM, Koelle DM. A case of Ramsay Hunt–like syndrome caused by herpes simplex virus type 2. Clin Infect Dis. 2005;40(10):1545-1547.

13. Miravalle AA. Ramsay Hunt syndrome. http://emedicine.medscape.com/article/1166804-over iew. Accessed July 22, 2011.

14. Hunt JR. On herpetic inflammation of the geniculate ganglion: a new syndrome and its complications. J Nerv Ment Dis. 1907;34:73-96.

15. Sandoval CC, Núñez FA, Lizama CM, et al. Ramsay Hunt syndrome in children: four cases and review [in Spanish]. Rev Chilena Infectol. 2008; 25(6):458-464.

16. Murakami S, Nakashiro Y, Mizobuchi M, et al. Varicella-zoster virus distribution in Ramsay Hunt syndrome revealed by polymerase chain reaction. Acta Otolaryngol. 1998;118(2):145-149.

17. Hiroshige K, Ikeda M, Hondo R. Detection of varicella zoster virus DNA in tear fluid and saliva of patients with Ramsay Hunt syndrome. Otol Neurol. 2002;23(4):602-607.

18. Sweeney CJ, Gilden DH. Ramsay Hunt syndrome. J Neurol Neurosurg Psychiatr. 2001;71(2):148-154.

19. Murakami S, Honda N, Mizobuchi M, et al. Rapid diagnosis of varicella zoster virus infection in acute facial palsy. Neurology. 1998;51(4):1202-1205.

20. Kim IS, Shin SH, Kim J, et al. Correlation between MRI and operative findings in Bell’s palsy and Ramsay Hunt syndrome. Yonsei Med J. 2007;48(6):963-968.

21. Engström M, Berg T, Stjernquist-Desatnik A, et al. Prednisolone and valaciclovir in Bell’s palsy: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet Neurol. 2008;7(11):993-1000.

22. Hato N, Yamada H, Kohno H, et al. Valacyclovir and prednisolone treatment for Bell’s palsy: a multicenter, randomized, placebo-controlled study. Otol Neurotol. 2007;28(3):408-413.

23. Murakami S, Hato N, Horiuchi J, et al. Treatment of Ramsay Hunt syndrome with acyclovir-prednisone: significance of early diagnosis and treatment. Ann Neurol. 1997;41(3):353-357.

A 46-year-old man presented to a hospital emergency department (ED) with a four-day history of right ear pain. He described the pain as a constant, dull, burning pain radiating to the neck and face, associated with a feeling of congestion. The patient also stated that the right side of his face had felt numb for about one day.

Three days earlier, the man had been seen by his primary health care provider, who told him that his ear looked normal and free of infection. The day before his current presentation to the ED, however, he noticed what he described as an “acne-like” rash on his ear lobe. Shortly before coming to the ED, the patient also developed numbness over his right upper lip, which he likened to the effects of procaine during a dental visit. He reported drooling from the right side of his mouth while drinking water and difficulty blinking his right eye. 

He denied any tinnitus, fever, headache, or change in hearing. A review of symptoms was positive only for mild dizziness during the previous two to three days.

The patient was a well-appearing white man. He was alert and oriented to identity, time, and place. His skin was warm, dry, and intact. The examiner noticed a small area of erythematous rash with vesicles on the man’s right ear lobe. The external auditory canals appeared within normal limits, with no erythema or edema, and were nontender bilaterally. The tympanic membranes were normal bilaterally, without bulging or discernible fluid levels.

The ocular exam was normal with no visual acuity changes and no fluorescein uptake; external ocular movements were intact. A slight droop was noted in the right eyelid, but there was no droop on the contralateral side of his face. When asked to puff up his cheeks, the patient found it difficult to do so on the right side of his mouth without releasing air from his lips.

The remainder of the cranial nerves were intact. Muscle strength was 5/5 in all extremities and equal bilaterally. The man’s gait was within normal limits, and the remaining findings in the physical exam were normal.

The initial diagnosis considered in the differential was otitis externa, because it is a common explanation for ear pain in patients who present to the ED.^1,2 Also, in otitis, pain is characteristically present in the affected ear, and erythema is often found in the external auditory canal.³ However, this diagnosis was deemed unlikely because otitis externa would not explain the neurologic findings or the vesicular rash.¹

Bell’s palsy was next in the differential, as it was considered consistent with the patient’s unilateral neurologic deficits.⁴ In addition to weakness or palsy of the facial nerve, many patients with Bell’s palsy complain of mastoid pain, which can be confused with a complaint of ear pain.⁵ However, patients with Bell’s palsy have no rash, and this diagnosis was considered unlikely.

The painful, burning rash on the patient’s face was characteristic of herpes zoster (shingles), which was next in the differential. Infrequently, shingles can also cause weakness in the nerve it affects. In the case patient, weakness that was evident in the affected nerve resembled that seen in Bell’s palsy. This combination of symptoms is referred to as Ramsay Hunt syndrome—which in this case was decided to be the correct diagnosis.

DISCUSSION
Ramsay Hunt syndrome (RHS, also known as geniculate herpes^5,6) is caused by the varicella-zoster virus, most commonly known as the cause of chickenpox. In the United States, RHS is believed to affect only about one in 1,500 persons, although 20% to 30% of persons experience herpes zoster infection at some time.⁷

Soon after a chickenpox infection subsides, the virus spreads along the sensory nerve fibers of the peripheral and cranial nerves. The virus then becomes dormant in the dorsal root ganglion, where in some patients it later reactivates in the form of shingles.⁸

In RHS, the ganglia of cranial nerve VII (CN VII, the facial nerve, which innervates the facial muscles) are infected; for this reason, the condition is also referred to as zoster oticus.⁹ Because of the involvement and weakening of the facial nerve, the presentation of RHS often resembles that of Bell’s palsy or facial nerve palsy.

While most cases of Bell’s palsy are idiopathic,^10,11 RHS can usually be attributed to viral infection—most commonly, infection with herpes simplex virus type 1 (HSV-1).¹² RHS can be differentiated from Bell’s palsy by the presence of a rash on the ipsilateral side. The rash appears in the form of inflamed vesicles on an erythematous base and may be present around the ear (see figure), the eardrum, the hard and soft palate, or the tongue.⁶ When the rash is painful, it is often described as a burning pain. Loss of taste may occur in the anterior portion of the tongue.^9,12

Unlike shingles, which usually manifests as a sensory neuropathy, RHS is distinguished by motor neuropathy.⁷ The patient usually reports weakness in the facial muscles on one side, leading to difficulty drinking water or puffing out the cheek and to drooling on one side of the face. A complaint of dryness in the ipsilateral eye may result from weakness or an inability to close the eyelid.

It is important to note that as in Bell’s palsy, RHS can be differentiated from stroke by the patient’s inability to wrinkle the forehead. The motor muscles of the forehead are innervated by both sides of the brain; in the case of stroke, only one side of the brain is affected, and movement of the forehead remains possible on the contralateral side. In facial nerve palsy, the nerve itself is affected; thus, no movement of the forehead is possible.¹³ Other common complaints in patients with facial nerve palsy include vertigo, hearing loss, and changes in facial sensation.

RHS was first described in 1907 as herpes zoster associated with Bell’s palsy by the neurologist J. Ramsay Hunt, for whom the condition is named.^9,14 RHS is more common in men than women. It occurs most commonly in adults and is rare in children younger than 6.^13,15

Diagnosis
In most cases, a diagnosis of RHS is made on a clinical basis.¹ However, a polymerase chain reaction (PCR) assay can be performed on samples of tear fluid or submandibular saliva to detect the zoster virus.^16,17 PCR can also be performed using exudates from the geniculate zone of the ear (a small area in the center of the auricle^6,14), which is more sensitive than tears or blood.^18,19 Findings from a complete blood count and the erythrocyte sedimentation rate can be used to differentiate between infectious and inflammatory causes.¹³

Head CT or MRI can be obtained to rule out any structural lesions. In one study, Kim et al²⁰ examined MRI changes in patients with either Bell’s palsy or RHS. In both conditions, researchers were able to identify swelling of the labyrinthine segment of the facial nerve on temporal MRI scans.²⁰ Although CT has not been shown to have any prognostic or diagnostic application, it can occasionally be used if decompression of the facial nerve is warranted.¹¹

Treatment
Data used to support the use of corticosteroids for treatment of Bell’s palsy^10,21,22 have been extrapolated to justify their use for treatment of RHS,²³ and prednisolone is the most common choice.¹⁰ Steroids reduce the associated inflammation, resulting in decreased pain and neurologic symptoms. A daily dose for one to two weeks, followed by a slow taper, is the preferred prescribing method.¹⁰

The addition of acyclovir has been recommended to inhibit viral DNA replication^9,23 (valacyclovir and famciclovir have also been mentioned^12,18). If started within three days of symptom onset, acyclovir can help reduce pain and hasten resolution of symptoms.

In a large retrospective study, it was demonstrated that patients treated with prednisone at 1.0 mg/kg/d for five days, followed by a 10-day taper, combined with acyclovir, showed long-term improvement that was statistically significant.²³ Complete facial recovery was reported in only 52% of patients, however. Risk factors for a poor prognosis include hypertension, diabetes mellitus, and advancing age.⁷

Artificial tears are also prescribed to keep the affected eye from becoming irritated and dry. The patient can be instructed to tape the eye closed at night.¹⁰

Early diagnosis and treatment (ie, within three days of symptom onset, and preferably with a combination of acyclovir and steroids²³) is an important factor in a good prognosis.^7,23 Because RHS-affected patients have only about a 50% chance of full recovery,²³ proper follow-up care is extremely important. Follow-up visits are recommended at two weeks, six weeks, and three months.¹³ For optimal outcomes in patients with this neurologic diagnosis, referral to a neurologist is recommended for ongoing management. This practitioner is likely to detect subtle changes in patient presentation and can perform follow-up testing as needed.

THE CASE PATIENT
One week after the patient’s visit to the ED, he was contacted by hospital staff for a standard satisfaction and quality control survey. The patient (who had been treated with steroids and acyclovir, ibuprofen, and artificial tears) reported almost complete resolution of his pain; any mild pain, he said, was easily tolerated or could be resolved with OTC medication. He reported only minimal persistent facial weakness, stating that he was able to eat, drink, and speak normally.

The patient had not been seen by any health care provider for follow-up, but he agreed to make an appointment as soon as possible.     

REFERENCES
1. Kim D, Bhimani M. Ramsay Hunt syndrome presenting as simple otitis externa. CJEM. 2008;10(3):247-250.

2. Agius AM, Pickles JM, Burch KL. A prospective study of otitis externa. Clin Otolaryngol. 1992;17(2):150-154.

3. Rosenfeld RM, Brown L, Cannon CR, et al; American Academy of Otolaryngology—Head and Neck Surgery Foundation. Clinical practice guideline: acute otitis externa. Otolaryngol Head Neck Surg. 2006;134(4 suppl):S4-S23.

4. Holland J, Bernstein J. Bell’s palsy. Clin Evid (Online). 2011 Mar 7;2011.pii:1204.

5. Jacewicz M. Bell’s palsy (2007). www.merckmanuals.com/professional/sec16/ch219/ch219i.html. Accessed May 26, 2011.

6. Harrison K. Discussion: the Ramsay Hunt Syndrome. Proc Royal Soc Med. 1953;47(371):11-24.

7. Bhupal HK. Ramsay Hunt syndrome presenting in primary care. Practitioner. 2010;254(1727):33-35.

8. Aizawa H, Ohtani F, Furuta Y, et al. Variable patterns of varicella-zoster virus reactivation in Ramsay Hunt syndrome. J Med Virol. 2004;74(2):355-360.

9. Gondivkar S, Parikh V, Parikh R. Herpes zoster oticus: a rare clinical entity. Contemp Clin Dent. 2010;1(2):127-129.

10. Sullivan FM, Swan IRC, Donnan PT, et al. Early treatment with prednisolone or acyclovir in Bell’s palsy. N Engl J Med. 2007;357(16):1598-1607.

11. Gilden DH. Bell’s palsy. N Engl J Med. 2004;351(13):1323-1331.

12. Diaz GA, Rakita RM, Koelle DM. A case of Ramsay Hunt–like syndrome caused by herpes simplex virus type 2. Clin Infect Dis. 2005;40(10):1545-1547.

13. Miravalle AA. Ramsay Hunt syndrome. http://emedicine.medscape.com/article/1166804-over iew. Accessed July 22, 2011.

14. Hunt JR. On herpetic inflammation of the geniculate ganglion: a new syndrome and its complications. J Nerv Ment Dis. 1907;34:73-96.

15. Sandoval CC, Núñez FA, Lizama CM, et al. Ramsay Hunt syndrome in children: four cases and review [in Spanish]. Rev Chilena Infectol. 2008; 25(6):458-464.

16. Murakami S, Nakashiro Y, Mizobuchi M, et al. Varicella-zoster virus distribution in Ramsay Hunt syndrome revealed by polymerase chain reaction. Acta Otolaryngol. 1998;118(2):145-149.

17. Hiroshige K, Ikeda M, Hondo R. Detection of varicella zoster virus DNA in tear fluid and saliva of patients with Ramsay Hunt syndrome. Otol Neurol. 2002;23(4):602-607.

18. Sweeney CJ, Gilden DH. Ramsay Hunt syndrome. J Neurol Neurosurg Psychiatr. 2001;71(2):148-154.

19. Murakami S, Honda N, Mizobuchi M, et al. Rapid diagnosis of varicella zoster virus infection in acute facial palsy. Neurology. 1998;51(4):1202-1205.

20. Kim IS, Shin SH, Kim J, et al. Correlation between MRI and operative findings in Bell’s palsy and Ramsay Hunt syndrome. Yonsei Med J. 2007;48(6):963-968.

21. Engström M, Berg T, Stjernquist-Desatnik A, et al. Prednisolone and valaciclovir in Bell’s palsy: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet Neurol. 2008;7(11):993-1000.

22. Hato N, Yamada H, Kohno H, et al. Valacyclovir and prednisolone treatment for Bell’s palsy: a multicenter, randomized, placebo-controlled study. Otol Neurotol. 2007;28(3):408-413.

23. Murakami S, Hato N, Horiuchi J, et al. Treatment of Ramsay Hunt syndrome with acyclovir-prednisone: significance of early diagnosis and treatment. Ann Neurol. 1997;41(3):353-357.

A 46-year-old man presented to a hospital emergency department (ED) with a four-day history of right ear pain. He described the pain as a constant, dull, burning pain radiating to the neck and face, associated with a feeling of congestion. The patient also stated that the right side of his face had felt numb for about one day.

Three days earlier, the man had been seen by his primary health care provider, who told him that his ear looked normal and free of infection. The day before his current presentation to the ED, however, he noticed what he described as an “acne-like” rash on his ear lobe. Shortly before coming to the ED, the patient also developed numbness over his right upper lip, which he likened to the effects of procaine during a dental visit. He reported drooling from the right side of his mouth while drinking water and difficulty blinking his right eye. 

He denied any tinnitus, fever, headache, or change in hearing. A review of symptoms was positive only for mild dizziness during the previous two to three days.

The patient was a well-appearing white man. He was alert and oriented to identity, time, and place. His skin was warm, dry, and intact. The examiner noticed a small area of erythematous rash with vesicles on the man’s right ear lobe. The external auditory canals appeared within normal limits, with no erythema or edema, and were nontender bilaterally. The tympanic membranes were normal bilaterally, without bulging or discernible fluid levels.

The ocular exam was normal with no visual acuity changes and no fluorescein uptake; external ocular movements were intact. A slight droop was noted in the right eyelid, but there was no droop on the contralateral side of his face. When asked to puff up his cheeks, the patient found it difficult to do so on the right side of his mouth without releasing air from his lips.

The remainder of the cranial nerves were intact. Muscle strength was 5/5 in all extremities and equal bilaterally. The man’s gait was within normal limits, and the remaining findings in the physical exam were normal.

The initial diagnosis considered in the differential was otitis externa, because it is a common explanation for ear pain in patients who present to the ED.^1,2 Also, in otitis, pain is characteristically present in the affected ear, and erythema is often found in the external auditory canal.³ However, this diagnosis was deemed unlikely because otitis externa would not explain the neurologic findings or the vesicular rash.¹

Bell’s palsy was next in the differential, as it was considered consistent with the patient’s unilateral neurologic deficits.⁴ In addition to weakness or palsy of the facial nerve, many patients with Bell’s palsy complain of mastoid pain, which can be confused with a complaint of ear pain.⁵ However, patients with Bell’s palsy have no rash, and this diagnosis was considered unlikely.

The painful, burning rash on the patient’s face was characteristic of herpes zoster (shingles), which was next in the differential. Infrequently, shingles can also cause weakness in the nerve it affects. In the case patient, weakness that was evident in the affected nerve resembled that seen in Bell’s palsy. This combination of symptoms is referred to as Ramsay Hunt syndrome—which in this case was decided to be the correct diagnosis.

DISCUSSION
Ramsay Hunt syndrome (RHS, also known as geniculate herpes^5,6) is caused by the varicella-zoster virus, most commonly known as the cause of chickenpox. In the United States, RHS is believed to affect only about one in 1,500 persons, although 20% to 30% of persons experience herpes zoster infection at some time.⁷

Soon after a chickenpox infection subsides, the virus spreads along the sensory nerve fibers of the peripheral and cranial nerves. The virus then becomes dormant in the dorsal root ganglion, where in some patients it later reactivates in the form of shingles.⁸

In RHS, the ganglia of cranial nerve VII (CN VII, the facial nerve, which innervates the facial muscles) are infected; for this reason, the condition is also referred to as zoster oticus.⁹ Because of the involvement and weakening of the facial nerve, the presentation of RHS often resembles that of Bell’s palsy or facial nerve palsy.

While most cases of Bell’s palsy are idiopathic,^10,11 RHS can usually be attributed to viral infection—most commonly, infection with herpes simplex virus type 1 (HSV-1).¹² RHS can be differentiated from Bell’s palsy by the presence of a rash on the ipsilateral side. The rash appears in the form of inflamed vesicles on an erythematous base and may be present around the ear (see figure), the eardrum, the hard and soft palate, or the tongue.⁶ When the rash is painful, it is often described as a burning pain. Loss of taste may occur in the anterior portion of the tongue.^9,12

Unlike shingles, which usually manifests as a sensory neuropathy, RHS is distinguished by motor neuropathy.⁷ The patient usually reports weakness in the facial muscles on one side, leading to difficulty drinking water or puffing out the cheek and to drooling on one side of the face. A complaint of dryness in the ipsilateral eye may result from weakness or an inability to close the eyelid.

It is important to note that as in Bell’s palsy, RHS can be differentiated from stroke by the patient’s inability to wrinkle the forehead. The motor muscles of the forehead are innervated by both sides of the brain; in the case of stroke, only one side of the brain is affected, and movement of the forehead remains possible on the contralateral side. In facial nerve palsy, the nerve itself is affected; thus, no movement of the forehead is possible.¹³ Other common complaints in patients with facial nerve palsy include vertigo, hearing loss, and changes in facial sensation.

RHS was first described in 1907 as herpes zoster associated with Bell’s palsy by the neurologist J. Ramsay Hunt, for whom the condition is named.^9,14 RHS is more common in men than women. It occurs most commonly in adults and is rare in children younger than 6.^13,15

Diagnosis
In most cases, a diagnosis of RHS is made on a clinical basis.¹ However, a polymerase chain reaction (PCR) assay can be performed on samples of tear fluid or submandibular saliva to detect the zoster virus.^16,17 PCR can also be performed using exudates from the geniculate zone of the ear (a small area in the center of the auricle^6,14), which is more sensitive than tears or blood.^18,19 Findings from a complete blood count and the erythrocyte sedimentation rate can be used to differentiate between infectious and inflammatory causes.¹³

Head CT or MRI can be obtained to rule out any structural lesions. In one study, Kim et al²⁰ examined MRI changes in patients with either Bell’s palsy or RHS. In both conditions, researchers were able to identify swelling of the labyrinthine segment of the facial nerve on temporal MRI scans.²⁰ Although CT has not been shown to have any prognostic or diagnostic application, it can occasionally be used if decompression of the facial nerve is warranted.¹¹

Treatment
Data used to support the use of corticosteroids for treatment of Bell’s palsy^10,21,22 have been extrapolated to justify their use for treatment of RHS,²³ and prednisolone is the most common choice.¹⁰ Steroids reduce the associated inflammation, resulting in decreased pain and neurologic symptoms. A daily dose for one to two weeks, followed by a slow taper, is the preferred prescribing method.¹⁰

The addition of acyclovir has been recommended to inhibit viral DNA replication^9,23 (valacyclovir and famciclovir have also been mentioned^12,18). If started within three days of symptom onset, acyclovir can help reduce pain and hasten resolution of symptoms.

In a large retrospective study, it was demonstrated that patients treated with prednisone at 1.0 mg/kg/d for five days, followed by a 10-day taper, combined with acyclovir, showed long-term improvement that was statistically significant.²³ Complete facial recovery was reported in only 52% of patients, however. Risk factors for a poor prognosis include hypertension, diabetes mellitus, and advancing age.⁷

Artificial tears are also prescribed to keep the affected eye from becoming irritated and dry. The patient can be instructed to tape the eye closed at night.¹⁰

Early diagnosis and treatment (ie, within three days of symptom onset, and preferably with a combination of acyclovir and steroids²³) is an important factor in a good prognosis.^7,23 Because RHS-affected patients have only about a 50% chance of full recovery,²³ proper follow-up care is extremely important. Follow-up visits are recommended at two weeks, six weeks, and three months.¹³ For optimal outcomes in patients with this neurologic diagnosis, referral to a neurologist is recommended for ongoing management. This practitioner is likely to detect subtle changes in patient presentation and can perform follow-up testing as needed.

THE CASE PATIENT
One week after the patient’s visit to the ED, he was contacted by hospital staff for a standard satisfaction and quality control survey. The patient (who had been treated with steroids and acyclovir, ibuprofen, and artificial tears) reported almost complete resolution of his pain; any mild pain, he said, was easily tolerated or could be resolved with OTC medication. He reported only minimal persistent facial weakness, stating that he was able to eat, drink, and speak normally.

The patient had not been seen by any health care provider for follow-up, but he agreed to make an appointment as soon as possible.     

REFERENCES
1. Kim D, Bhimani M. Ramsay Hunt syndrome presenting as simple otitis externa. CJEM. 2008;10(3):247-250.

2. Agius AM, Pickles JM, Burch KL. A prospective study of otitis externa. Clin Otolaryngol. 1992;17(2):150-154.

3. Rosenfeld RM, Brown L, Cannon CR, et al; American Academy of Otolaryngology—Head and Neck Surgery Foundation. Clinical practice guideline: acute otitis externa. Otolaryngol Head Neck Surg. 2006;134(4 suppl):S4-S23.

4. Holland J, Bernstein J. Bell’s palsy. Clin Evid (Online). 2011 Mar 7;2011.pii:1204.

5. Jacewicz M. Bell’s palsy (2007). www.merckmanuals.com/professional/sec16/ch219/ch219i.html. Accessed May 26, 2011.

6. Harrison K. Discussion: the Ramsay Hunt Syndrome. Proc Royal Soc Med. 1953;47(371):11-24.

7. Bhupal HK. Ramsay Hunt syndrome presenting in primary care. Practitioner. 2010;254(1727):33-35.

8. Aizawa H, Ohtani F, Furuta Y, et al. Variable patterns of varicella-zoster virus reactivation in Ramsay Hunt syndrome. J Med Virol. 2004;74(2):355-360.

9. Gondivkar S, Parikh V, Parikh R. Herpes zoster oticus: a rare clinical entity. Contemp Clin Dent. 2010;1(2):127-129.

10. Sullivan FM, Swan IRC, Donnan PT, et al. Early treatment with prednisolone or acyclovir in Bell’s palsy. N Engl J Med. 2007;357(16):1598-1607.

11. Gilden DH. Bell’s palsy. N Engl J Med. 2004;351(13):1323-1331.

12. Diaz GA, Rakita RM, Koelle DM. A case of Ramsay Hunt–like syndrome caused by herpes simplex virus type 2. Clin Infect Dis. 2005;40(10):1545-1547.

13. Miravalle AA. Ramsay Hunt syndrome. http://emedicine.medscape.com/article/1166804-over iew. Accessed July 22, 2011.

14. Hunt JR. On herpetic inflammation of the geniculate ganglion: a new syndrome and its complications. J Nerv Ment Dis. 1907;34:73-96.

15. Sandoval CC, Núñez FA, Lizama CM, et al. Ramsay Hunt syndrome in children: four cases and review [in Spanish]. Rev Chilena Infectol. 2008; 25(6):458-464.

16. Murakami S, Nakashiro Y, Mizobuchi M, et al. Varicella-zoster virus distribution in Ramsay Hunt syndrome revealed by polymerase chain reaction. Acta Otolaryngol. 1998;118(2):145-149.

17. Hiroshige K, Ikeda M, Hondo R. Detection of varicella zoster virus DNA in tear fluid and saliva of patients with Ramsay Hunt syndrome. Otol Neurol. 2002;23(4):602-607.

18. Sweeney CJ, Gilden DH. Ramsay Hunt syndrome. J Neurol Neurosurg Psychiatr. 2001;71(2):148-154.

19. Murakami S, Honda N, Mizobuchi M, et al. Rapid diagnosis of varicella zoster virus infection in acute facial palsy. Neurology. 1998;51(4):1202-1205.

20. Kim IS, Shin SH, Kim J, et al. Correlation between MRI and operative findings in Bell’s palsy and Ramsay Hunt syndrome. Yonsei Med J. 2007;48(6):963-968.

21. Engström M, Berg T, Stjernquist-Desatnik A, et al. Prednisolone and valaciclovir in Bell’s palsy: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet Neurol. 2008;7(11):993-1000.

22. Hato N, Yamada H, Kohno H, et al. Valacyclovir and prednisolone treatment for Bell’s palsy: a multicenter, randomized, placebo-controlled study. Otol Neurotol. 2007;28(3):408-413.

23. Murakami S, Hato N, Horiuchi J, et al. Treatment of Ramsay Hunt syndrome with acyclovir-prednisone: significance of early diagnosis and treatment. Ann Neurol. 1997;41(3):353-357.

A 30-year-old man experienced an episode of syncope while at work. He fully recovered consciousness within 2 minutes, but the emergency services team was called. As he was being loaded into the ambulance he again lost consciousness, and he was noted to be in ventricular fibrillation. Advanced cardiac life support was immediately started and continued for 50 minutes before a hemodynamically stable spontaneous rhythm was obtained.

On arrival at the emergency department of the local hospital, he was intubated to protect his airway, as he was comatose. A 12-lead electrocardiogram showed ST-segment elevations in leads V₁, V₂, and V₃ and a wide QRS complex with an rSR′ pattern, consistent with right bundle branch block.

Mild therapeutic hypothermia was initiated by infusing intravenous saline solution chilled to 4°C and by applying cooling blankets, and he was transferred to our hospital on an emergency basis for further management. Here, hypothermia was maintained using an intravenous cooling catheter.

HYPOTHERMIA: BENEFICIAL, BUT SLOW TO BE ADOPTED

Mild therapeutic hypothermia is a recommended therapeutic intervention for out-of-hospital cardiac arrest due to ventricular fibrillation. Nonetheless, first-responders, emergency-room staff, and intensive-care teams have been slow to adopt and integrate it into a comprehensive postresuscitation strategy. This article summarizes the evidence supporting this therapy and how it is performed.

PROPOSED MECHANISMS OF BENEFIT

Mild therapeutic hypothermia is thought to protect against anoxic brain injury in survivors of cardiac arrest via several mechanisms:

• Decreasing neuronal metabolism in the early stage of ischemic injury
• Decreasing glucose and oxygen consumption by the brain,¹ which reduces supply-demand mismatch
• Decreasing the release of excitatory amino acids (eg, glutamate) that normally trigger cytotoxic cascades in the intermediate phase of injury²
• Reducing the production of harmful reactive oxygen species³
• Maintaining cellular pH⁴
• Reducing cell death⁵
• Slowing the breakdown of the blood-brain barrier that worsens cerebral edema.⁶

CLINICAL DATA SUPPORTING HYPOTHERMIA

There has been an interest in therapeutic hypothermia for several decades. In the 1950s, it was used in small numbers of cases in a variety of cardiac arrest situations.^7,8 Interest was rekindled in the mid-1990s after a number of animal studies suggested it might be beneficial in prolonged cerebral ischemia and anoxia,^9,10 and reports of case-series described its use in adults with out-of-hospital cardiac arrest.^11,12

In October 2002, the International Liaison Committee on Resuscitation (ILCOR), made up of executive members of several organizations including the American Heart Association, recommended that “unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest” should be cooled to 32°C to 34°C [89.6°F–93.2°F] for 12 to 24 hours “when the initial rhythm was ventricular fibrillation.”¹³

Two large randomized trials

This position statement was based largely on the results of two randomized clinical trials published simultaneously earlier in 2002.^14,15 These two trials were important not only because they were the largest randomized trials of this therapy to that point, but also because they used meaningful, prospectively defined clinical end points: all-cause mortality and degree of cognitive preservation as assessed using the Glasgow-Pittsburgh Cerebral Performance Category (CPC) scale.

Bernard et al¹⁴ performed a randomized trial in four centers in Australia, assigning 77 patients either to a goal temperature of 32°C to 34°C or to normothermia for 12 hours, with all other resuscitative measures being the same in both groups. The primary outcome measured was survival to hospital discharge with sufficient neurologic function to be discharged to home or to a rehabilitation facility, ie, a CPC score of 1 or 2.

In the hypothermia group, 21 (49%) of the 43 patients survived and had an outcome that was considered “good” (ie, they were discharged home or to a rehabilitation facility), compared with 9 (26%) of the 34 patients in the normothermia group (unadjusted odds ratio 2.65, 95% confidence interval [CI] 1.02–6.88, P = .046). Proportionally fewer patients in the hypothermia group died—22 (51%) of 43 vs 23 (68%) of 34; however, the difference was not statistically significant (P = .145).

The Hypothermia After Cardiac Arrest Study Group¹⁵ screened 3,551 European patients who suffered out-of-hospital cardiac arrest¹⁵; 275 patients were randomized to mild therapeutic hypothermia or normothermia for 24 hours. The primary outcome was the percentage of patients who had a CPC score of 1 or 2 (vs 3 to 5) at 6 months, and the secondary outcome was the rate of death at 6 months.

At 6 months, 75 (55%) of the 136 patients in the hypothermia group had a CPC score of 1 or 2, compared with 54 (39%) of the 137 patients in the normothermia group (P = .009). The rate of death was also lower with hypothermia: 55% vs 41% (P = .02).

In both trials, patients were included only if their cardiac arrest was witnessed, if their initial cardiac rhythm was ventricular fibrillation or pulseless ventricular tachycardia, if circulation spontaneously returned within 60 minutes with standard basic and advanced cardiac life support protocols, and if they were still comatose on arrival at the hospital. They were excluded if they were over age 75, if they had suffered a cerebrovascular accident at the time of cardiac arrest, or if the arrest was caused by trauma or drug overdose. In addition, the European trial excluded patients who suffered another cardiac arrest after the initial return of spontaneous circulation but before cooling was started.

In view of the available clinical data, the 2002 ILCOR guidelines and a 2005 statement from the American Heart Association advocated mild therapeutic hypothermia for survivors of out-of-hospital ventricular tachycardia or fibrillation.¹⁶ Subsequently, this therapy has become more widely practiced and accepted as the standard of care among critical-care providers.

Of note, some public health officials and local governments are strongly promoting this treatment for survivors of cardiac arrest in the community.¹⁷ More and more of these groups are mandating that these patients be transported only to hospitals that have therapeutic hypothermia protocols in place, bypassing those not equipped to provide this treatment.¹⁸

INDICATIONS, CONTRAINDICATIONS, AND GRAY AREAS

What are the indications and contraindications to the use of hypothermia after out-of-hospital cardiac arrest? What are some of the “gray areas”?

Indications. This treatment is indicated for comatose adults who have had a witnessed cardiac arrest, whose initial cardiac rhythm was ventricular fibrillation or pulseless ventricular tachycardia, and whose circulation spontaneously returned in less than 60 minutes with basic and advanced cardiac life support. This carries a class I recommendation, level of evidence B, and was recently reinforced in the 2010 update to the American Heart Association guidelines for cardiopulmonary resuscitation.¹⁹

Absolute contraindications include hemorrhagic stroke (which must be proved by computed tomography) and cardiac arrest due to trauma (Table 2). Other major contraindications are a Glasgow Coma Scale score of 8 or higher before the initiation of mild therapeutic hypothermia, cardiac arrest due to drug overdose, and preexisting hypothermia (< 34°C) when first-responders arrive.

Relative contraindications include baseline coagulopathy and severe hypotension (mean atrial pressure < 60 mm Hg) that is not correctable by fluid infusion, vasopressors, or invasive hemodynamic support.

Gray areas. There are not enough data to make a firm recommendation about whether to apply mild therapeutic hypothermia if a witnessed cardiac arrest with ventricular fibrillation or ventricular tachycardia occurs in the hospital, but data from out-of-hospital cardiac arrest patients appear applicable for hospitalized patients.

The data are also quite limited and equivocal on its use for out-of-hospital cardiac arrest in patients whose initial cardiac rhythm is pulseless electrical activity or asystole,^20,21 likely because of the competing risk of comorbidities and the resultant lower baseline survival rate in these patients.

Consequently, for in-hospital postarrest patients with any initial rhythm and for out-of-hospital cardiac arrest patients with rhythms other than ventricular tachycardia or ventricular fibrillation, the 2010 guideline recommendation on the use of mild therapeutic hypothermia is less enthusiastic (class IIb, level of evidence B).¹⁹

There are also few data on the use of mild therapeutic hypothermia in post-arrest patients in circulatory shock requiring vasopressors or intra-aortic balloon counterpulsation, largely limited to case series and comparisons with historical controls.^22,23 Further investigation is clearly needed in these areas. Until then, it should be considered at the physician’s and the team’s discretion, on a case-by-case basis.

HYPOTHERMIA IN CASES OF VENTRICULAR FIBRILLATION AND ACUTE CORONARY SYNDROME

The value of coronary angiography after out-of-hospital cardiac arrest was first highlighted by Spaulding et al,²⁴ who performed it urgently in 84 consecutive survivors of out-of-hospital cardiac arrest, 36 of whom had ST-segment elevation myocardial infarction (STEMI). Angiography uncovered an acute coronary occlusion in 40 (48%) of the 84 patients.

In this series, ST-segment elevation was a strong predictor of acute coronary occlusion (odds ratio 4.3; 95% CI 1.6–2.0; P = .004). However, 9 patients without chest pain or ST elevation were also found to have an occluded infarct-related artery. Successful angioplasty was an independent predictor of survival, highlighting the importance of an angiographic definition in this population.

These findings were recently confirmed in the larger Parisian Region Out of Hospital Cardiac Arrest (PROCAT) registry in 435 patients who had no obvious extracardiac cause of arrest, for whom successful culprit coronary angioplasty was associated with survival.²⁵

Angioplasty comes first, but neither treatment need be delayed

Efforts to induce hypothermia must not be allowed to delay the door-to-balloon time of post-arrest patients in the setting of STEMI. The top priority is establishing patency of the infarct-related artery with a goal of salvaging ischemic myocardium and obtaining mechanical and electrical stabilization.

Fortunately, mild therapeutic hypothermia does not necessarily delay emergency revascularization if hypothermia protocols are well established. In fact, induction of mild therapeutic hypothermia prior to or on arrival at the catheterization laboratory has been shown to be feasible and safe.^26,27

We believe that all centers performing primary percutaneous coronary intervention for STEMI should have immediate access to and expertise in mild therapeutic hypothermia. Regional planning and integration of STEMI and out-of-hospital cardiac arrest networks will ensure that most patients with STEMI have access to this treatment when it is indicated.

Does hypothermia help the heart? Does it increase bleeding?

Researchers have been interested in therapeutic hypothermia as a means of reducing myocardial infarct size,^28,29 but clinical trials have not shown a clear-cut benefit in this regard. However, these investigations have also added to the evidence that antiplatelet and anticoagulation therapy in patients undergoing mild therapeutic hypothermia does not result in a statistically significant excess of major bleeding events, which is a potential concern.

Of note, these studies were neither powered nor specifically designed to evaluate for major bleeding as an end point. Therefore, these complications should still be carefully monitored for.

IS THERE AN OPTIMAL TIME TO BEGIN MILD THERAPEUTIC HYPOTHERMIA?

Experimental data suggest that mild therapeutic hypothermia should be started as soon as possible after a comprehensive clinical evaluation indicates the patient is eligible.^30–33 However, clinical data are not robustly in favor of starting it before the patient reaches the hospital rather than on hospital arrival.

In a recent randomized trial in 2,334 survivors of out-of-hospital cardiac arrest, outcomes were no better if hypothermia was started by paramedics than if it was started on arrival at the hospital (47.5% vs 52.6% discharged to home or rehabilitation; 95% CI 0.70–1.17; P = .43).³⁴

Earlier data from smaller studies had suggested that prehospital initiation of hypothermia (for example, using chilled intravenous saline infusions) in carefully selected patients with out-of-hospital cardiac arrest was safe and showed a nonsignificant trend toward better outcomes.^20,35

The randomized controlled trials that showed hypothermia to be beneficial used very slow cooling methods; consequently, it is reasonable to allow up to 6 hours from initial presentation to first-responders to start it. There are, however, no conclusive data in humans for or against starting it later than 6 hours after presentation. Most experts believe that its potential neurologic and mortality benefits are largely lost if it is delayed more than 6 hours.

The overall message from these data seems to be that, in patients who survive cardiac arrest outside the hospital with ventricular tachycardia or fibrillation, mild therapeutic hypothermia is effective and safe and should be started as soon as possible after arrival at the hospital.

METHODS FOR INDUCING AND MAINTAINING HYPOTHERMIA

Cooling the patient

To cool the patient and keep him or her cold, caregivers have used ice packs placed around the head, groin, and axillae; intravenous infusion of saline maintained at 4°C (39°F); and cooling-air blankets. More recently, thermal wraps and intravascular cooling catheters have been used.^36–38 The newer methods are more effective in rapidly bringing patients to the target temperature of 32 to 34°C (usually within 3 or 4 hours) and keeping them within this range, and they auto-adjust their output on the basis of measured core temperature.

The Pre ROSC Intranasal Cooling Effectiveness (PRINCE) trial demonstrated the safety and efficacy of nasopharyngeal cooling using a perfluorocarbon aerosol given via a nasopharyngeal cannula in patients with out-of-hospital cardiac arrest.³⁹

Monitoring the core temperature

The patient’s core temperature is most commonly monitored with a probe in the esophagus, bladder, rectum, or pulmonary artery.⁴⁰

Of these, the bladder and rectum are considered “intermediate” monitoring sites, as their temperatures tend to lag behind the core temperature. Furthermore, the bladder temperature can be significantly altered by the flow of urine, which can vary considerably during the cooling and rewarming process.

Esophageal temperature monitoring is relatively noninvasive and tends to reliably and accurately reflect core temperature as long as the probe is placed far enough down (about 45 cm from the nose in an average adult) that it is not affected by proximity to the trachea.

Pulmonary artery catheters are considered the gold standard for core temperature monitoring, but they pose risks such as bloodstream infection and large-vessel damage. In practice, many patients admitted to the coronary intensive care unit after out-of-hospital cardiac arrest require pulmonary artery catheterization anyway for other indications, and in these situations it is the preferred method of monitoring the core temperature.

However, no approach is ideal in terms of measuring the temperature in the critical end organs. Rather, core temperature monitoring serves as a guide to help ensure consistent clinical practice in attaining and maintaining mild therapeutic hypothermia.

Preventing shivering

To achieve and maintain the goal temperature, the body’s natural response to a decrease in core temperature—shivering—must be watched for and eliminated. A number of drugs may be used for this purpose.⁴¹

Paralytic drugs are used to reduce shivering; nursing staff must be trained to monitor for signs of occult shivering (eg, jaw vibration) and adjust the dose of paralytic drug accordingly. Since the patients are paralyzed, they must also receive continuous intravenous sedation.

Other commonly used drugs that decrease the hypothalamic drive to shiver include buspirone (BuSpar), a serotonin 5HT-1A partial agonist, and meperidine (Demerol), an opiate agonist of kappa and mu receptors.

Rewarming after 24 hours

Rewarming is conventionally started after 24 hours of mild therapeutic hypothermia, at a rate no greater than 0.5°C (1°F) per hour.

Because sedation is used during the hypothermia period of 24 hours, a washout period for these medications is necessary, and the neurologic prognosis of cardiac arrest patients who undergo mild therapeutic hypothermia cannot be adequately assessed until 72 hours after rewarming.

ADVERSE EFFECTS OF MILD THERAPEUTIC HYPOTHERMIA

Some of these effects are predictable. Decreasing the body temperature causes potassium to shift into the cells, and this same potassium will leave the intracellular space during the rewarming phase. For this reason, aggressive potassium repletion for mild hypokalemia (potassium levels of 3.0–3.5 mmol/L) during mild therapeutic hypothermia can result in dangerous hyperkalemia during rewarming and should generally be avoided.

As another example, the enzymes involved in coagulation are less effective at lower temperatures. Thus, if it occurs, active bleeding requiring transfusion warrants consideration of stopping the hypothermia.

Adverse effects should be watched for (eg, by checking electrolyte levels frequently, monitoring blood glucose, continuous electroencephalographic monitoring during the cooling phase, and avoiding placement of intracardiac catheters once the goal temperature is reached) and addressed as they happen. However, in a recent review of this subject⁴² the balance of evidence continued to indicate that the benefit of this treatment exceeds its risks.

OUR PATIENT RECOVERS

After 24 hours of therapeutic hypothermia, our patient was gradually rewarmed to a normal temperature, and sedation and paralysis were discontinued.

Analysis of his prearrest and postarrest 12-lead electrocardiograms revealed a type I Brugada pattern (coved ST elevation and negative T waves in V₁, V₂, and V₃, caused by abnormal repolarization due to inherited mutations in SCN5A). Cardiac catheterization revealed normal coronary arteries, and MRI revealed no evidence of arrhythmogenic right ventricular cardiomyopathy or other structural abnormalities.

In the next 72 hours the patient was successfully extubated, and he gradually returned to full neurologic function. Before he went home a few days later, a single-lead cardioverter-defibrillator was implanted to prevent sudden cardiac death. All of his first-degree relatives were encouraged to undergo genetic screening for SCN5A mutations. The patient is currently back to his previous high level of functioning as a marketing manager, husband, and father of two young children.

A 30-year-old man experienced an episode of syncope while at work. He fully recovered consciousness within 2 minutes, but the emergency services team was called. As he was being loaded into the ambulance he again lost consciousness, and he was noted to be in ventricular fibrillation. Advanced cardiac life support was immediately started and continued for 50 minutes before a hemodynamically stable spontaneous rhythm was obtained.

On arrival at the emergency department of the local hospital, he was intubated to protect his airway, as he was comatose. A 12-lead electrocardiogram showed ST-segment elevations in leads V₁, V₂, and V₃ and a wide QRS complex with an rSR′ pattern, consistent with right bundle branch block.

Mild therapeutic hypothermia was initiated by infusing intravenous saline solution chilled to 4°C and by applying cooling blankets, and he was transferred to our hospital on an emergency basis for further management. Here, hypothermia was maintained using an intravenous cooling catheter.

HYPOTHERMIA: BENEFICIAL, BUT SLOW TO BE ADOPTED

Mild therapeutic hypothermia is a recommended therapeutic intervention for out-of-hospital cardiac arrest due to ventricular fibrillation. Nonetheless, first-responders, emergency-room staff, and intensive-care teams have been slow to adopt and integrate it into a comprehensive postresuscitation strategy. This article summarizes the evidence supporting this therapy and how it is performed.

PROPOSED MECHANISMS OF BENEFIT

Mild therapeutic hypothermia is thought to protect against anoxic brain injury in survivors of cardiac arrest via several mechanisms:

• Decreasing neuronal metabolism in the early stage of ischemic injury
• Decreasing glucose and oxygen consumption by the brain,¹ which reduces supply-demand mismatch
• Decreasing the release of excitatory amino acids (eg, glutamate) that normally trigger cytotoxic cascades in the intermediate phase of injury²
• Reducing the production of harmful reactive oxygen species³
• Maintaining cellular pH⁴
• Reducing cell death⁵
• Slowing the breakdown of the blood-brain barrier that worsens cerebral edema.⁶

CLINICAL DATA SUPPORTING HYPOTHERMIA

There has been an interest in therapeutic hypothermia for several decades. In the 1950s, it was used in small numbers of cases in a variety of cardiac arrest situations.^7,8 Interest was rekindled in the mid-1990s after a number of animal studies suggested it might be beneficial in prolonged cerebral ischemia and anoxia,^9,10 and reports of case-series described its use in adults with out-of-hospital cardiac arrest.^11,12

In October 2002, the International Liaison Committee on Resuscitation (ILCOR), made up of executive members of several organizations including the American Heart Association, recommended that “unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest” should be cooled to 32°C to 34°C [89.6°F–93.2°F] for 12 to 24 hours “when the initial rhythm was ventricular fibrillation.”¹³

Two large randomized trials

This position statement was based largely on the results of two randomized clinical trials published simultaneously earlier in 2002.^14,15 These two trials were important not only because they were the largest randomized trials of this therapy to that point, but also because they used meaningful, prospectively defined clinical end points: all-cause mortality and degree of cognitive preservation as assessed using the Glasgow-Pittsburgh Cerebral Performance Category (CPC) scale.

Bernard et al¹⁴ performed a randomized trial in four centers in Australia, assigning 77 patients either to a goal temperature of 32°C to 34°C or to normothermia for 12 hours, with all other resuscitative measures being the same in both groups. The primary outcome measured was survival to hospital discharge with sufficient neurologic function to be discharged to home or to a rehabilitation facility, ie, a CPC score of 1 or 2.

In the hypothermia group, 21 (49%) of the 43 patients survived and had an outcome that was considered “good” (ie, they were discharged home or to a rehabilitation facility), compared with 9 (26%) of the 34 patients in the normothermia group (unadjusted odds ratio 2.65, 95% confidence interval [CI] 1.02–6.88, P = .046). Proportionally fewer patients in the hypothermia group died—22 (51%) of 43 vs 23 (68%) of 34; however, the difference was not statistically significant (P = .145).

The Hypothermia After Cardiac Arrest Study Group¹⁵ screened 3,551 European patients who suffered out-of-hospital cardiac arrest¹⁵; 275 patients were randomized to mild therapeutic hypothermia or normothermia for 24 hours. The primary outcome was the percentage of patients who had a CPC score of 1 or 2 (vs 3 to 5) at 6 months, and the secondary outcome was the rate of death at 6 months.

At 6 months, 75 (55%) of the 136 patients in the hypothermia group had a CPC score of 1 or 2, compared with 54 (39%) of the 137 patients in the normothermia group (P = .009). The rate of death was also lower with hypothermia: 55% vs 41% (P = .02).

In both trials, patients were included only if their cardiac arrest was witnessed, if their initial cardiac rhythm was ventricular fibrillation or pulseless ventricular tachycardia, if circulation spontaneously returned within 60 minutes with standard basic and advanced cardiac life support protocols, and if they were still comatose on arrival at the hospital. They were excluded if they were over age 75, if they had suffered a cerebrovascular accident at the time of cardiac arrest, or if the arrest was caused by trauma or drug overdose. In addition, the European trial excluded patients who suffered another cardiac arrest after the initial return of spontaneous circulation but before cooling was started.

In view of the available clinical data, the 2002 ILCOR guidelines and a 2005 statement from the American Heart Association advocated mild therapeutic hypothermia for survivors of out-of-hospital ventricular tachycardia or fibrillation.¹⁶ Subsequently, this therapy has become more widely practiced and accepted as the standard of care among critical-care providers.

Of note, some public health officials and local governments are strongly promoting this treatment for survivors of cardiac arrest in the community.¹⁷ More and more of these groups are mandating that these patients be transported only to hospitals that have therapeutic hypothermia protocols in place, bypassing those not equipped to provide this treatment.¹⁸

INDICATIONS, CONTRAINDICATIONS, AND GRAY AREAS

What are the indications and contraindications to the use of hypothermia after out-of-hospital cardiac arrest? What are some of the “gray areas”?

Indications. This treatment is indicated for comatose adults who have had a witnessed cardiac arrest, whose initial cardiac rhythm was ventricular fibrillation or pulseless ventricular tachycardia, and whose circulation spontaneously returned in less than 60 minutes with basic and advanced cardiac life support. This carries a class I recommendation, level of evidence B, and was recently reinforced in the 2010 update to the American Heart Association guidelines for cardiopulmonary resuscitation.¹⁹

Absolute contraindications include hemorrhagic stroke (which must be proved by computed tomography) and cardiac arrest due to trauma (Table 2). Other major contraindications are a Glasgow Coma Scale score of 8 or higher before the initiation of mild therapeutic hypothermia, cardiac arrest due to drug overdose, and preexisting hypothermia (< 34°C) when first-responders arrive.

Relative contraindications include baseline coagulopathy and severe hypotension (mean atrial pressure < 60 mm Hg) that is not correctable by fluid infusion, vasopressors, or invasive hemodynamic support.

Gray areas. There are not enough data to make a firm recommendation about whether to apply mild therapeutic hypothermia if a witnessed cardiac arrest with ventricular fibrillation or ventricular tachycardia occurs in the hospital, but data from out-of-hospital cardiac arrest patients appear applicable for hospitalized patients.

The data are also quite limited and equivocal on its use for out-of-hospital cardiac arrest in patients whose initial cardiac rhythm is pulseless electrical activity or asystole,^20,21 likely because of the competing risk of comorbidities and the resultant lower baseline survival rate in these patients.

Consequently, for in-hospital postarrest patients with any initial rhythm and for out-of-hospital cardiac arrest patients with rhythms other than ventricular tachycardia or ventricular fibrillation, the 2010 guideline recommendation on the use of mild therapeutic hypothermia is less enthusiastic (class IIb, level of evidence B).¹⁹

There are also few data on the use of mild therapeutic hypothermia in post-arrest patients in circulatory shock requiring vasopressors or intra-aortic balloon counterpulsation, largely limited to case series and comparisons with historical controls.^22,23 Further investigation is clearly needed in these areas. Until then, it should be considered at the physician’s and the team’s discretion, on a case-by-case basis.

HYPOTHERMIA IN CASES OF VENTRICULAR FIBRILLATION AND ACUTE CORONARY SYNDROME

The value of coronary angiography after out-of-hospital cardiac arrest was first highlighted by Spaulding et al,²⁴ who performed it urgently in 84 consecutive survivors of out-of-hospital cardiac arrest, 36 of whom had ST-segment elevation myocardial infarction (STEMI). Angiography uncovered an acute coronary occlusion in 40 (48%) of the 84 patients.

In this series, ST-segment elevation was a strong predictor of acute coronary occlusion (odds ratio 4.3; 95% CI 1.6–2.0; P = .004). However, 9 patients without chest pain or ST elevation were also found to have an occluded infarct-related artery. Successful angioplasty was an independent predictor of survival, highlighting the importance of an angiographic definition in this population.

These findings were recently confirmed in the larger Parisian Region Out of Hospital Cardiac Arrest (PROCAT) registry in 435 patients who had no obvious extracardiac cause of arrest, for whom successful culprit coronary angioplasty was associated with survival.²⁵

Angioplasty comes first, but neither treatment need be delayed

Efforts to induce hypothermia must not be allowed to delay the door-to-balloon time of post-arrest patients in the setting of STEMI. The top priority is establishing patency of the infarct-related artery with a goal of salvaging ischemic myocardium and obtaining mechanical and electrical stabilization.

Fortunately, mild therapeutic hypothermia does not necessarily delay emergency revascularization if hypothermia protocols are well established. In fact, induction of mild therapeutic hypothermia prior to or on arrival at the catheterization laboratory has been shown to be feasible and safe.^26,27

We believe that all centers performing primary percutaneous coronary intervention for STEMI should have immediate access to and expertise in mild therapeutic hypothermia. Regional planning and integration of STEMI and out-of-hospital cardiac arrest networks will ensure that most patients with STEMI have access to this treatment when it is indicated.

Does hypothermia help the heart? Does it increase bleeding?

Researchers have been interested in therapeutic hypothermia as a means of reducing myocardial infarct size,^28,29 but clinical trials have not shown a clear-cut benefit in this regard. However, these investigations have also added to the evidence that antiplatelet and anticoagulation therapy in patients undergoing mild therapeutic hypothermia does not result in a statistically significant excess of major bleeding events, which is a potential concern.

Of note, these studies were neither powered nor specifically designed to evaluate for major bleeding as an end point. Therefore, these complications should still be carefully monitored for.

IS THERE AN OPTIMAL TIME TO BEGIN MILD THERAPEUTIC HYPOTHERMIA?

Experimental data suggest that mild therapeutic hypothermia should be started as soon as possible after a comprehensive clinical evaluation indicates the patient is eligible.^30–33 However, clinical data are not robustly in favor of starting it before the patient reaches the hospital rather than on hospital arrival.

In a recent randomized trial in 2,334 survivors of out-of-hospital cardiac arrest, outcomes were no better if hypothermia was started by paramedics than if it was started on arrival at the hospital (47.5% vs 52.6% discharged to home or rehabilitation; 95% CI 0.70–1.17; P = .43).³⁴

Earlier data from smaller studies had suggested that prehospital initiation of hypothermia (for example, using chilled intravenous saline infusions) in carefully selected patients with out-of-hospital cardiac arrest was safe and showed a nonsignificant trend toward better outcomes.^20,35

The randomized controlled trials that showed hypothermia to be beneficial used very slow cooling methods; consequently, it is reasonable to allow up to 6 hours from initial presentation to first-responders to start it. There are, however, no conclusive data in humans for or against starting it later than 6 hours after presentation. Most experts believe that its potential neurologic and mortality benefits are largely lost if it is delayed more than 6 hours.

The overall message from these data seems to be that, in patients who survive cardiac arrest outside the hospital with ventricular tachycardia or fibrillation, mild therapeutic hypothermia is effective and safe and should be started as soon as possible after arrival at the hospital.

METHODS FOR INDUCING AND MAINTAINING HYPOTHERMIA

Cooling the patient

To cool the patient and keep him or her cold, caregivers have used ice packs placed around the head, groin, and axillae; intravenous infusion of saline maintained at 4°C (39°F); and cooling-air blankets. More recently, thermal wraps and intravascular cooling catheters have been used.^36–38 The newer methods are more effective in rapidly bringing patients to the target temperature of 32 to 34°C (usually within 3 or 4 hours) and keeping them within this range, and they auto-adjust their output on the basis of measured core temperature.

The Pre ROSC Intranasal Cooling Effectiveness (PRINCE) trial demonstrated the safety and efficacy of nasopharyngeal cooling using a perfluorocarbon aerosol given via a nasopharyngeal cannula in patients with out-of-hospital cardiac arrest.³⁹

Monitoring the core temperature

The patient’s core temperature is most commonly monitored with a probe in the esophagus, bladder, rectum, or pulmonary artery.⁴⁰

Of these, the bladder and rectum are considered “intermediate” monitoring sites, as their temperatures tend to lag behind the core temperature. Furthermore, the bladder temperature can be significantly altered by the flow of urine, which can vary considerably during the cooling and rewarming process.

Esophageal temperature monitoring is relatively noninvasive and tends to reliably and accurately reflect core temperature as long as the probe is placed far enough down (about 45 cm from the nose in an average adult) that it is not affected by proximity to the trachea.

Pulmonary artery catheters are considered the gold standard for core temperature monitoring, but they pose risks such as bloodstream infection and large-vessel damage. In practice, many patients admitted to the coronary intensive care unit after out-of-hospital cardiac arrest require pulmonary artery catheterization anyway for other indications, and in these situations it is the preferred method of monitoring the core temperature.

However, no approach is ideal in terms of measuring the temperature in the critical end organs. Rather, core temperature monitoring serves as a guide to help ensure consistent clinical practice in attaining and maintaining mild therapeutic hypothermia.

Preventing shivering

To achieve and maintain the goal temperature, the body’s natural response to a decrease in core temperature—shivering—must be watched for and eliminated. A number of drugs may be used for this purpose.⁴¹

Paralytic drugs are used to reduce shivering; nursing staff must be trained to monitor for signs of occult shivering (eg, jaw vibration) and adjust the dose of paralytic drug accordingly. Since the patients are paralyzed, they must also receive continuous intravenous sedation.

Other commonly used drugs that decrease the hypothalamic drive to shiver include buspirone (BuSpar), a serotonin 5HT-1A partial agonist, and meperidine (Demerol), an opiate agonist of kappa and mu receptors.

Rewarming after 24 hours

Rewarming is conventionally started after 24 hours of mild therapeutic hypothermia, at a rate no greater than 0.5°C (1°F) per hour.

Because sedation is used during the hypothermia period of 24 hours, a washout period for these medications is necessary, and the neurologic prognosis of cardiac arrest patients who undergo mild therapeutic hypothermia cannot be adequately assessed until 72 hours after rewarming.

ADVERSE EFFECTS OF MILD THERAPEUTIC HYPOTHERMIA

Some of these effects are predictable. Decreasing the body temperature causes potassium to shift into the cells, and this same potassium will leave the intracellular space during the rewarming phase. For this reason, aggressive potassium repletion for mild hypokalemia (potassium levels of 3.0–3.5 mmol/L) during mild therapeutic hypothermia can result in dangerous hyperkalemia during rewarming and should generally be avoided.

As another example, the enzymes involved in coagulation are less effective at lower temperatures. Thus, if it occurs, active bleeding requiring transfusion warrants consideration of stopping the hypothermia.

Adverse effects should be watched for (eg, by checking electrolyte levels frequently, monitoring blood glucose, continuous electroencephalographic monitoring during the cooling phase, and avoiding placement of intracardiac catheters once the goal temperature is reached) and addressed as they happen. However, in a recent review of this subject⁴² the balance of evidence continued to indicate that the benefit of this treatment exceeds its risks.

OUR PATIENT RECOVERS

After 24 hours of therapeutic hypothermia, our patient was gradually rewarmed to a normal temperature, and sedation and paralysis were discontinued.

Analysis of his prearrest and postarrest 12-lead electrocardiograms revealed a type I Brugada pattern (coved ST elevation and negative T waves in V₁, V₂, and V₃, caused by abnormal repolarization due to inherited mutations in SCN5A). Cardiac catheterization revealed normal coronary arteries, and MRI revealed no evidence of arrhythmogenic right ventricular cardiomyopathy or other structural abnormalities.

In the next 72 hours the patient was successfully extubated, and he gradually returned to full neurologic function. Before he went home a few days later, a single-lead cardioverter-defibrillator was implanted to prevent sudden cardiac death. All of his first-degree relatives were encouraged to undergo genetic screening for SCN5A mutations. The patient is currently back to his previous high level of functioning as a marketing manager, husband, and father of two young children.

A 30-year-old man experienced an episode of syncope while at work. He fully recovered consciousness within 2 minutes, but the emergency services team was called. As he was being loaded into the ambulance he again lost consciousness, and he was noted to be in ventricular fibrillation. Advanced cardiac life support was immediately started and continued for 50 minutes before a hemodynamically stable spontaneous rhythm was obtained.

On arrival at the emergency department of the local hospital, he was intubated to protect his airway, as he was comatose. A 12-lead electrocardiogram showed ST-segment elevations in leads V₁, V₂, and V₃ and a wide QRS complex with an rSR′ pattern, consistent with right bundle branch block.

Mild therapeutic hypothermia was initiated by infusing intravenous saline solution chilled to 4°C and by applying cooling blankets, and he was transferred to our hospital on an emergency basis for further management. Here, hypothermia was maintained using an intravenous cooling catheter.

HYPOTHERMIA: BENEFICIAL, BUT SLOW TO BE ADOPTED

Mild therapeutic hypothermia is a recommended therapeutic intervention for out-of-hospital cardiac arrest due to ventricular fibrillation. Nonetheless, first-responders, emergency-room staff, and intensive-care teams have been slow to adopt and integrate it into a comprehensive postresuscitation strategy. This article summarizes the evidence supporting this therapy and how it is performed.

PROPOSED MECHANISMS OF BENEFIT

Mild therapeutic hypothermia is thought to protect against anoxic brain injury in survivors of cardiac arrest via several mechanisms:

• Decreasing neuronal metabolism in the early stage of ischemic injury
• Decreasing glucose and oxygen consumption by the brain,¹ which reduces supply-demand mismatch
• Decreasing the release of excitatory amino acids (eg, glutamate) that normally trigger cytotoxic cascades in the intermediate phase of injury²
• Reducing the production of harmful reactive oxygen species³
• Maintaining cellular pH⁴
• Reducing cell death⁵
• Slowing the breakdown of the blood-brain barrier that worsens cerebral edema.⁶

CLINICAL DATA SUPPORTING HYPOTHERMIA

There has been an interest in therapeutic hypothermia for several decades. In the 1950s, it was used in small numbers of cases in a variety of cardiac arrest situations.^7,8 Interest was rekindled in the mid-1990s after a number of animal studies suggested it might be beneficial in prolonged cerebral ischemia and anoxia,^9,10 and reports of case-series described its use in adults with out-of-hospital cardiac arrest.^11,12

In October 2002, the International Liaison Committee on Resuscitation (ILCOR), made up of executive members of several organizations including the American Heart Association, recommended that “unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest” should be cooled to 32°C to 34°C [89.6°F–93.2°F] for 12 to 24 hours “when the initial rhythm was ventricular fibrillation.”¹³

Two large randomized trials

This position statement was based largely on the results of two randomized clinical trials published simultaneously earlier in 2002.^14,15 These two trials were important not only because they were the largest randomized trials of this therapy to that point, but also because they used meaningful, prospectively defined clinical end points: all-cause mortality and degree of cognitive preservation as assessed using the Glasgow-Pittsburgh Cerebral Performance Category (CPC) scale.

Bernard et al¹⁴ performed a randomized trial in four centers in Australia, assigning 77 patients either to a goal temperature of 32°C to 34°C or to normothermia for 12 hours, with all other resuscitative measures being the same in both groups. The primary outcome measured was survival to hospital discharge with sufficient neurologic function to be discharged to home or to a rehabilitation facility, ie, a CPC score of 1 or 2.

In the hypothermia group, 21 (49%) of the 43 patients survived and had an outcome that was considered “good” (ie, they were discharged home or to a rehabilitation facility), compared with 9 (26%) of the 34 patients in the normothermia group (unadjusted odds ratio 2.65, 95% confidence interval [CI] 1.02–6.88, P = .046). Proportionally fewer patients in the hypothermia group died—22 (51%) of 43 vs 23 (68%) of 34; however, the difference was not statistically significant (P = .145).

The Hypothermia After Cardiac Arrest Study Group¹⁵ screened 3,551 European patients who suffered out-of-hospital cardiac arrest¹⁵; 275 patients were randomized to mild therapeutic hypothermia or normothermia for 24 hours. The primary outcome was the percentage of patients who had a CPC score of 1 or 2 (vs 3 to 5) at 6 months, and the secondary outcome was the rate of death at 6 months.

At 6 months, 75 (55%) of the 136 patients in the hypothermia group had a CPC score of 1 or 2, compared with 54 (39%) of the 137 patients in the normothermia group (P = .009). The rate of death was also lower with hypothermia: 55% vs 41% (P = .02).

In both trials, patients were included only if their cardiac arrest was witnessed, if their initial cardiac rhythm was ventricular fibrillation or pulseless ventricular tachycardia, if circulation spontaneously returned within 60 minutes with standard basic and advanced cardiac life support protocols, and if they were still comatose on arrival at the hospital. They were excluded if they were over age 75, if they had suffered a cerebrovascular accident at the time of cardiac arrest, or if the arrest was caused by trauma or drug overdose. In addition, the European trial excluded patients who suffered another cardiac arrest after the initial return of spontaneous circulation but before cooling was started.

In view of the available clinical data, the 2002 ILCOR guidelines and a 2005 statement from the American Heart Association advocated mild therapeutic hypothermia for survivors of out-of-hospital ventricular tachycardia or fibrillation.¹⁶ Subsequently, this therapy has become more widely practiced and accepted as the standard of care among critical-care providers.

Of note, some public health officials and local governments are strongly promoting this treatment for survivors of cardiac arrest in the community.¹⁷ More and more of these groups are mandating that these patients be transported only to hospitals that have therapeutic hypothermia protocols in place, bypassing those not equipped to provide this treatment.¹⁸

INDICATIONS, CONTRAINDICATIONS, AND GRAY AREAS

What are the indications and contraindications to the use of hypothermia after out-of-hospital cardiac arrest? What are some of the “gray areas”?

Indications. This treatment is indicated for comatose adults who have had a witnessed cardiac arrest, whose initial cardiac rhythm was ventricular fibrillation or pulseless ventricular tachycardia, and whose circulation spontaneously returned in less than 60 minutes with basic and advanced cardiac life support. This carries a class I recommendation, level of evidence B, and was recently reinforced in the 2010 update to the American Heart Association guidelines for cardiopulmonary resuscitation.¹⁹

Absolute contraindications include hemorrhagic stroke (which must be proved by computed tomography) and cardiac arrest due to trauma (Table 2). Other major contraindications are a Glasgow Coma Scale score of 8 or higher before the initiation of mild therapeutic hypothermia, cardiac arrest due to drug overdose, and preexisting hypothermia (< 34°C) when first-responders arrive.

Relative contraindications include baseline coagulopathy and severe hypotension (mean atrial pressure < 60 mm Hg) that is not correctable by fluid infusion, vasopressors, or invasive hemodynamic support.

Gray areas. There are not enough data to make a firm recommendation about whether to apply mild therapeutic hypothermia if a witnessed cardiac arrest with ventricular fibrillation or ventricular tachycardia occurs in the hospital, but data from out-of-hospital cardiac arrest patients appear applicable for hospitalized patients.

The data are also quite limited and equivocal on its use for out-of-hospital cardiac arrest in patients whose initial cardiac rhythm is pulseless electrical activity or asystole,^20,21 likely because of the competing risk of comorbidities and the resultant lower baseline survival rate in these patients.

Consequently, for in-hospital postarrest patients with any initial rhythm and for out-of-hospital cardiac arrest patients with rhythms other than ventricular tachycardia or ventricular fibrillation, the 2010 guideline recommendation on the use of mild therapeutic hypothermia is less enthusiastic (class IIb, level of evidence B).¹⁹

There are also few data on the use of mild therapeutic hypothermia in post-arrest patients in circulatory shock requiring vasopressors or intra-aortic balloon counterpulsation, largely limited to case series and comparisons with historical controls.^22,23 Further investigation is clearly needed in these areas. Until then, it should be considered at the physician’s and the team’s discretion, on a case-by-case basis.

HYPOTHERMIA IN CASES OF VENTRICULAR FIBRILLATION AND ACUTE CORONARY SYNDROME

The value of coronary angiography after out-of-hospital cardiac arrest was first highlighted by Spaulding et al,²⁴ who performed it urgently in 84 consecutive survivors of out-of-hospital cardiac arrest, 36 of whom had ST-segment elevation myocardial infarction (STEMI). Angiography uncovered an acute coronary occlusion in 40 (48%) of the 84 patients.

In this series, ST-segment elevation was a strong predictor of acute coronary occlusion (odds ratio 4.3; 95% CI 1.6–2.0; P = .004). However, 9 patients without chest pain or ST elevation were also found to have an occluded infarct-related artery. Successful angioplasty was an independent predictor of survival, highlighting the importance of an angiographic definition in this population.

These findings were recently confirmed in the larger Parisian Region Out of Hospital Cardiac Arrest (PROCAT) registry in 435 patients who had no obvious extracardiac cause of arrest, for whom successful culprit coronary angioplasty was associated with survival.²⁵

Angioplasty comes first, but neither treatment need be delayed

Efforts to induce hypothermia must not be allowed to delay the door-to-balloon time of post-arrest patients in the setting of STEMI. The top priority is establishing patency of the infarct-related artery with a goal of salvaging ischemic myocardium and obtaining mechanical and electrical stabilization.

Fortunately, mild therapeutic hypothermia does not necessarily delay emergency revascularization if hypothermia protocols are well established. In fact, induction of mild therapeutic hypothermia prior to or on arrival at the catheterization laboratory has been shown to be feasible and safe.^26,27

We believe that all centers performing primary percutaneous coronary intervention for STEMI should have immediate access to and expertise in mild therapeutic hypothermia. Regional planning and integration of STEMI and out-of-hospital cardiac arrest networks will ensure that most patients with STEMI have access to this treatment when it is indicated.

Does hypothermia help the heart? Does it increase bleeding?

Researchers have been interested in therapeutic hypothermia as a means of reducing myocardial infarct size,^28,29 but clinical trials have not shown a clear-cut benefit in this regard. However, these investigations have also added to the evidence that antiplatelet and anticoagulation therapy in patients undergoing mild therapeutic hypothermia does not result in a statistically significant excess of major bleeding events, which is a potential concern.

Of note, these studies were neither powered nor specifically designed to evaluate for major bleeding as an end point. Therefore, these complications should still be carefully monitored for.

IS THERE AN OPTIMAL TIME TO BEGIN MILD THERAPEUTIC HYPOTHERMIA?

Experimental data suggest that mild therapeutic hypothermia should be started as soon as possible after a comprehensive clinical evaluation indicates the patient is eligible.^30–33 However, clinical data are not robustly in favor of starting it before the patient reaches the hospital rather than on hospital arrival.

In a recent randomized trial in 2,334 survivors of out-of-hospital cardiac arrest, outcomes were no better if hypothermia was started by paramedics than if it was started on arrival at the hospital (47.5% vs 52.6% discharged to home or rehabilitation; 95% CI 0.70–1.17; P = .43).³⁴

Earlier data from smaller studies had suggested that prehospital initiation of hypothermia (for example, using chilled intravenous saline infusions) in carefully selected patients with out-of-hospital cardiac arrest was safe and showed a nonsignificant trend toward better outcomes.^20,35

The randomized controlled trials that showed hypothermia to be beneficial used very slow cooling methods; consequently, it is reasonable to allow up to 6 hours from initial presentation to first-responders to start it. There are, however, no conclusive data in humans for or against starting it later than 6 hours after presentation. Most experts believe that its potential neurologic and mortality benefits are largely lost if it is delayed more than 6 hours.

The overall message from these data seems to be that, in patients who survive cardiac arrest outside the hospital with ventricular tachycardia or fibrillation, mild therapeutic hypothermia is effective and safe and should be started as soon as possible after arrival at the hospital.

METHODS FOR INDUCING AND MAINTAINING HYPOTHERMIA

Cooling the patient

To cool the patient and keep him or her cold, caregivers have used ice packs placed around the head, groin, and axillae; intravenous infusion of saline maintained at 4°C (39°F); and cooling-air blankets. More recently, thermal wraps and intravascular cooling catheters have been used.^36–38 The newer methods are more effective in rapidly bringing patients to the target temperature of 32 to 34°C (usually within 3 or 4 hours) and keeping them within this range, and they auto-adjust their output on the basis of measured core temperature.

The Pre ROSC Intranasal Cooling Effectiveness (PRINCE) trial demonstrated the safety and efficacy of nasopharyngeal cooling using a perfluorocarbon aerosol given via a nasopharyngeal cannula in patients with out-of-hospital cardiac arrest.³⁹

Monitoring the core temperature

The patient’s core temperature is most commonly monitored with a probe in the esophagus, bladder, rectum, or pulmonary artery.⁴⁰

Of these, the bladder and rectum are considered “intermediate” monitoring sites, as their temperatures tend to lag behind the core temperature. Furthermore, the bladder temperature can be significantly altered by the flow of urine, which can vary considerably during the cooling and rewarming process.

Esophageal temperature monitoring is relatively noninvasive and tends to reliably and accurately reflect core temperature as long as the probe is placed far enough down (about 45 cm from the nose in an average adult) that it is not affected by proximity to the trachea.

Pulmonary artery catheters are considered the gold standard for core temperature monitoring, but they pose risks such as bloodstream infection and large-vessel damage. In practice, many patients admitted to the coronary intensive care unit after out-of-hospital cardiac arrest require pulmonary artery catheterization anyway for other indications, and in these situations it is the preferred method of monitoring the core temperature.

However, no approach is ideal in terms of measuring the temperature in the critical end organs. Rather, core temperature monitoring serves as a guide to help ensure consistent clinical practice in attaining and maintaining mild therapeutic hypothermia.

Preventing shivering

To achieve and maintain the goal temperature, the body’s natural response to a decrease in core temperature—shivering—must be watched for and eliminated. A number of drugs may be used for this purpose.⁴¹

Paralytic drugs are used to reduce shivering; nursing staff must be trained to monitor for signs of occult shivering (eg, jaw vibration) and adjust the dose of paralytic drug accordingly. Since the patients are paralyzed, they must also receive continuous intravenous sedation.

Other commonly used drugs that decrease the hypothalamic drive to shiver include buspirone (BuSpar), a serotonin 5HT-1A partial agonist, and meperidine (Demerol), an opiate agonist of kappa and mu receptors.

Rewarming after 24 hours

Rewarming is conventionally started after 24 hours of mild therapeutic hypothermia, at a rate no greater than 0.5°C (1°F) per hour.

Because sedation is used during the hypothermia period of 24 hours, a washout period for these medications is necessary, and the neurologic prognosis of cardiac arrest patients who undergo mild therapeutic hypothermia cannot be adequately assessed until 72 hours after rewarming.

ADVERSE EFFECTS OF MILD THERAPEUTIC HYPOTHERMIA

Some of these effects are predictable. Decreasing the body temperature causes potassium to shift into the cells, and this same potassium will leave the intracellular space during the rewarming phase. For this reason, aggressive potassium repletion for mild hypokalemia (potassium levels of 3.0–3.5 mmol/L) during mild therapeutic hypothermia can result in dangerous hyperkalemia during rewarming and should generally be avoided.

As another example, the enzymes involved in coagulation are less effective at lower temperatures. Thus, if it occurs, active bleeding requiring transfusion warrants consideration of stopping the hypothermia.

Adverse effects should be watched for (eg, by checking electrolyte levels frequently, monitoring blood glucose, continuous electroencephalographic monitoring during the cooling phase, and avoiding placement of intracardiac catheters once the goal temperature is reached) and addressed as they happen. However, in a recent review of this subject⁴² the balance of evidence continued to indicate that the benefit of this treatment exceeds its risks.

OUR PATIENT RECOVERS

After 24 hours of therapeutic hypothermia, our patient was gradually rewarmed to a normal temperature, and sedation and paralysis were discontinued.

Analysis of his prearrest and postarrest 12-lead electrocardiograms revealed a type I Brugada pattern (coved ST elevation and negative T waves in V₁, V₂, and V₃, caused by abnormal repolarization due to inherited mutations in SCN5A). Cardiac catheterization revealed normal coronary arteries, and MRI revealed no evidence of arrhythmogenic right ventricular cardiomyopathy or other structural abnormalities.

In the next 72 hours the patient was successfully extubated, and he gradually returned to full neurologic function. Before he went home a few days later, a single-lead cardioverter-defibrillator was implanted to prevent sudden cardiac death. All of his first-degree relatives were encouraged to undergo genetic screening for SCN5A mutations. The patient is currently back to his previous high level of functioning as a marketing manager, husband, and father of two young children.

A 20-year-old woman presented to her primary care clinic with a chief complaint of lower leg weakness and difficulty walking. The weakness she described had been worsening over the previous four days, with progressively worsening tingling and numbness of her toes bilaterally.

The day before the patient presented, she noticed numbness and paresthesia in both calves. At the time of her presentation to the clinic, she complained of low back ache, paresthesia of both hands, numbness bilaterally to her groin, difficulty sitting upright, ataxia, and a numb, thick-feeling tongue. She denied fever, neck stiffness, shortness of breath, headache, or visual changes.

The patient stated that 10 days earlier, she had developed an upper respiratory infection for which she was seen at the clinic and treated with a seven-day course of amoxicillin/clavulanate 875/125 mg twice daily. She said that she had recovered completely.

A review of the patient’s systems revealed proximal muscle weakness bilaterally (2/5) and loss of touch-pressure in the lower extremities. She was experiencing paresthesia of the hands and mild weakness bilaterally (4/5). She also walked with an ataxic gait and had reduced deep tendon reflexes in the lower limbs. All cranial nerves were intact, and her vital signs were stable.

The woman’s medical history was positive only for asthma. Her family history included ischemic stroke in the maternal grandfather and brain tumor in the paternal grandfather. Social history was positive for alcohol intake (ranging from four to 12 beers per week). The patient said she had never smoked or used illicit drugs. She was an unmarried college student, living in a dorm on campus. She participated in track at school.

The patient was admitted to the hospital telemetry step-down unit, and a neurology consultation was requested. Tests were ordered, among them MRI of the head and spine and comprehensive blood work, to rule out neurologic, infectious, or metabolic causes of the patient’s weakness; urinalysis was also obtained. These tests all yielded negative results.

A lumbar puncture performed the following day revealed a cerebrospinal fluid (CSF) protein level of 570 mg/L (normal range, 150 to 450 mg/L). Leukocytes numbered 2 cells/mm³ (normal count, 0 to 10 cells/mm³).

Based on the patient’s presentation, history, and symptoms, a neurologist made a diagnosis of Guillain-Barré syndrome. It was decided that no electromyographic (EMG) study was required to rule out other disease processes (eg, spinal cord disease, multiple sclerosis, tumors).

The patient underwent a five-dose course of immunomodulatory therapy with IV immunoglobulin (IVIG). In the step-down unit, she experienced one incident of sinus bradycardia (ie, resting heart rate between 40 and 50 beats/min). Her blood pressure remained stable, as did her respiratory status, according to peak expiratory flow measured frequently at her bedside.

Physical therapy was initiated, consisting of passive and active range of motion, crossovers with the patient’s feet, and stair training. This was done in response to a complaint of ankle weakness, and it helped to strengthen weakened muscles and improve alignment while the patient was bedridden and in a weakened, fatigued state. Additionally, the patient was given enoxaparin, wore antiembolic hose, and used sequential compression devices while in bed. As a result of these measures, she never experienced a pulmonary embolus or deep vein thrombosis (DVT) as a result of being immobilized.

By the seventh day of hospitalization, the patient had stable vital signs and improved lower limb strength, and numbness was resolving in her hands and lower extremities. She was discharged to home, with physical therapy to resume on an outpatient basis.

Discussion
Guillain-Barré syndrome (GBS), an acute immune-mediated paralytic disorder,¹ manifests in the form of weakness and diminished reflexes. Affecting the peripheral nerves, GBS is characterized by progressive symmetrical ascending weakness with varying degrees of sensory complaints.^2,3

GBS occurs worldwide, and incidence is estimated between 1.1 and 1.8 cases per 100,000 persons.⁴ In the United States, GBS can be found in all age-groups, with peak incidence noted in elderly persons and young adults.^5,6 Even with treatment, 3% to 10% of patients are reported to die of this illness, and 20% cannot walk six months after symptom onset.⁷ In one prospective population-based study of patients with confirmed GBS, 6% of patients died within 30 days of symptom onset, often as a result of respiratory complications.⁸

GBS is a postinfectious disorder, with cases developing several days or weeks after a viral or bacterial illness—most commonly, an upper respiratory infection or diarrhea (see Table 1^9-13). The most common trigger of GBS is infection with the bacterial microorganism Campylobacter jejuni (occurring in 15% to 40% of patients with GBS),^9,14 a pathogen that can produce demyelination-causing antibodies. Other responsible pathogens include cytomegalovirus and Epstein-Barr virus.⁹ In a process called molecular mimicry, the immune system is unable to distinguish the amino acid of an infectious organism from the proteinaceous content of the peripheral nerve.¹⁵ Subsequently, the immune system attacks and destroys the myelin sheath.

An example of this is the apparent cross-reaction of the ganglioside GM1 with C jejuni lipopolysaccharide antigens.^14,15 The resulting effect is immunologic damage to the peripheral nervous system. The flaccid paralysis that occurs in patients with GBS is thought to be caused by lymphocytic infiltration and complement activation of the spinal roots and peripheral nerves, where macrophages strip the myelin.^5,15,16

Stages and Variants
Three stages characterize the course of GBS. The acute phase, which lasts one to four weeks, begins with onset of symptoms and persists until the associated neurologic deterioration has ceased. During the second phase, the plateau period, symptoms persist with no further deterioration; this stage can last several days to several weeks or months. The final phase, the recovery period, can last from four months to two years after symptom onset.^15,17,18

The clinical course of GBS is highly variable and in many cases difficult to predict. Certain factors have been associated with a poor outcome: advancing age, previous presence of diarrhea, need for mechanical ventilation, an extended plateau phase, and a lower patient score on the Erasmus GBS Outcome Scale,¹⁹ when measured two weeks after GBS onset.^8,20 This score can help predict the patient’s chance of independent walking after six months.^15,19

Although the classic presenting symptom of GBS is symmetric ascending weakness, several disease variants have been identified, with differing symptoms and degrees of recovery. These variants also differ in terms of the muscle groups affected; in some, visual defects may be present at onset. GBS variants include²¹:

• Acute motor axonal neuropathy (AMAN)^1,22

• Acute inflammatory demyelinating polyneuropathy (AIDP)¹

• Pharyngeal-cervical-brachial variant²³

• Purely sensory variant24

• Miller-Fisher syndrome, which manifests with ophthalmoplegia, in addition to ataxia and areflexia²⁵

• Axonal form.^5,21

AMAN and AIDP are the most common subtypes of GBS.¹

Symptoms, Signs, and Disease Manifestations
Limb weakness, the classic presenting symptom of GBS, is both symmetrical and ascending. Weakness can develop acutely and progress over days to weeks.^2,15 Hughes and Cornblath²⁶ also note pain, numbness, and paresthesias among the initial symptoms of GBS. Others include sensory changes, cranial nerve involvement, various autonomic changes, and respiratory or oropharyngeal weakness. Reflexes, particularly the tendon reflexes, may be diminished or absent.^15,18,21 In many cases, sensory changes (ie, pain) may precede the onset of weakness, often making diagnosis difficult.¹⁵

Cranial nerves most commonly affected are V, VI, VII, X, XI, and  XII, with manifestations that include dysphagia, dysarthria, diplopia, limitation to eye movements, and facial droop and weakness. Usually facial and oropharyngeal weakness occur after the extremities and trunk are affected. Blindness may occur if demyelination of the optic nerve occurs; this is seen in Miller-Fisher syndrome.^10,15,25,27

In GBS, many patients report pain, which can present as bilateral sciatica or as throbbing or aching in the large muscles of the upper legs, flanks, or back.28 This pain, which results from the demyelination of the sensory nerve fibers, can be severe.10

Patients with GBS may experience manifestations of autonomic nervous system dysfunction—for example, arrhythmias, hypotension or hypertension, urinary retention, cardiomyopathy, and paralytic ileus.^10,20 Dysautonomia often impedes patients’ progress in inpatient rehabilitation. Patients may have persistent problems involving postural hypotension, hypertension, excessive sympathetic outflow, or bladder and bowel dysfunction.²⁹

Blood pressure fluctuations, often attributed to changes in catecholamine levels and disturbances in the baroreceptor reflex pathway, are common and are considered characteristic of GBS. Transient or persistent hypotension is caused by the dysregulation of the parasympathetic and sympathetic systems, with subsequent alterations in venomotor tone.³ Additionally, an increased sensitivity to catecholamine can lead to cardiovascular disturbances, resulting in denervation hypersensitivity and impairment of the carotid sinus reflex.

Arrhythmias occur in perhaps half of patients with GBS. The most common is sustained sinus tachycardia, which usually requires no treatment. Bradycardia leading to atrioventricular blocks and asystole is believed to result from afferent baroreceptor reflex failure. Treatment may be required—either administration of atropine or insertion of a pacemaker, depending on the severity of the arrhythmia.^3,10

Myocardial involvement can range from asymptomatic mycocarditis to neurogenic stunned myocardium and heart failure. Patients with ECG abnormalities should undergo two-dimensional echocardiographic studies and other testing to explore cardiac involvement. Acute coronary syndromes, including ST-segment elevation MI, have been reported, in some cases associated with IVIG treatment. In one patient, coronary spasm was reported, with clean coronary arteries found on cardiac catheterization.³

Patients with GBS are at risk for compromised neuromuscular respiratory function; demyelination of the nerves that innervate the intercostal muscles and the diaphragm can result in respiratory failure. Key clinical indicators of respiratory muscle fatigue include tachypnea, diaphoresis, and asynchronous movements of the abdomen and chest;¹⁰ other symptoms relevant to respiratory or oropharyngeal weakness include slurred speech, dyspnea (with or without exertion), difficulty swallowing, and inability to cough.^2,10 Serial respiratory function testing is advisable to detect patients at risk for respiratory failure.³⁰

Diagnosis
Guillain-Barré is a syndrome diagnosed by a collection of symptoms (see Table 2^2,21,31), including subacute developing paralysis, symmetrical bilateral weakness beginning at onset, and diminishing to absent reflexes.^21,31 Other causes for rapidly developing weaknesses should be ruled out (see Table 3^10,21,26,31). Lumbar puncture typically shows increased protein levels with a normal white cell count; however, neither this test nor electrophysiologic evaluation offers significant value for diagnosis of GBS.^21,26,31

During the acute phase of GBS (within three weeks of onset), there is found an elevation of CSF protein (> 550 mg/L) without an elevation in white blood cells. This phenomenon, called albuminocytologic dissociation, reflects inflammation of the nerve roots and is considered the hallmark of GBS.²

MRI can also facilitate the diagnosis of GBS; it demonstrates anterior and posterior intrathecal spinal nerve roots and cauda equina.³² In patients with GBS, evidence supporting breakdown of the blood–nerve barrier can be seen in abnormal gadolinium enhancement of the intrathecal nerve roots on MRI.³³

When electrophysiologic studies are performed, they typically reveal slowing nerve conduction, prolonged distal latencies, and partial motor conduction block.³⁴ The characteristic finding of early demyelination is conduction block, a reduction in the amplitude of the muscle action potential after stimulation of the distal, as opposed to the proximal, nerve.²⁸ Nerve conduction studies may help in the diagnosis and classification of GBS—and, to a limited extent, formulation of a prognosis. Such alternative diagnoses as myositis and myasthenia gravis may be excluded by neurophysiology.²⁶ Early in GBS, neurophysiologic abnormalities may be very mild or occasionally normal; test results may not correlate with clinical disability.^35,36

The clinician cannot depend on clinical features alone to predict respiratory decline.³¹ Frequent evaluations of respiratory effort, by measurement of maximal inspiratory pressures and vital capacity, should be performed at the bedside to monitor diaphragmatic strength. Respiratory ventilation should be initiated if the patient becomes hypoxic or experiences a rapid decline in vital capacity (ie, below 60% of predicted value).¹⁰ Mechanical ventilation is more likely to be required in patients with a negative inspiratory force of less than 30 cm H2O.³¹

Treatment
Guillain-Barré syndrome has an acute onset and progression. Patients quickly become nonambulatory and may require total ventilation due to paralysis. Therapeutic options are IVIG or plasmapheresis (plasma exchange).^37-40 Corticosteroids do not appear to benefit patients with GBS.^41,42

Several mechanisms appear to contribute to the effectiveness of immunoglobulin.^38,39 Infused IVIG interferes with antigen presentation, inhibits antibody production, neutralizes pathologic autoantibodies, and modulates other immunologic events involved in the pathogenesis of autoimmune neuromuscular diseases, including GBS.⁴³ Adverse reactions, which are usually minor, include headache, fever, chills, myalgia, and malaise. In rare instances, anaphylaxis or renal failure may occur.^15,44

In plasmapheresis, blood is removed from the body and dialyzed, with circulating antibodies and immunoglobulins removed from the plasma; fresh frozen plasma, albumin, or saline is administered. This treatment, performed via central venous catheter, should be initiated as soon as possible after onset of symptoms but can be implemented as late as 30 days after GBS onset. Plasmapheresis requires personnel trained in dialysis, which may not be performed in all hospitals. Possible adverse events include infection and hemorrhage. Laboratory values must be monitored for hypokalemia and hypocalcemia.^45,46

Supportive Care
Patients with GBS require intensive care and very close monitoring for complications of respiratory difficulty and autonomic dysfunction. Individualized programs should be initiated for patients in the acute phase of GBS, aimed at the prevention of contractures and skin breakdown.¹⁰ Exercise programs, as conducted with the case patient, should also help relieve the fatigue syndromes that accompany GBS.

Immobilization associated with bed rest incurs a risk for pulmonary emboli and DVT; this has been found true during the first 12 weeks after symptom onset in patients with GBS who remain immobile.⁴⁷ The use of antiembolic hose and sequential compression devices can help reduce the risk for thrombotic events.¹⁰ Use of enoxaparin or heparin is recommended for nonambulating patients until they are able to walk, with Gaber et al⁴⁷ specifying the use of low-molecular-weight heparin to reduce, but not eliminate, the risk for DVT.

The pain associated with GBS can be severe. Narcotic analgesics may be administered with careful monitoring of autonomic denervation. Long-term management of neuropathic pain may require adjuvant therapy, such as tricyclic antidepressants, gabapentin, or tramadol hydrochloride.¹⁰ According to Pandey et al,⁴⁸ gabapentin alone may suffice for pain control in GBS, with minimal adverse effects. In certain rehabilitation facilities, tricyclic antidepressants, capsaicin, and transcutaneous nerve stimulation have been reported effective; during the early stages of treatment, until these treatments reach their full effect, pain medications such as tramadol or narcotics can provide temporary relief.²⁹

More than one-half of patients with GBS in the acute phase can develop ileus. Constipation can also occur as a result of pain medication use, prolonged bed rest, and poor intake. Auscultation of bowel sounds and abdominal assessment should be performed daily to monitor for ileus. Hughes et al¹⁰ do not recommend the use of promotility drugs in patients with dysautonomia.

After hospital discharge, easy fatigability can affect work and social activities. With continued physical therapy, occupational therapy, and monitoring, however, patients with GBS can expect to return to an optimal level of functioning. Speed of recovery varies with these patients from a few months to several years, depending on such factors as age and the extent to which axonal degeneration has occurred.^6,49

The Case Patient
For several weeks after discharge, the case patient continued to experience fatigue, low back pain, and general muscle pain. With her family’s support, she continued to receive outpatient physical therapy, and within one month she had regained her ankle strength. She was soon able to resume her classes, despite some lingering fatigue.

Conclusion
Guillain-Barré syndrome is a potentially life-threatening disease whose symptoms health care providers need to recognize quickly to provide prompt treatment. Supportive care for both patient and family is of key importance for maximum rehabilitation and return to the previous lifestyle. The clinical course of GBS is highly variable and difficult to predict. The patient’s outcome depends on several factors, including age and severity of illness. GBS patients can experience long-term psychosocial effects.

References
1. Magira EE, Papaioakim M, Nachamkin I, et al. Differential distribution of HLA-DQ beta/DR beta epitopes in the two forms of Guillain-Barré syndrome, acute motor axonal neuropathy and acute inflammatory demyelinating polyneuropathy (AIDP): identification of DQ beta epitopes associated with susceptibility to and protection from AIDP. J Immunol. 2003;170(6):3074-3080.

2. Tremblay ME, Closon A, D’Anjou G, Bussières JF. Guillain-Barré syndrome following H1N1 immunization in a pediatric patient. Ann Pharmacother. 2010;44(7-8):1330-1333.

3. Mukerji S, Aloka F, Farooq MU, et al. Cardiovascular complications of the Guillain-Barré syndrome. Am J Cardiol. 2009;104(10):1452-1455.

4. McGrogan A, Madle GC, Seaman HE, de Vries CS. The epidemiology of Guillain-Barré syndrome worldwide: a systematic literature review. Neuroepidemiology. 2009;32(2):150-163.

5. Haber P, Sejvar J, Mikaeloff Y, DeStefano F. Vaccines and Guillain-Barré syndrome. Drug Saf. 2009; 32(4):309-323.

6. van Doorn PA. What’s new in Guillain-Barré syndrome in 2007-2008? J Periph Nerv Syst. 2009;14(2):72-74.

7. van Doorn PA, Ruts L, Jacobs BC. Clinical features, pathogenesis, and treatment of Guillain-Barré syndrome. Lancet Neurol. 2008;7(10):939-950.

8. Chiò A, Cocito D, Leone M, et al; Piemonte and alle d’Aosta Register for Guillain-Barré Syndrome. Guillain-Barré syndrome: a prospective, population-based incidence and outcome survey. Neurology. 2003; 60(7):1146-1150.

9. Hadden RD, Karch H, Hartung HP, et al. Preceding infections, immune factors, and outcome in Guillain-Barré syndrome. Neurology. 2001;56(6):758-765.

10. Hughes RA, Wijdicks EF, Benson E, et al. Supportive care for patients with Guillain-Barré syndrome. Arch Neurol. 2005;62(8):1194-1198.

11. Aluka KJ, Turner PL, Fullum TM. Guillain-Barré syndrome and postbariatric surgery polyneuropathies. JSLS. 2009;13(2):250-253.

12. Brannagan TH 3rd, Zhou Y. HIV-associated Guillain-Barré syndrome. J Neurol Sci. 2003;208(1-2):39-42.

13. Lin WC, Lee PI, Lu CY, et al. Mycoplasma pneumoniae encephalitis in childhood. J Microbiol Immunol Infect. 2002;35(3):173-178.

14. Sivadon-Tardy V, Orlikowski D, Porcher R, et al. Detection of Campylobacter jejuni by culture and real-time PCR in a French cohort of patients with Guillain-Barre syndrome. J Clin Microbiol. 2010;48 (6):2278-2281.

15. van Doorn PA, Kuitwaard K, Walgaard C, et al. IVIG treatment and prognosis in Guillain-Barré syndrome. J Clin Immunol. 2010;30 suppl 1:S74-S78.

16. Kaida K, Kusunoki S. Guillan-Barré syndrome: update on immunobiology and treatment. Expert Rev Neurother. 2009;9(9):1307-1319.

17. Forsberg A, Press R, Einarsson U, et al. Disability and health-related quality of life in Guillain-Barré syndrome during the first two years after onset: a prospective study. Clin Rehabil. 2005;19(8):900-909.

18. Criteria for diagnosis of Guillain-Barré syndrome. Ann Neurol. 1978;3(6):565-566.

19. van Koningsveld R, Steyerberg EW, Hughes RA, et al. A clinical progostic scoring system for Guillain-Barré syndrome. Lancet Neurol. 2007;6(7):589-594.

20. Koeppen S, Kraywinkel K, Wessendorf TE, et al. Long-term outcome of Guillain-Barré syndrome. Neuro­crit Care. 2006;5(3)235-242.

21. Sheridan JM, Smith D. Atypical Guillain-Barré in the emergency department. West J Emerg Med. 2010;11(1):80-82.

22. Ogawara K, Kuwabara S, Koga M, et al. Anti-GM1b IgG antibody is associated with acute motor axonal neuropathy and Campylobacter jejuni infection. J Neurol Sci. 2003;210(1-2):41-45.

23. Nagashima T, Koga M, Odaka M, et al. Continuous spectrum of pharyngeal-cervical-brachial variant of Guillain-Barré syndrome. Arch Neurol. 2007;64(10):1519-1523.

24. Oh SJ, LaGanke C, Claussen GC. Sensory Guillain-Barré syndrome. Neurology. 2001;56(1):82-86.

25. Aráranyi Z, Kovács T, Sipos I, Bereczki D. Miller Fisher syndrome: brief overview and update with a focus on electrophysiological findings. Eur J Neurol. 2011 Jun 1. [Epub ahead of print]

26. Hughes RA, Cornblath, DR. Guillain-Barré syndrome. Lancet. 2005;366(9497):1653-1666.

27. Snyder LA, Rismondo V, Miller NR. The Fisher variant of Guillain-Barré syndrome (Fisher syndrome). J Neuroophthalmol. 2009;29(4):312-324.

28. Ropper AH. The Guillain-Barré syndrome. N Engl J Med.1992;326(17):1130-1136.

29. Meythaler JM. Rehabilitation of Guillain-Barré syndrome. Arch Phys Med Rehabil.1997;78(8):872-879.

30. Sharshar T, Chevret S, Bourdain F, et al; French Cooperative Group on Plasma Exchange in Guillain-Barré syndrome. Early predictors of mechanical ventilation in Guillain-Barré syndrome. Crit Care Med. 2003; 31(1):278-283.

31. McGillicuddy DC, Walker O, Shapiro NI, et al. Guillain-Barré syndrome in the emergency department. Ann Emerg Med. 2006;47(4):390-393.

32. Yikilmaz A, Doganay S, Gumus H, et al. Magnetic resonance imaging of childhood Guillain-Barré syndrome. Childs Nerv Syst. 2010;26(8):1103-1108.

33. Gonzalez-Quevedo A, Carriera RF, O’Farrill ZL, et al. An appraisal of blood-cerebrospinal fluid barrier dysfunction during the course of Guillain-Barré syndrome. Neurol India. 2009;57(3):288-294.

34. Abai S, Kim SB, Kim JP, Lim YJ. Guillan-Barré syndrome combined with acute cervical myelopathy. J Korean Neurosurg Soc. 2010;48(3):298-300.

35. Uncini A, Yuki N. Electrophysiologic and immunopathologic correlates in Guillain-Barré syndrome subtypes. Expert Rev Neurother. 2009;9(6):869-884.

36. Hadden RD, Hughes RA. Management of inflammatory neuropathies. J Neurol Neurosurg Psychiatry. 2003;74 suppl 2:ii9-ii14.

37. Raphaël JC, Chevret S, Hughes RA, Annane D. Plasma exchange for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2002;(2):CD001798.

38. Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2010 Jun 16; (6):CD002063.

39. Human immunoglobulin and the Guillain-Barré syndrome: new indication. An alternative to plasmapheresis. Prescrire Int. 2000;9(49):142-143.

40. van der Meché FG, Schmitz PI; Dutch Guillain-Barré Study Group. A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barré syndrome. N Engl J Med. 1992;327(17):1123-1129.

41. Hughes RA, Swan AV, van Doorn PA. Corticosteroids for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2010 Feb 16;(2):CD001446.

42. Hahn AF. Guillain-Barré syndrome. Lancet. 1998; 352(9128):635-641.

43. Dalakas MC. Intravenous immunoglobulin in autoimmune neuromuscular diseases. JAMA. 2004;291(19):2367-2375.

44. Kuitwaard K, de Gelder J, Tio-Gillen AP, et al. Pharmacokenetics of intravenous immunoglobulin and outcome in Guillain-Barré syndrome. Ann Neurol. 2009;66(5):597-603.

45. Atkinson SB, Carr RL, Maybee P, Haynes D. The challenges of managing and treating Guillain-Barré syndrome during the acute phase. Dimens Crit Care Nurs. 2006;25(6):256-263.

46. van Doorn PA. Treatment of Guillain-Barré syndrome and CIDP. J Periph Nerv Syst. 2005;10(2):113-127.

47. Gaber TA, Kirker SGB, Jenner JR. Current practice of prophylactic anticoagulation in Guillain-Barré syndrome. Clin Rehabil. 2002;16(2):190-193.

48. Pandey CK, Bose N, Garg G, et al. Gabapentin for the treatment of pain in Guillain-Barré syndrome: a double-blinded, placebo-controlled, crossover study. Anesth Analg. 2002;95(6):1719-1723.

49. de Vries JM, Hagemans ML, Bussmann JB, et al. Fatigue in neuromuscular disorders: focus on Guillain-Barré syndrome and Pompe disease. Cell Mol Life Sci. 2010;67(5):701-713.

A 20-year-old woman presented to her primary care clinic with a chief complaint of lower leg weakness and difficulty walking. The weakness she described had been worsening over the previous four days, with progressively worsening tingling and numbness of her toes bilaterally.

The day before the patient presented, she noticed numbness and paresthesia in both calves. At the time of her presentation to the clinic, she complained of low back ache, paresthesia of both hands, numbness bilaterally to her groin, difficulty sitting upright, ataxia, and a numb, thick-feeling tongue. She denied fever, neck stiffness, shortness of breath, headache, or visual changes.

The patient stated that 10 days earlier, she had developed an upper respiratory infection for which she was seen at the clinic and treated with a seven-day course of amoxicillin/clavulanate 875/125 mg twice daily. She said that she had recovered completely.

A review of the patient’s systems revealed proximal muscle weakness bilaterally (2/5) and loss of touch-pressure in the lower extremities. She was experiencing paresthesia of the hands and mild weakness bilaterally (4/5). She also walked with an ataxic gait and had reduced deep tendon reflexes in the lower limbs. All cranial nerves were intact, and her vital signs were stable.

The woman’s medical history was positive only for asthma. Her family history included ischemic stroke in the maternal grandfather and brain tumor in the paternal grandfather. Social history was positive for alcohol intake (ranging from four to 12 beers per week). The patient said she had never smoked or used illicit drugs. She was an unmarried college student, living in a dorm on campus. She participated in track at school.

The patient was admitted to the hospital telemetry step-down unit, and a neurology consultation was requested. Tests were ordered, among them MRI of the head and spine and comprehensive blood work, to rule out neurologic, infectious, or metabolic causes of the patient’s weakness; urinalysis was also obtained. These tests all yielded negative results.

A lumbar puncture performed the following day revealed a cerebrospinal fluid (CSF) protein level of 570 mg/L (normal range, 150 to 450 mg/L). Leukocytes numbered 2 cells/mm³ (normal count, 0 to 10 cells/mm³).

Based on the patient’s presentation, history, and symptoms, a neurologist made a diagnosis of Guillain-Barré syndrome. It was decided that no electromyographic (EMG) study was required to rule out other disease processes (eg, spinal cord disease, multiple sclerosis, tumors).

The patient underwent a five-dose course of immunomodulatory therapy with IV immunoglobulin (IVIG). In the step-down unit, she experienced one incident of sinus bradycardia (ie, resting heart rate between 40 and 50 beats/min). Her blood pressure remained stable, as did her respiratory status, according to peak expiratory flow measured frequently at her bedside.

Physical therapy was initiated, consisting of passive and active range of motion, crossovers with the patient’s feet, and stair training. This was done in response to a complaint of ankle weakness, and it helped to strengthen weakened muscles and improve alignment while the patient was bedridden and in a weakened, fatigued state. Additionally, the patient was given enoxaparin, wore antiembolic hose, and used sequential compression devices while in bed. As a result of these measures, she never experienced a pulmonary embolus or deep vein thrombosis (DVT) as a result of being immobilized.

By the seventh day of hospitalization, the patient had stable vital signs and improved lower limb strength, and numbness was resolving in her hands and lower extremities. She was discharged to home, with physical therapy to resume on an outpatient basis.

Discussion
Guillain-Barré syndrome (GBS), an acute immune-mediated paralytic disorder,¹ manifests in the form of weakness and diminished reflexes. Affecting the peripheral nerves, GBS is characterized by progressive symmetrical ascending weakness with varying degrees of sensory complaints.^2,3

GBS occurs worldwide, and incidence is estimated between 1.1 and 1.8 cases per 100,000 persons.⁴ In the United States, GBS can be found in all age-groups, with peak incidence noted in elderly persons and young adults.^5,6 Even with treatment, 3% to 10% of patients are reported to die of this illness, and 20% cannot walk six months after symptom onset.⁷ In one prospective population-based study of patients with confirmed GBS, 6% of patients died within 30 days of symptom onset, often as a result of respiratory complications.⁸

GBS is a postinfectious disorder, with cases developing several days or weeks after a viral or bacterial illness—most commonly, an upper respiratory infection or diarrhea (see Table 1^9-13). The most common trigger of GBS is infection with the bacterial microorganism Campylobacter jejuni (occurring in 15% to 40% of patients with GBS),^9,14 a pathogen that can produce demyelination-causing antibodies. Other responsible pathogens include cytomegalovirus and Epstein-Barr virus.⁹ In a process called molecular mimicry, the immune system is unable to distinguish the amino acid of an infectious organism from the proteinaceous content of the peripheral nerve.¹⁵ Subsequently, the immune system attacks and destroys the myelin sheath.

An example of this is the apparent cross-reaction of the ganglioside GM1 with C jejuni lipopolysaccharide antigens.^14,15 The resulting effect is immunologic damage to the peripheral nervous system. The flaccid paralysis that occurs in patients with GBS is thought to be caused by lymphocytic infiltration and complement activation of the spinal roots and peripheral nerves, where macrophages strip the myelin.^5,15,16

Stages and Variants
Three stages characterize the course of GBS. The acute phase, which lasts one to four weeks, begins with onset of symptoms and persists until the associated neurologic deterioration has ceased. During the second phase, the plateau period, symptoms persist with no further deterioration; this stage can last several days to several weeks or months. The final phase, the recovery period, can last from four months to two years after symptom onset.^15,17,18

The clinical course of GBS is highly variable and in many cases difficult to predict. Certain factors have been associated with a poor outcome: advancing age, previous presence of diarrhea, need for mechanical ventilation, an extended plateau phase, and a lower patient score on the Erasmus GBS Outcome Scale,¹⁹ when measured two weeks after GBS onset.^8,20 This score can help predict the patient’s chance of independent walking after six months.^15,19

Although the classic presenting symptom of GBS is symmetric ascending weakness, several disease variants have been identified, with differing symptoms and degrees of recovery. These variants also differ in terms of the muscle groups affected; in some, visual defects may be present at onset. GBS variants include²¹:

• Acute motor axonal neuropathy (AMAN)^1,22

• Acute inflammatory demyelinating polyneuropathy (AIDP)¹

• Pharyngeal-cervical-brachial variant²³

• Purely sensory variant24

• Miller-Fisher syndrome, which manifests with ophthalmoplegia, in addition to ataxia and areflexia²⁵

• Axonal form.^5,21

AMAN and AIDP are the most common subtypes of GBS.¹

Symptoms, Signs, and Disease Manifestations
Limb weakness, the classic presenting symptom of GBS, is both symmetrical and ascending. Weakness can develop acutely and progress over days to weeks.^2,15 Hughes and Cornblath²⁶ also note pain, numbness, and paresthesias among the initial symptoms of GBS. Others include sensory changes, cranial nerve involvement, various autonomic changes, and respiratory or oropharyngeal weakness. Reflexes, particularly the tendon reflexes, may be diminished or absent.^15,18,21 In many cases, sensory changes (ie, pain) may precede the onset of weakness, often making diagnosis difficult.¹⁵

Cranial nerves most commonly affected are V, VI, VII, X, XI, and  XII, with manifestations that include dysphagia, dysarthria, diplopia, limitation to eye movements, and facial droop and weakness. Usually facial and oropharyngeal weakness occur after the extremities and trunk are affected. Blindness may occur if demyelination of the optic nerve occurs; this is seen in Miller-Fisher syndrome.^10,15,25,27

In GBS, many patients report pain, which can present as bilateral sciatica or as throbbing or aching in the large muscles of the upper legs, flanks, or back.28 This pain, which results from the demyelination of the sensory nerve fibers, can be severe.10

Patients with GBS may experience manifestations of autonomic nervous system dysfunction—for example, arrhythmias, hypotension or hypertension, urinary retention, cardiomyopathy, and paralytic ileus.^10,20 Dysautonomia often impedes patients’ progress in inpatient rehabilitation. Patients may have persistent problems involving postural hypotension, hypertension, excessive sympathetic outflow, or bladder and bowel dysfunction.²⁹

Blood pressure fluctuations, often attributed to changes in catecholamine levels and disturbances in the baroreceptor reflex pathway, are common and are considered characteristic of GBS. Transient or persistent hypotension is caused by the dysregulation of the parasympathetic and sympathetic systems, with subsequent alterations in venomotor tone.³ Additionally, an increased sensitivity to catecholamine can lead to cardiovascular disturbances, resulting in denervation hypersensitivity and impairment of the carotid sinus reflex.

Arrhythmias occur in perhaps half of patients with GBS. The most common is sustained sinus tachycardia, which usually requires no treatment. Bradycardia leading to atrioventricular blocks and asystole is believed to result from afferent baroreceptor reflex failure. Treatment may be required—either administration of atropine or insertion of a pacemaker, depending on the severity of the arrhythmia.^3,10

Myocardial involvement can range from asymptomatic mycocarditis to neurogenic stunned myocardium and heart failure. Patients with ECG abnormalities should undergo two-dimensional echocardiographic studies and other testing to explore cardiac involvement. Acute coronary syndromes, including ST-segment elevation MI, have been reported, in some cases associated with IVIG treatment. In one patient, coronary spasm was reported, with clean coronary arteries found on cardiac catheterization.³

Patients with GBS are at risk for compromised neuromuscular respiratory function; demyelination of the nerves that innervate the intercostal muscles and the diaphragm can result in respiratory failure. Key clinical indicators of respiratory muscle fatigue include tachypnea, diaphoresis, and asynchronous movements of the abdomen and chest;¹⁰ other symptoms relevant to respiratory or oropharyngeal weakness include slurred speech, dyspnea (with or without exertion), difficulty swallowing, and inability to cough.^2,10 Serial respiratory function testing is advisable to detect patients at risk for respiratory failure.³⁰

Diagnosis
Guillain-Barré is a syndrome diagnosed by a collection of symptoms (see Table 2^2,21,31), including subacute developing paralysis, symmetrical bilateral weakness beginning at onset, and diminishing to absent reflexes.^21,31 Other causes for rapidly developing weaknesses should be ruled out (see Table 3^10,21,26,31). Lumbar puncture typically shows increased protein levels with a normal white cell count; however, neither this test nor electrophysiologic evaluation offers significant value for diagnosis of GBS.^21,26,31

During the acute phase of GBS (within three weeks of onset), there is found an elevation of CSF protein (> 550 mg/L) without an elevation in white blood cells. This phenomenon, called albuminocytologic dissociation, reflects inflammation of the nerve roots and is considered the hallmark of GBS.²

MRI can also facilitate the diagnosis of GBS; it demonstrates anterior and posterior intrathecal spinal nerve roots and cauda equina.³² In patients with GBS, evidence supporting breakdown of the blood–nerve barrier can be seen in abnormal gadolinium enhancement of the intrathecal nerve roots on MRI.³³

When electrophysiologic studies are performed, they typically reveal slowing nerve conduction, prolonged distal latencies, and partial motor conduction block.³⁴ The characteristic finding of early demyelination is conduction block, a reduction in the amplitude of the muscle action potential after stimulation of the distal, as opposed to the proximal, nerve.²⁸ Nerve conduction studies may help in the diagnosis and classification of GBS—and, to a limited extent, formulation of a prognosis. Such alternative diagnoses as myositis and myasthenia gravis may be excluded by neurophysiology.²⁶ Early in GBS, neurophysiologic abnormalities may be very mild or occasionally normal; test results may not correlate with clinical disability.^35,36

The clinician cannot depend on clinical features alone to predict respiratory decline.³¹ Frequent evaluations of respiratory effort, by measurement of maximal inspiratory pressures and vital capacity, should be performed at the bedside to monitor diaphragmatic strength. Respiratory ventilation should be initiated if the patient becomes hypoxic or experiences a rapid decline in vital capacity (ie, below 60% of predicted value).¹⁰ Mechanical ventilation is more likely to be required in patients with a negative inspiratory force of less than 30 cm H2O.³¹

Treatment
Guillain-Barré syndrome has an acute onset and progression. Patients quickly become nonambulatory and may require total ventilation due to paralysis. Therapeutic options are IVIG or plasmapheresis (plasma exchange).^37-40 Corticosteroids do not appear to benefit patients with GBS.^41,42

Several mechanisms appear to contribute to the effectiveness of immunoglobulin.^38,39 Infused IVIG interferes with antigen presentation, inhibits antibody production, neutralizes pathologic autoantibodies, and modulates other immunologic events involved in the pathogenesis of autoimmune neuromuscular diseases, including GBS.⁴³ Adverse reactions, which are usually minor, include headache, fever, chills, myalgia, and malaise. In rare instances, anaphylaxis or renal failure may occur.^15,44

In plasmapheresis, blood is removed from the body and dialyzed, with circulating antibodies and immunoglobulins removed from the plasma; fresh frozen plasma, albumin, or saline is administered. This treatment, performed via central venous catheter, should be initiated as soon as possible after onset of symptoms but can be implemented as late as 30 days after GBS onset. Plasmapheresis requires personnel trained in dialysis, which may not be performed in all hospitals. Possible adverse events include infection and hemorrhage. Laboratory values must be monitored for hypokalemia and hypocalcemia.^45,46

Supportive Care
Patients with GBS require intensive care and very close monitoring for complications of respiratory difficulty and autonomic dysfunction. Individualized programs should be initiated for patients in the acute phase of GBS, aimed at the prevention of contractures and skin breakdown.¹⁰ Exercise programs, as conducted with the case patient, should also help relieve the fatigue syndromes that accompany GBS.

Immobilization associated with bed rest incurs a risk for pulmonary emboli and DVT; this has been found true during the first 12 weeks after symptom onset in patients with GBS who remain immobile.⁴⁷ The use of antiembolic hose and sequential compression devices can help reduce the risk for thrombotic events.¹⁰ Use of enoxaparin or heparin is recommended for nonambulating patients until they are able to walk, with Gaber et al⁴⁷ specifying the use of low-molecular-weight heparin to reduce, but not eliminate, the risk for DVT.

The pain associated with GBS can be severe. Narcotic analgesics may be administered with careful monitoring of autonomic denervation. Long-term management of neuropathic pain may require adjuvant therapy, such as tricyclic antidepressants, gabapentin, or tramadol hydrochloride.¹⁰ According to Pandey et al,⁴⁸ gabapentin alone may suffice for pain control in GBS, with minimal adverse effects. In certain rehabilitation facilities, tricyclic antidepressants, capsaicin, and transcutaneous nerve stimulation have been reported effective; during the early stages of treatment, until these treatments reach their full effect, pain medications such as tramadol or narcotics can provide temporary relief.²⁹

More than one-half of patients with GBS in the acute phase can develop ileus. Constipation can also occur as a result of pain medication use, prolonged bed rest, and poor intake. Auscultation of bowel sounds and abdominal assessment should be performed daily to monitor for ileus. Hughes et al¹⁰ do not recommend the use of promotility drugs in patients with dysautonomia.

After hospital discharge, easy fatigability can affect work and social activities. With continued physical therapy, occupational therapy, and monitoring, however, patients with GBS can expect to return to an optimal level of functioning. Speed of recovery varies with these patients from a few months to several years, depending on such factors as age and the extent to which axonal degeneration has occurred.^6,49

The Case Patient
For several weeks after discharge, the case patient continued to experience fatigue, low back pain, and general muscle pain. With her family’s support, she continued to receive outpatient physical therapy, and within one month she had regained her ankle strength. She was soon able to resume her classes, despite some lingering fatigue.

Conclusion
Guillain-Barré syndrome is a potentially life-threatening disease whose symptoms health care providers need to recognize quickly to provide prompt treatment. Supportive care for both patient and family is of key importance for maximum rehabilitation and return to the previous lifestyle. The clinical course of GBS is highly variable and difficult to predict. The patient’s outcome depends on several factors, including age and severity of illness. GBS patients can experience long-term psychosocial effects.

References
1. Magira EE, Papaioakim M, Nachamkin I, et al. Differential distribution of HLA-DQ beta/DR beta epitopes in the two forms of Guillain-Barré syndrome, acute motor axonal neuropathy and acute inflammatory demyelinating polyneuropathy (AIDP): identification of DQ beta epitopes associated with susceptibility to and protection from AIDP. J Immunol. 2003;170(6):3074-3080.

2. Tremblay ME, Closon A, D’Anjou G, Bussières JF. Guillain-Barré syndrome following H1N1 immunization in a pediatric patient. Ann Pharmacother. 2010;44(7-8):1330-1333.

3. Mukerji S, Aloka F, Farooq MU, et al. Cardiovascular complications of the Guillain-Barré syndrome. Am J Cardiol. 2009;104(10):1452-1455.

4. McGrogan A, Madle GC, Seaman HE, de Vries CS. The epidemiology of Guillain-Barré syndrome worldwide: a systematic literature review. Neuroepidemiology. 2009;32(2):150-163.

5. Haber P, Sejvar J, Mikaeloff Y, DeStefano F. Vaccines and Guillain-Barré syndrome. Drug Saf. 2009; 32(4):309-323.

6. van Doorn PA. What’s new in Guillain-Barré syndrome in 2007-2008? J Periph Nerv Syst. 2009;14(2):72-74.

7. van Doorn PA, Ruts L, Jacobs BC. Clinical features, pathogenesis, and treatment of Guillain-Barré syndrome. Lancet Neurol. 2008;7(10):939-950.

8. Chiò A, Cocito D, Leone M, et al; Piemonte and alle d’Aosta Register for Guillain-Barré Syndrome. Guillain-Barré syndrome: a prospective, population-based incidence and outcome survey. Neurology. 2003; 60(7):1146-1150.

9. Hadden RD, Karch H, Hartung HP, et al. Preceding infections, immune factors, and outcome in Guillain-Barré syndrome. Neurology. 2001;56(6):758-765.

10. Hughes RA, Wijdicks EF, Benson E, et al. Supportive care for patients with Guillain-Barré syndrome. Arch Neurol. 2005;62(8):1194-1198.

11. Aluka KJ, Turner PL, Fullum TM. Guillain-Barré syndrome and postbariatric surgery polyneuropathies. JSLS. 2009;13(2):250-253.

12. Brannagan TH 3rd, Zhou Y. HIV-associated Guillain-Barré syndrome. J Neurol Sci. 2003;208(1-2):39-42.

13. Lin WC, Lee PI, Lu CY, et al. Mycoplasma pneumoniae encephalitis in childhood. J Microbiol Immunol Infect. 2002;35(3):173-178.

14. Sivadon-Tardy V, Orlikowski D, Porcher R, et al. Detection of Campylobacter jejuni by culture and real-time PCR in a French cohort of patients with Guillain-Barre syndrome. J Clin Microbiol. 2010;48 (6):2278-2281.

15. van Doorn PA, Kuitwaard K, Walgaard C, et al. IVIG treatment and prognosis in Guillain-Barré syndrome. J Clin Immunol. 2010;30 suppl 1:S74-S78.

16. Kaida K, Kusunoki S. Guillan-Barré syndrome: update on immunobiology and treatment. Expert Rev Neurother. 2009;9(9):1307-1319.

17. Forsberg A, Press R, Einarsson U, et al. Disability and health-related quality of life in Guillain-Barré syndrome during the first two years after onset: a prospective study. Clin Rehabil. 2005;19(8):900-909.

18. Criteria for diagnosis of Guillain-Barré syndrome. Ann Neurol. 1978;3(6):565-566.

19. van Koningsveld R, Steyerberg EW, Hughes RA, et al. A clinical progostic scoring system for Guillain-Barré syndrome. Lancet Neurol. 2007;6(7):589-594.

20. Koeppen S, Kraywinkel K, Wessendorf TE, et al. Long-term outcome of Guillain-Barré syndrome. Neuro­crit Care. 2006;5(3)235-242.

21. Sheridan JM, Smith D. Atypical Guillain-Barré in the emergency department. West J Emerg Med. 2010;11(1):80-82.

22. Ogawara K, Kuwabara S, Koga M, et al. Anti-GM1b IgG antibody is associated with acute motor axonal neuropathy and Campylobacter jejuni infection. J Neurol Sci. 2003;210(1-2):41-45.

23. Nagashima T, Koga M, Odaka M, et al. Continuous spectrum of pharyngeal-cervical-brachial variant of Guillain-Barré syndrome. Arch Neurol. 2007;64(10):1519-1523.

24. Oh SJ, LaGanke C, Claussen GC. Sensory Guillain-Barré syndrome. Neurology. 2001;56(1):82-86.

25. Aráranyi Z, Kovács T, Sipos I, Bereczki D. Miller Fisher syndrome: brief overview and update with a focus on electrophysiological findings. Eur J Neurol. 2011 Jun 1. [Epub ahead of print]

26. Hughes RA, Cornblath, DR. Guillain-Barré syndrome. Lancet. 2005;366(9497):1653-1666.

27. Snyder LA, Rismondo V, Miller NR. The Fisher variant of Guillain-Barré syndrome (Fisher syndrome). J Neuroophthalmol. 2009;29(4):312-324.

28. Ropper AH. The Guillain-Barré syndrome. N Engl J Med.1992;326(17):1130-1136.

29. Meythaler JM. Rehabilitation of Guillain-Barré syndrome. Arch Phys Med Rehabil.1997;78(8):872-879.

30. Sharshar T, Chevret S, Bourdain F, et al; French Cooperative Group on Plasma Exchange in Guillain-Barré syndrome. Early predictors of mechanical ventilation in Guillain-Barré syndrome. Crit Care Med. 2003; 31(1):278-283.

31. McGillicuddy DC, Walker O, Shapiro NI, et al. Guillain-Barré syndrome in the emergency department. Ann Emerg Med. 2006;47(4):390-393.

32. Yikilmaz A, Doganay S, Gumus H, et al. Magnetic resonance imaging of childhood Guillain-Barré syndrome. Childs Nerv Syst. 2010;26(8):1103-1108.

33. Gonzalez-Quevedo A, Carriera RF, O’Farrill ZL, et al. An appraisal of blood-cerebrospinal fluid barrier dysfunction during the course of Guillain-Barré syndrome. Neurol India. 2009;57(3):288-294.

34. Abai S, Kim SB, Kim JP, Lim YJ. Guillan-Barré syndrome combined with acute cervical myelopathy. J Korean Neurosurg Soc. 2010;48(3):298-300.

35. Uncini A, Yuki N. Electrophysiologic and immunopathologic correlates in Guillain-Barré syndrome subtypes. Expert Rev Neurother. 2009;9(6):869-884.

36. Hadden RD, Hughes RA. Management of inflammatory neuropathies. J Neurol Neurosurg Psychiatry. 2003;74 suppl 2:ii9-ii14.

37. Raphaël JC, Chevret S, Hughes RA, Annane D. Plasma exchange for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2002;(2):CD001798.

38. Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2010 Jun 16; (6):CD002063.

39. Human immunoglobulin and the Guillain-Barré syndrome: new indication. An alternative to plasmapheresis. Prescrire Int. 2000;9(49):142-143.

40. van der Meché FG, Schmitz PI; Dutch Guillain-Barré Study Group. A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barré syndrome. N Engl J Med. 1992;327(17):1123-1129.

41. Hughes RA, Swan AV, van Doorn PA. Corticosteroids for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2010 Feb 16;(2):CD001446.

42. Hahn AF. Guillain-Barré syndrome. Lancet. 1998; 352(9128):635-641.

43. Dalakas MC. Intravenous immunoglobulin in autoimmune neuromuscular diseases. JAMA. 2004;291(19):2367-2375.

44. Kuitwaard K, de Gelder J, Tio-Gillen AP, et al. Pharmacokenetics of intravenous immunoglobulin and outcome in Guillain-Barré syndrome. Ann Neurol. 2009;66(5):597-603.

45. Atkinson SB, Carr RL, Maybee P, Haynes D. The challenges of managing and treating Guillain-Barré syndrome during the acute phase. Dimens Crit Care Nurs. 2006;25(6):256-263.

46. van Doorn PA. Treatment of Guillain-Barré syndrome and CIDP. J Periph Nerv Syst. 2005;10(2):113-127.

47. Gaber TA, Kirker SGB, Jenner JR. Current practice of prophylactic anticoagulation in Guillain-Barré syndrome. Clin Rehabil. 2002;16(2):190-193.

48. Pandey CK, Bose N, Garg G, et al. Gabapentin for the treatment of pain in Guillain-Barré syndrome: a double-blinded, placebo-controlled, crossover study. Anesth Analg. 2002;95(6):1719-1723.

49. de Vries JM, Hagemans ML, Bussmann JB, et al. Fatigue in neuromuscular disorders: focus on Guillain-Barré syndrome and Pompe disease. Cell Mol Life Sci. 2010;67(5):701-713.

A 20-year-old woman presented to her primary care clinic with a chief complaint of lower leg weakness and difficulty walking. The weakness she described had been worsening over the previous four days, with progressively worsening tingling and numbness of her toes bilaterally.

The day before the patient presented, she noticed numbness and paresthesia in both calves. At the time of her presentation to the clinic, she complained of low back ache, paresthesia of both hands, numbness bilaterally to her groin, difficulty sitting upright, ataxia, and a numb, thick-feeling tongue. She denied fever, neck stiffness, shortness of breath, headache, or visual changes.

The patient stated that 10 days earlier, she had developed an upper respiratory infection for which she was seen at the clinic and treated with a seven-day course of amoxicillin/clavulanate 875/125 mg twice daily. She said that she had recovered completely.

A review of the patient’s systems revealed proximal muscle weakness bilaterally (2/5) and loss of touch-pressure in the lower extremities. She was experiencing paresthesia of the hands and mild weakness bilaterally (4/5). She also walked with an ataxic gait and had reduced deep tendon reflexes in the lower limbs. All cranial nerves were intact, and her vital signs were stable.

The woman’s medical history was positive only for asthma. Her family history included ischemic stroke in the maternal grandfather and brain tumor in the paternal grandfather. Social history was positive for alcohol intake (ranging from four to 12 beers per week). The patient said she had never smoked or used illicit drugs. She was an unmarried college student, living in a dorm on campus. She participated in track at school.

The patient was admitted to the hospital telemetry step-down unit, and a neurology consultation was requested. Tests were ordered, among them MRI of the head and spine and comprehensive blood work, to rule out neurologic, infectious, or metabolic causes of the patient’s weakness; urinalysis was also obtained. These tests all yielded negative results.

A lumbar puncture performed the following day revealed a cerebrospinal fluid (CSF) protein level of 570 mg/L (normal range, 150 to 450 mg/L). Leukocytes numbered 2 cells/mm³ (normal count, 0 to 10 cells/mm³).

Based on the patient’s presentation, history, and symptoms, a neurologist made a diagnosis of Guillain-Barré syndrome. It was decided that no electromyographic (EMG) study was required to rule out other disease processes (eg, spinal cord disease, multiple sclerosis, tumors).

The patient underwent a five-dose course of immunomodulatory therapy with IV immunoglobulin (IVIG). In the step-down unit, she experienced one incident of sinus bradycardia (ie, resting heart rate between 40 and 50 beats/min). Her blood pressure remained stable, as did her respiratory status, according to peak expiratory flow measured frequently at her bedside.

Physical therapy was initiated, consisting of passive and active range of motion, crossovers with the patient’s feet, and stair training. This was done in response to a complaint of ankle weakness, and it helped to strengthen weakened muscles and improve alignment while the patient was bedridden and in a weakened, fatigued state. Additionally, the patient was given enoxaparin, wore antiembolic hose, and used sequential compression devices while in bed. As a result of these measures, she never experienced a pulmonary embolus or deep vein thrombosis (DVT) as a result of being immobilized.

By the seventh day of hospitalization, the patient had stable vital signs and improved lower limb strength, and numbness was resolving in her hands and lower extremities. She was discharged to home, with physical therapy to resume on an outpatient basis.

Discussion
Guillain-Barré syndrome (GBS), an acute immune-mediated paralytic disorder,¹ manifests in the form of weakness and diminished reflexes. Affecting the peripheral nerves, GBS is characterized by progressive symmetrical ascending weakness with varying degrees of sensory complaints.^2,3

GBS occurs worldwide, and incidence is estimated between 1.1 and 1.8 cases per 100,000 persons.⁴ In the United States, GBS can be found in all age-groups, with peak incidence noted in elderly persons and young adults.^5,6 Even with treatment, 3% to 10% of patients are reported to die of this illness, and 20% cannot walk six months after symptom onset.⁷ In one prospective population-based study of patients with confirmed GBS, 6% of patients died within 30 days of symptom onset, often as a result of respiratory complications.⁸

GBS is a postinfectious disorder, with cases developing several days or weeks after a viral or bacterial illness—most commonly, an upper respiratory infection or diarrhea (see Table 1^9-13). The most common trigger of GBS is infection with the bacterial microorganism Campylobacter jejuni (occurring in 15% to 40% of patients with GBS),^9,14 a pathogen that can produce demyelination-causing antibodies. Other responsible pathogens include cytomegalovirus and Epstein-Barr virus.⁹ In a process called molecular mimicry, the immune system is unable to distinguish the amino acid of an infectious organism from the proteinaceous content of the peripheral nerve.¹⁵ Subsequently, the immune system attacks and destroys the myelin sheath.

An example of this is the apparent cross-reaction of the ganglioside GM1 with C jejuni lipopolysaccharide antigens.^14,15 The resulting effect is immunologic damage to the peripheral nervous system. The flaccid paralysis that occurs in patients with GBS is thought to be caused by lymphocytic infiltration and complement activation of the spinal roots and peripheral nerves, where macrophages strip the myelin.^5,15,16

Stages and Variants
Three stages characterize the course of GBS. The acute phase, which lasts one to four weeks, begins with onset of symptoms and persists until the associated neurologic deterioration has ceased. During the second phase, the plateau period, symptoms persist with no further deterioration; this stage can last several days to several weeks or months. The final phase, the recovery period, can last from four months to two years after symptom onset.^15,17,18

The clinical course of GBS is highly variable and in many cases difficult to predict. Certain factors have been associated with a poor outcome: advancing age, previous presence of diarrhea, need for mechanical ventilation, an extended plateau phase, and a lower patient score on the Erasmus GBS Outcome Scale,¹⁹ when measured two weeks after GBS onset.^8,20 This score can help predict the patient’s chance of independent walking after six months.^15,19

Although the classic presenting symptom of GBS is symmetric ascending weakness, several disease variants have been identified, with differing symptoms and degrees of recovery. These variants also differ in terms of the muscle groups affected; in some, visual defects may be present at onset. GBS variants include²¹:

• Acute motor axonal neuropathy (AMAN)^1,22

• Acute inflammatory demyelinating polyneuropathy (AIDP)¹

• Pharyngeal-cervical-brachial variant²³

• Purely sensory variant24

• Miller-Fisher syndrome, which manifests with ophthalmoplegia, in addition to ataxia and areflexia²⁵

• Axonal form.^5,21

AMAN and AIDP are the most common subtypes of GBS.¹

Symptoms, Signs, and Disease Manifestations
Limb weakness, the classic presenting symptom of GBS, is both symmetrical and ascending. Weakness can develop acutely and progress over days to weeks.^2,15 Hughes and Cornblath²⁶ also note pain, numbness, and paresthesias among the initial symptoms of GBS. Others include sensory changes, cranial nerve involvement, various autonomic changes, and respiratory or oropharyngeal weakness. Reflexes, particularly the tendon reflexes, may be diminished or absent.^15,18,21 In many cases, sensory changes (ie, pain) may precede the onset of weakness, often making diagnosis difficult.¹⁵

Cranial nerves most commonly affected are V, VI, VII, X, XI, and  XII, with manifestations that include dysphagia, dysarthria, diplopia, limitation to eye movements, and facial droop and weakness. Usually facial and oropharyngeal weakness occur after the extremities and trunk are affected. Blindness may occur if demyelination of the optic nerve occurs; this is seen in Miller-Fisher syndrome.^10,15,25,27

In GBS, many patients report pain, which can present as bilateral sciatica or as throbbing or aching in the large muscles of the upper legs, flanks, or back.28 This pain, which results from the demyelination of the sensory nerve fibers, can be severe.10

Patients with GBS may experience manifestations of autonomic nervous system dysfunction—for example, arrhythmias, hypotension or hypertension, urinary retention, cardiomyopathy, and paralytic ileus.^10,20 Dysautonomia often impedes patients’ progress in inpatient rehabilitation. Patients may have persistent problems involving postural hypotension, hypertension, excessive sympathetic outflow, or bladder and bowel dysfunction.²⁹

Blood pressure fluctuations, often attributed to changes in catecholamine levels and disturbances in the baroreceptor reflex pathway, are common and are considered characteristic of GBS. Transient or persistent hypotension is caused by the dysregulation of the parasympathetic and sympathetic systems, with subsequent alterations in venomotor tone.³ Additionally, an increased sensitivity to catecholamine can lead to cardiovascular disturbances, resulting in denervation hypersensitivity and impairment of the carotid sinus reflex.

Arrhythmias occur in perhaps half of patients with GBS. The most common is sustained sinus tachycardia, which usually requires no treatment. Bradycardia leading to atrioventricular blocks and asystole is believed to result from afferent baroreceptor reflex failure. Treatment may be required—either administration of atropine or insertion of a pacemaker, depending on the severity of the arrhythmia.^3,10

Myocardial involvement can range from asymptomatic mycocarditis to neurogenic stunned myocardium and heart failure. Patients with ECG abnormalities should undergo two-dimensional echocardiographic studies and other testing to explore cardiac involvement. Acute coronary syndromes, including ST-segment elevation MI, have been reported, in some cases associated with IVIG treatment. In one patient, coronary spasm was reported, with clean coronary arteries found on cardiac catheterization.³

Patients with GBS are at risk for compromised neuromuscular respiratory function; demyelination of the nerves that innervate the intercostal muscles and the diaphragm can result in respiratory failure. Key clinical indicators of respiratory muscle fatigue include tachypnea, diaphoresis, and asynchronous movements of the abdomen and chest;¹⁰ other symptoms relevant to respiratory or oropharyngeal weakness include slurred speech, dyspnea (with or without exertion), difficulty swallowing, and inability to cough.^2,10 Serial respiratory function testing is advisable to detect patients at risk for respiratory failure.³⁰

Diagnosis
Guillain-Barré is a syndrome diagnosed by a collection of symptoms (see Table 2^2,21,31), including subacute developing paralysis, symmetrical bilateral weakness beginning at onset, and diminishing to absent reflexes.^21,31 Other causes for rapidly developing weaknesses should be ruled out (see Table 3^10,21,26,31). Lumbar puncture typically shows increased protein levels with a normal white cell count; however, neither this test nor electrophysiologic evaluation offers significant value for diagnosis of GBS.^21,26,31

During the acute phase of GBS (within three weeks of onset), there is found an elevation of CSF protein (> 550 mg/L) without an elevation in white blood cells. This phenomenon, called albuminocytologic dissociation, reflects inflammation of the nerve roots and is considered the hallmark of GBS.²

MRI can also facilitate the diagnosis of GBS; it demonstrates anterior and posterior intrathecal spinal nerve roots and cauda equina.³² In patients with GBS, evidence supporting breakdown of the blood–nerve barrier can be seen in abnormal gadolinium enhancement of the intrathecal nerve roots on MRI.³³

When electrophysiologic studies are performed, they typically reveal slowing nerve conduction, prolonged distal latencies, and partial motor conduction block.³⁴ The characteristic finding of early demyelination is conduction block, a reduction in the amplitude of the muscle action potential after stimulation of the distal, as opposed to the proximal, nerve.²⁸ Nerve conduction studies may help in the diagnosis and classification of GBS—and, to a limited extent, formulation of a prognosis. Such alternative diagnoses as myositis and myasthenia gravis may be excluded by neurophysiology.²⁶ Early in GBS, neurophysiologic abnormalities may be very mild or occasionally normal; test results may not correlate with clinical disability.^35,36

The clinician cannot depend on clinical features alone to predict respiratory decline.³¹ Frequent evaluations of respiratory effort, by measurement of maximal inspiratory pressures and vital capacity, should be performed at the bedside to monitor diaphragmatic strength. Respiratory ventilation should be initiated if the patient becomes hypoxic or experiences a rapid decline in vital capacity (ie, below 60% of predicted value).¹⁰ Mechanical ventilation is more likely to be required in patients with a negative inspiratory force of less than 30 cm H2O.³¹

Treatment
Guillain-Barré syndrome has an acute onset and progression. Patients quickly become nonambulatory and may require total ventilation due to paralysis. Therapeutic options are IVIG or plasmapheresis (plasma exchange).^37-40 Corticosteroids do not appear to benefit patients with GBS.^41,42

Several mechanisms appear to contribute to the effectiveness of immunoglobulin.^38,39 Infused IVIG interferes with antigen presentation, inhibits antibody production, neutralizes pathologic autoantibodies, and modulates other immunologic events involved in the pathogenesis of autoimmune neuromuscular diseases, including GBS.⁴³ Adverse reactions, which are usually minor, include headache, fever, chills, myalgia, and malaise. In rare instances, anaphylaxis or renal failure may occur.^15,44

In plasmapheresis, blood is removed from the body and dialyzed, with circulating antibodies and immunoglobulins removed from the plasma; fresh frozen plasma, albumin, or saline is administered. This treatment, performed via central venous catheter, should be initiated as soon as possible after onset of symptoms but can be implemented as late as 30 days after GBS onset. Plasmapheresis requires personnel trained in dialysis, which may not be performed in all hospitals. Possible adverse events include infection and hemorrhage. Laboratory values must be monitored for hypokalemia and hypocalcemia.^45,46

Supportive Care
Patients with GBS require intensive care and very close monitoring for complications of respiratory difficulty and autonomic dysfunction. Individualized programs should be initiated for patients in the acute phase of GBS, aimed at the prevention of contractures and skin breakdown.¹⁰ Exercise programs, as conducted with the case patient, should also help relieve the fatigue syndromes that accompany GBS.

Immobilization associated with bed rest incurs a risk for pulmonary emboli and DVT; this has been found true during the first 12 weeks after symptom onset in patients with GBS who remain immobile.⁴⁷ The use of antiembolic hose and sequential compression devices can help reduce the risk for thrombotic events.¹⁰ Use of enoxaparin or heparin is recommended for nonambulating patients until they are able to walk, with Gaber et al⁴⁷ specifying the use of low-molecular-weight heparin to reduce, but not eliminate, the risk for DVT.

The pain associated with GBS can be severe. Narcotic analgesics may be administered with careful monitoring of autonomic denervation. Long-term management of neuropathic pain may require adjuvant therapy, such as tricyclic antidepressants, gabapentin, or tramadol hydrochloride.¹⁰ According to Pandey et al,⁴⁸ gabapentin alone may suffice for pain control in GBS, with minimal adverse effects. In certain rehabilitation facilities, tricyclic antidepressants, capsaicin, and transcutaneous nerve stimulation have been reported effective; during the early stages of treatment, until these treatments reach their full effect, pain medications such as tramadol or narcotics can provide temporary relief.²⁹

More than one-half of patients with GBS in the acute phase can develop ileus. Constipation can also occur as a result of pain medication use, prolonged bed rest, and poor intake. Auscultation of bowel sounds and abdominal assessment should be performed daily to monitor for ileus. Hughes et al¹⁰ do not recommend the use of promotility drugs in patients with dysautonomia.

After hospital discharge, easy fatigability can affect work and social activities. With continued physical therapy, occupational therapy, and monitoring, however, patients with GBS can expect to return to an optimal level of functioning. Speed of recovery varies with these patients from a few months to several years, depending on such factors as age and the extent to which axonal degeneration has occurred.^6,49

The Case Patient
For several weeks after discharge, the case patient continued to experience fatigue, low back pain, and general muscle pain. With her family’s support, she continued to receive outpatient physical therapy, and within one month she had regained her ankle strength. She was soon able to resume her classes, despite some lingering fatigue.

Conclusion
Guillain-Barré syndrome is a potentially life-threatening disease whose symptoms health care providers need to recognize quickly to provide prompt treatment. Supportive care for both patient and family is of key importance for maximum rehabilitation and return to the previous lifestyle. The clinical course of GBS is highly variable and difficult to predict. The patient’s outcome depends on several factors, including age and severity of illness. GBS patients can experience long-term psychosocial effects.

References
1. Magira EE, Papaioakim M, Nachamkin I, et al. Differential distribution of HLA-DQ beta/DR beta epitopes in the two forms of Guillain-Barré syndrome, acute motor axonal neuropathy and acute inflammatory demyelinating polyneuropathy (AIDP): identification of DQ beta epitopes associated with susceptibility to and protection from AIDP. J Immunol. 2003;170(6):3074-3080.

2. Tremblay ME, Closon A, D’Anjou G, Bussières JF. Guillain-Barré syndrome following H1N1 immunization in a pediatric patient. Ann Pharmacother. 2010;44(7-8):1330-1333.

3. Mukerji S, Aloka F, Farooq MU, et al. Cardiovascular complications of the Guillain-Barré syndrome. Am J Cardiol. 2009;104(10):1452-1455.

4. McGrogan A, Madle GC, Seaman HE, de Vries CS. The epidemiology of Guillain-Barré syndrome worldwide: a systematic literature review. Neuroepidemiology. 2009;32(2):150-163.

5. Haber P, Sejvar J, Mikaeloff Y, DeStefano F. Vaccines and Guillain-Barré syndrome. Drug Saf. 2009; 32(4):309-323.

6. van Doorn PA. What’s new in Guillain-Barré syndrome in 2007-2008? J Periph Nerv Syst. 2009;14(2):72-74.

7. van Doorn PA, Ruts L, Jacobs BC. Clinical features, pathogenesis, and treatment of Guillain-Barré syndrome. Lancet Neurol. 2008;7(10):939-950.

8. Chiò A, Cocito D, Leone M, et al; Piemonte and alle d’Aosta Register for Guillain-Barré Syndrome. Guillain-Barré syndrome: a prospective, population-based incidence and outcome survey. Neurology. 2003; 60(7):1146-1150.

9. Hadden RD, Karch H, Hartung HP, et al. Preceding infections, immune factors, and outcome in Guillain-Barré syndrome. Neurology. 2001;56(6):758-765.

10. Hughes RA, Wijdicks EF, Benson E, et al. Supportive care for patients with Guillain-Barré syndrome. Arch Neurol. 2005;62(8):1194-1198.

11. Aluka KJ, Turner PL, Fullum TM. Guillain-Barré syndrome and postbariatric surgery polyneuropathies. JSLS. 2009;13(2):250-253.

12. Brannagan TH 3rd, Zhou Y. HIV-associated Guillain-Barré syndrome. J Neurol Sci. 2003;208(1-2):39-42.

13. Lin WC, Lee PI, Lu CY, et al. Mycoplasma pneumoniae encephalitis in childhood. J Microbiol Immunol Infect. 2002;35(3):173-178.

14. Sivadon-Tardy V, Orlikowski D, Porcher R, et al. Detection of Campylobacter jejuni by culture and real-time PCR in a French cohort of patients with Guillain-Barre syndrome. J Clin Microbiol. 2010;48 (6):2278-2281.

15. van Doorn PA, Kuitwaard K, Walgaard C, et al. IVIG treatment and prognosis in Guillain-Barré syndrome. J Clin Immunol. 2010;30 suppl 1:S74-S78.

16. Kaida K, Kusunoki S. Guillan-Barré syndrome: update on immunobiology and treatment. Expert Rev Neurother. 2009;9(9):1307-1319.

17. Forsberg A, Press R, Einarsson U, et al. Disability and health-related quality of life in Guillain-Barré syndrome during the first two years after onset: a prospective study. Clin Rehabil. 2005;19(8):900-909.

18. Criteria for diagnosis of Guillain-Barré syndrome. Ann Neurol. 1978;3(6):565-566.

19. van Koningsveld R, Steyerberg EW, Hughes RA, et al. A clinical progostic scoring system for Guillain-Barré syndrome. Lancet Neurol. 2007;6(7):589-594.

20. Koeppen S, Kraywinkel K, Wessendorf TE, et al. Long-term outcome of Guillain-Barré syndrome. Neuro­crit Care. 2006;5(3)235-242.

21. Sheridan JM, Smith D. Atypical Guillain-Barré in the emergency department. West J Emerg Med. 2010;11(1):80-82.

22. Ogawara K, Kuwabara S, Koga M, et al. Anti-GM1b IgG antibody is associated with acute motor axonal neuropathy and Campylobacter jejuni infection. J Neurol Sci. 2003;210(1-2):41-45.

23. Nagashima T, Koga M, Odaka M, et al. Continuous spectrum of pharyngeal-cervical-brachial variant of Guillain-Barré syndrome. Arch Neurol. 2007;64(10):1519-1523.

24. Oh SJ, LaGanke C, Claussen GC. Sensory Guillain-Barré syndrome. Neurology. 2001;56(1):82-86.

25. Aráranyi Z, Kovács T, Sipos I, Bereczki D. Miller Fisher syndrome: brief overview and update with a focus on electrophysiological findings. Eur J Neurol. 2011 Jun 1. [Epub ahead of print]

26. Hughes RA, Cornblath, DR. Guillain-Barré syndrome. Lancet. 2005;366(9497):1653-1666.

27. Snyder LA, Rismondo V, Miller NR. The Fisher variant of Guillain-Barré syndrome (Fisher syndrome). J Neuroophthalmol. 2009;29(4):312-324.

28. Ropper AH. The Guillain-Barré syndrome. N Engl J Med.1992;326(17):1130-1136.

29. Meythaler JM. Rehabilitation of Guillain-Barré syndrome. Arch Phys Med Rehabil.1997;78(8):872-879.

30. Sharshar T, Chevret S, Bourdain F, et al; French Cooperative Group on Plasma Exchange in Guillain-Barré syndrome. Early predictors of mechanical ventilation in Guillain-Barré syndrome. Crit Care Med. 2003; 31(1):278-283.

31. McGillicuddy DC, Walker O, Shapiro NI, et al. Guillain-Barré syndrome in the emergency department. Ann Emerg Med. 2006;47(4):390-393.

32. Yikilmaz A, Doganay S, Gumus H, et al. Magnetic resonance imaging of childhood Guillain-Barré syndrome. Childs Nerv Syst. 2010;26(8):1103-1108.

33. Gonzalez-Quevedo A, Carriera RF, O’Farrill ZL, et al. An appraisal of blood-cerebrospinal fluid barrier dysfunction during the course of Guillain-Barré syndrome. Neurol India. 2009;57(3):288-294.

34. Abai S, Kim SB, Kim JP, Lim YJ. Guillan-Barré syndrome combined with acute cervical myelopathy. J Korean Neurosurg Soc. 2010;48(3):298-300.

35. Uncini A, Yuki N. Electrophysiologic and immunopathologic correlates in Guillain-Barré syndrome subtypes. Expert Rev Neurother. 2009;9(6):869-884.

36. Hadden RD, Hughes RA. Management of inflammatory neuropathies. J Neurol Neurosurg Psychiatry. 2003;74 suppl 2:ii9-ii14.

37. Raphaël JC, Chevret S, Hughes RA, Annane D. Plasma exchange for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2002;(2):CD001798.

38. Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2010 Jun 16; (6):CD002063.

39. Human immunoglobulin and the Guillain-Barré syndrome: new indication. An alternative to plasmapheresis. Prescrire Int. 2000;9(49):142-143.

40. van der Meché FG, Schmitz PI; Dutch Guillain-Barré Study Group. A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barré syndrome. N Engl J Med. 1992;327(17):1123-1129.

41. Hughes RA, Swan AV, van Doorn PA. Corticosteroids for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2010 Feb 16;(2):CD001446.

42. Hahn AF. Guillain-Barré syndrome. Lancet. 1998; 352(9128):635-641.

43. Dalakas MC. Intravenous immunoglobulin in autoimmune neuromuscular diseases. JAMA. 2004;291(19):2367-2375.

44. Kuitwaard K, de Gelder J, Tio-Gillen AP, et al. Pharmacokenetics of intravenous immunoglobulin and outcome in Guillain-Barré syndrome. Ann Neurol. 2009;66(5):597-603.

45. Atkinson SB, Carr RL, Maybee P, Haynes D. The challenges of managing and treating Guillain-Barré syndrome during the acute phase. Dimens Crit Care Nurs. 2006;25(6):256-263.

46. van Doorn PA. Treatment of Guillain-Barré syndrome and CIDP. J Periph Nerv Syst. 2005;10(2):113-127.

47. Gaber TA, Kirker SGB, Jenner JR. Current practice of prophylactic anticoagulation in Guillain-Barré syndrome. Clin Rehabil. 2002;16(2):190-193.

48. Pandey CK, Bose N, Garg G, et al. Gabapentin for the treatment of pain in Guillain-Barré syndrome: a double-blinded, placebo-controlled, crossover study. Anesth Analg. 2002;95(6):1719-1723.

49. de Vries JM, Hagemans ML, Bussmann JB, et al. Fatigue in neuromuscular disorders: focus on Guillain-Barré syndrome and Pompe disease. Cell Mol Life Sci. 2010;67(5):701-713.

Depression of the ST segment and inversion of the T wave are common electrocardiographic abnormalities. Knowing the various ischemic and nonischemic morphologic features is critical for a timely diagnosis of high-risk myocardial ischemia and electrolyte- or drug-related abnormalities. Moreover, it is important to recognize that true posterior infarction or subtle ST-segment elevation infarction may masquerade as ST-segment depression ischemia, and that pulmonary embolism may masquerade as anterior ischemia. These common electrocardiographic abnormalities are summarized in Table 1.

THE ST SEGMENT AND THE T WAVE: A PRIMER

The ST segment corresponds to the plateau phase of ventricular repolarization (phase 2 of the action potential), while the T wave corresponds to the phase of rapid ventricular repolarization (phase 3). ST-segment or T-wave changes may be secondary to abnormalities of depolarization, ie, pre-excitation or abnormalities of QRS voltage or duration.

On the other hand, ST-segment and T-wave abnormalities may be unrelated to any QRS abnormality, in which case they are called primary repolarization abnormalities. These are caused by ischemia, pericarditis, myocarditis, drugs (digoxin, antiarrhythmic drugs), and electrolyte abnormalities, particularly potassium abnormalities.

ST-segment deviation is usually measured at its junction with the end of the QRS complex, ie, the J point, and is referenced against the TP or PR segment.¹ But some prefer to measure the magnitude of the ST-segment deviation 40 to 80 ms after the J point, when all myocardial fibers are expected to have reached the same level of membrane potential and to form an isoelectric ST segment; at the very onset of repolarization, small differences in membrane potential may normally be seen and may cause deviation of the J point and of the early portion of the ST segment.²

Although a diagnosis of ST-segment elevation myocardial infarction (STEMI) that mandates emergency reperfusion therapy requires ST-segment elevation greater than 1 mm in at least two contiguous leads,³ any ST-segment depression or elevation (≥ 0.5 mm, using the usual standard of 1.0 mV = 10 mm) may be abnormal, particularly when the clinical context or the shape of the ST segment suggests ischemia, or when other ischemic signs such as T-wave abnormalities, Q waves, or reciprocal ST-segment changes are concomitantly present. On the other hand, ST-segment depression of up to 0.5 mm in leads V₂ and V₃ and 1 mm in the other leads may be normal.¹

In adults, the T wave normally is inverted in lead aVR; is upright or inverted in leads aVL, III, and V₁; and is upright in leads I, II, aVF, and V₂ through V₆. The T wave is considered inverted when it is deeper than 1 mm; it is considered flat when its peak amplitude is between 1.0 mm and −1.0 mm.¹

As we will discuss, certain features allow the various causes of ST-segment and T-wave abnormalities to be distinguished from one another.

SECONDARY ST-SEGMENT AND T-WAVE ABNORMALITIES

Modified with permission from Hanna EB, Quintal R, Jain N. Cardiology: Handbook for Clinicians. Arlington, VA: Scrubhill Press; 2009:328–354.

• The ST segment and T wave are directed opposite to the QRS: this is called discordance between the QRS complex and the ST-T abnormalities. In the case of right bundle branch block, the ST and T are directed opposite to the terminal portion of the QRS, ie, the part of the QRS deformed by the conduction abnormality.
• The ST segment and T wave are both abnormal and deviate in the same direction, ie, the ST segment is down-sloping and the T wave is inverted in leads with an upright QRS complex, which gives the ST-T complex a “reverse checkmark” asymmetric morphology.
• The ST and T abnormalities are not dynamic, ie, they do not change in the course of several hours to several days.

Thus, in cases of left ventricular hypertrophy or left bundle branch block, since the QRS complex is upright in the left lateral leads I, aVL, V₅, and V₆, the ST segment is characteristically depressed and the T wave is inverted in these leads (Figure 2). In cases of right ventricular hypertrophy or right bundle branch block, T waves are characteristically inverted in the right precordial leads V₁, V₂, and V₃.

Left bundle branch block is always associated with secondary ST-T abnormalities, the absence of which suggests associated ischemia. Left and right ventricular hypertrophy, on the other hand, are not always associated with ST-T abnormalities, but when these are present, they correlate with more severe hypertrophy or ventricular systolic dysfunction,⁴ and have been called strain pattern. In addition, while these morphologic features are consistent with secondary abnormalities, they do not rule out ischemia in a patient with angina.

Some exceptions to these typical morphologic features:

• Right ventricular hypertrophy and right bundle branch block may be associated with isolated T-wave inversion without ST-segment depression in precordial leads V₁, V₂, and V₃.
• Left ventricular hypertrophy may be associated with symmetric T-wave inversion without ST-segment depression or with a horizontally depressed ST segment. This may be the case in up to one-third of ST-T abnormalities secondary to left ventricular hypertrophy and is seen in hypertrophic cardiomyopathy, particularly the apical variant, in leads V₃ through V₆.⁵

ISCHEMIC ST-SEGMENT DEPRESSION, T-WAVE INVERSION, OR BOTH

ST-segment depression or T-wave inversion is consistent with ischemia if any of the following is true:

• The ST-segment depression or T-wave inversion is directed in the same direction as the QRS complex: this is called concordance between the QRS complex and the ST or T abnormality (Figure 1B).
• The ST segment is depressed but the T wave is upright (Figure 1C).
• The T wave has a positive-negative biphasic pattern (Figure 1D).
• The T wave is symmetrically inverted and has a pointed configuration, while the ST segment is not deviated or is upwardly bowed (coved) or horizontally depressed (Figure 1E).
• The magnitude of ST-segment depression progresses or regresses on serial tracings, or ST-segment depression progresses to T-wave abnormality during ischemia-free intervals (dynamic ST-segment depression).

Unlike ST-segment elevation, ST-segment depression does not localize ischemia.⁶ However, the extent and the magnitude of ST-segment depression correlate with the extent and the severity of ischemia. In fact, ST-segment depression in eight or more leads, combined with ST-segment elevation in leads aVR and V₁ and occurring during ischemic pain, is associated with a 75% predictive accuracy for left main coronary artery or three-vessel disease (Figure 3).^7,8 This finding may also be seen in cases of tight proximal stenosis of the left anterior descending coronary artery.⁹

Wellens syndrome

Wellens and his colleagues showed that 75% of patients who developed these T-wave abnormalities and who were treated medically without angiographic investigation went on to develop extensive anterior wall myocardial infarction within a mean of 8.5 days.¹⁰

In a later investigation of 1,260 patients presenting with unstable angina, 180 patients (14%) had this characteristic T-wave pattern.¹¹ All of the latter patients had stenosis of 50% or more in the proximal left anterior descending artery, and 18% had total occlusion of the left anterior descending artery.

Thus, although medical management may provide symptomatic improvement at first, early coronary angiography and revascularization should be strongly considered in anyone with Wellens syndrome because it usually predicts impending anterior myocardial infarction.

Wellens syndrome is characterized by two patterns of T-wave changes. In 75% of cases, T waves are deeply (≥ 5 mm) and symmetrically inverted in leads V₂ through V₄ (Figures 1E, 4B). In 25% of cases, the T wave has a characteristic positive-negative biphasic morphology in leads V₂ through V₄ (Figures 1D, 4A).¹⁰ In both patterns, the ST segment is isoelectric or minimally elevated (< 1 mm) with a straight or convex morphology, the down-slope of the T wave is sharp, and the QT interval is often prolonged. These abnormalities are characteristically seen hours to days after the ischemic chest pain resolves. In fact, the ischemic episode is usually associated with transient ST-segment elevation or depression that progresses to the T-wave abnormality after the pain subsides.¹¹

In Wellens’ original description, only 12% of patients had increases in their creatine kinase levels, and these were small. Therefore, the electrocardiogram may be the only indication of an impending large anterior infarction in a chest-pain-free patient.¹²

T waves that are symmetrically but less deeply inverted than Wellens-type T waves may still represent ischemia. However, this finding is less specific for ischemia and is associated with better outcomes than Wellens syndrome or ST-segment deviation, particularly when the T wave is less than 3 mm deep.¹⁴ In fact, one prospective cohort study found that isolated mild T-wave inversion in patients presenting with acute coronary syndrome is associated with a favorable long-term outcome, similar to that in patients with no electrocardiographic changes.¹⁵

FREQUENTLY MISSED DIAGNOSES MANIFESTING AS ST-SEGMENT DEPRESSION OR T-WAVE INVERSION

True posterior ST-segment elevation myocardial infarction

When accompanied by inferior STEMI, posterior infarction is easily recognized, but it can be difficult to diagnose when it occurs alone, the so-called true posterior STEMI.

In most cases of posterior infarction, the posterior chest leads V₇, V₈, and V₉ reveal ST-segment elevation.¹⁹ One study found that ST-segment depression in the anterior precordial leads was as sensitive as ST-segment elevation in leads V₇ through V₉ in identifying posterior myocardial infarction (sensitivity 80%),²⁰ while other studies found that ST-segment deviation on standard 12-lead electrocardiography has a lower sensitivity (about 60%) in identifying posterior infarction.^18,21

Tall or wide (≥ 0.04-s) R waves in leads V₁ or V₂, particularly when associated with upright T waves, suggest posterior infarction and may further corroborate this diagnosis, but this finding may take up to 24 hours to manifest and is seen in only about 50% of patients with posterior infarction.²¹

Studies have shown that ST-segment elevation on standard 12-lead electrocardiography is found in fewer than 50% of patients with acute left circumflex occlusion and inferoposterior infarction,¹⁸ yet these are cases of “missed” STEMI that indeed benefit from emergency angiography and reperfusion. In addition, studies of non–ST-segment elevation acute coronary syndrome consistently identify patients who have epicardial vessel occlusion (about 15%–20% of cases),¹⁸ yet their initial angiography is usually delayed for hours or days after the initial presentation.

A subgroup analysis from TRITON–TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel Thrombolysis in Myocardial Infarction 38) evaluated patients with isolated anterior ST-segment depression. An occluded “culprit” artery was found 26% of the time, most often the left circumflex artery. Moreover, those patients had a significantly higher rate of death or myocardial infarction at 30-day follow-up than patients without a culprit artery, probably related to delayed revascularization.²²

Recognizing that ST-segment depression that is greatest in leads V₁, V₂, or V₃ represents posterior infarction helps identify a portion of the missed STEMIs in a timely fashion. In addition, in cases of anterior ST-segment depression and in cases of chest pain with nondiagnostic electrocardiography, the recording of ST elevation in leads V₇, V₈, and V₉ is highly sensitive for detecting a true posterior injury.

An anterior ischemic pattern of symmetric T-wave inversion in the precordial leads V₁ through V₄ may also be a sign of acute or chronic right ventricular strain, particularly acute pulmonary embolism. Sinus tachycardia is usually present, but other signs of pulmonary embolism, such as right ventricular hypertrophy and right bundle branch block, may be absent. In fact, T-wave inversion in leads V₁ through V₄ is noted in 19% of patients with nonmassive pulmonary embolism and in 85% of patients with massive pulmonary embolism, and is the most sensitive and specific electrocardiographic finding in massive pulmonary embolism.²³

In addition, acute pulmonary embolism may be associated with T-wave inversion in leads III and aVF,²⁴ and changes of concomitant anterior and inferior ischemia should always raise the question of this diagnosis.

In one retrospective study of patients with acute pulmonary embolism, nonspecific ST-segment or T-wave changes were the most common finding on electrocardiography, noted in 49%.²⁵ Rapid regression of these changes on serial tracings favors pulmonary embolism rather than myocardial infarction.

ST-segment depression reciprocal to a subtle ST-segment elevation

When ST-segment elevation occurs in two contiguous standard leads while ST-segment depression occurs in other leads, and when the ST-segment and T-wave abnormalities are ischemic rather than secondary to depolarization abnormalities, ST-segment elevation is considered the primary ischemic abnormality whereas ST-segment depression is often considered a reciprocal “mirror image” change. This “reciprocal” change may also represent remote ischemia in a distant territory in patients with multivessel coronary disease.^26,27

Reciprocal ST-segment depression is present in all patients with inferior myocardial infarction and in 70% of patients with anterior myocardial infarction.²⁸

Hypokalemia and digitalis effect

DIFFUSE (GLOBAL) T-WAVE INVERSION

Reproduced with permission from Glancy DL, et al. Global T-wave inversion in a 77-year-old woman. Proc (Bayl Univ Med Cent) 2009; 22:81–82.

Walder and Spodick³⁶ have found this pattern to be caused most often by myocardial ischemia or neurologic events, particularly intracranial hemorrhage, and it seems more prevalent in women. Other causes include hypertrophic cardiomyopathy, stress-induced cardiomyopathy (takotsubo cardiomyopathy), cocaine abuse, pericarditis, pulmonary embolism, and advanced or complete atrioventricular block.^36,37

The prognosis in patients with global T-wave inversion is determined by the underlying disease, and the striking T-wave changes per se do not imply a poor prognosis.³⁸

OTHER CAUSES OF T-WAVE INVERSION OR ST-SEGMENT DEPRESSION

Various other entities may cause T-wave inversion, notably acute pericarditis or myocarditis, ^41,42 memory T-wave phenomenon,^43,44 and normal variants of repolarization (Table 1, Figure 9).⁴⁵ Additionally, a nonpathologic junctional ST-segment depression may be seen in tachycardia (Figure 10).

Depression of the ST segment and inversion of the T wave are common electrocardiographic abnormalities. Knowing the various ischemic and nonischemic morphologic features is critical for a timely diagnosis of high-risk myocardial ischemia and electrolyte- or drug-related abnormalities. Moreover, it is important to recognize that true posterior infarction or subtle ST-segment elevation infarction may masquerade as ST-segment depression ischemia, and that pulmonary embolism may masquerade as anterior ischemia. These common electrocardiographic abnormalities are summarized in Table 1.

THE ST SEGMENT AND THE T WAVE: A PRIMER

The ST segment corresponds to the plateau phase of ventricular repolarization (phase 2 of the action potential), while the T wave corresponds to the phase of rapid ventricular repolarization (phase 3). ST-segment or T-wave changes may be secondary to abnormalities of depolarization, ie, pre-excitation or abnormalities of QRS voltage or duration.

On the other hand, ST-segment and T-wave abnormalities may be unrelated to any QRS abnormality, in which case they are called primary repolarization abnormalities. These are caused by ischemia, pericarditis, myocarditis, drugs (digoxin, antiarrhythmic drugs), and electrolyte abnormalities, particularly potassium abnormalities.

ST-segment deviation is usually measured at its junction with the end of the QRS complex, ie, the J point, and is referenced against the TP or PR segment.¹ But some prefer to measure the magnitude of the ST-segment deviation 40 to 80 ms after the J point, when all myocardial fibers are expected to have reached the same level of membrane potential and to form an isoelectric ST segment; at the very onset of repolarization, small differences in membrane potential may normally be seen and may cause deviation of the J point and of the early portion of the ST segment.²

Although a diagnosis of ST-segment elevation myocardial infarction (STEMI) that mandates emergency reperfusion therapy requires ST-segment elevation greater than 1 mm in at least two contiguous leads,³ any ST-segment depression or elevation (≥ 0.5 mm, using the usual standard of 1.0 mV = 10 mm) may be abnormal, particularly when the clinical context or the shape of the ST segment suggests ischemia, or when other ischemic signs such as T-wave abnormalities, Q waves, or reciprocal ST-segment changes are concomitantly present. On the other hand, ST-segment depression of up to 0.5 mm in leads V₂ and V₃ and 1 mm in the other leads may be normal.¹

In adults, the T wave normally is inverted in lead aVR; is upright or inverted in leads aVL, III, and V₁; and is upright in leads I, II, aVF, and V₂ through V₆. The T wave is considered inverted when it is deeper than 1 mm; it is considered flat when its peak amplitude is between 1.0 mm and −1.0 mm.¹

As we will discuss, certain features allow the various causes of ST-segment and T-wave abnormalities to be distinguished from one another.

SECONDARY ST-SEGMENT AND T-WAVE ABNORMALITIES

Modified with permission from Hanna EB, Quintal R, Jain N. Cardiology: Handbook for Clinicians. Arlington, VA: Scrubhill Press; 2009:328–354.

• The ST segment and T wave are directed opposite to the QRS: this is called discordance between the QRS complex and the ST-T abnormalities. In the case of right bundle branch block, the ST and T are directed opposite to the terminal portion of the QRS, ie, the part of the QRS deformed by the conduction abnormality.
• The ST segment and T wave are both abnormal and deviate in the same direction, ie, the ST segment is down-sloping and the T wave is inverted in leads with an upright QRS complex, which gives the ST-T complex a “reverse checkmark” asymmetric morphology.
• The ST and T abnormalities are not dynamic, ie, they do not change in the course of several hours to several days.

Thus, in cases of left ventricular hypertrophy or left bundle branch block, since the QRS complex is upright in the left lateral leads I, aVL, V₅, and V₆, the ST segment is characteristically depressed and the T wave is inverted in these leads (Figure 2). In cases of right ventricular hypertrophy or right bundle branch block, T waves are characteristically inverted in the right precordial leads V₁, V₂, and V₃.

Left bundle branch block is always associated with secondary ST-T abnormalities, the absence of which suggests associated ischemia. Left and right ventricular hypertrophy, on the other hand, are not always associated with ST-T abnormalities, but when these are present, they correlate with more severe hypertrophy or ventricular systolic dysfunction,⁴ and have been called strain pattern. In addition, while these morphologic features are consistent with secondary abnormalities, they do not rule out ischemia in a patient with angina.

Some exceptions to these typical morphologic features:

• Right ventricular hypertrophy and right bundle branch block may be associated with isolated T-wave inversion without ST-segment depression in precordial leads V₁, V₂, and V₃.
• Left ventricular hypertrophy may be associated with symmetric T-wave inversion without ST-segment depression or with a horizontally depressed ST segment. This may be the case in up to one-third of ST-T abnormalities secondary to left ventricular hypertrophy and is seen in hypertrophic cardiomyopathy, particularly the apical variant, in leads V₃ through V₆.⁵

ISCHEMIC ST-SEGMENT DEPRESSION, T-WAVE INVERSION, OR BOTH

ST-segment depression or T-wave inversion is consistent with ischemia if any of the following is true:

• The ST-segment depression or T-wave inversion is directed in the same direction as the QRS complex: this is called concordance between the QRS complex and the ST or T abnormality (Figure 1B).
• The ST segment is depressed but the T wave is upright (Figure 1C).
• The T wave has a positive-negative biphasic pattern (Figure 1D).
• The T wave is symmetrically inverted and has a pointed configuration, while the ST segment is not deviated or is upwardly bowed (coved) or horizontally depressed (Figure 1E).
• The magnitude of ST-segment depression progresses or regresses on serial tracings, or ST-segment depression progresses to T-wave abnormality during ischemia-free intervals (dynamic ST-segment depression).

Unlike ST-segment elevation, ST-segment depression does not localize ischemia.⁶ However, the extent and the magnitude of ST-segment depression correlate with the extent and the severity of ischemia. In fact, ST-segment depression in eight or more leads, combined with ST-segment elevation in leads aVR and V₁ and occurring during ischemic pain, is associated with a 75% predictive accuracy for left main coronary artery or three-vessel disease (Figure 3).^7,8 This finding may also be seen in cases of tight proximal stenosis of the left anterior descending coronary artery.⁹

Wellens syndrome

Wellens and his colleagues showed that 75% of patients who developed these T-wave abnormalities and who were treated medically without angiographic investigation went on to develop extensive anterior wall myocardial infarction within a mean of 8.5 days.¹⁰

In a later investigation of 1,260 patients presenting with unstable angina, 180 patients (14%) had this characteristic T-wave pattern.¹¹ All of the latter patients had stenosis of 50% or more in the proximal left anterior descending artery, and 18% had total occlusion of the left anterior descending artery.

Thus, although medical management may provide symptomatic improvement at first, early coronary angiography and revascularization should be strongly considered in anyone with Wellens syndrome because it usually predicts impending anterior myocardial infarction.

Wellens syndrome is characterized by two patterns of T-wave changes. In 75% of cases, T waves are deeply (≥ 5 mm) and symmetrically inverted in leads V₂ through V₄ (Figures 1E, 4B). In 25% of cases, the T wave has a characteristic positive-negative biphasic morphology in leads V₂ through V₄ (Figures 1D, 4A).¹⁰ In both patterns, the ST segment is isoelectric or minimally elevated (< 1 mm) with a straight or convex morphology, the down-slope of the T wave is sharp, and the QT interval is often prolonged. These abnormalities are characteristically seen hours to days after the ischemic chest pain resolves. In fact, the ischemic episode is usually associated with transient ST-segment elevation or depression that progresses to the T-wave abnormality after the pain subsides.¹¹

In Wellens’ original description, only 12% of patients had increases in their creatine kinase levels, and these were small. Therefore, the electrocardiogram may be the only indication of an impending large anterior infarction in a chest-pain-free patient.¹²

T waves that are symmetrically but less deeply inverted than Wellens-type T waves may still represent ischemia. However, this finding is less specific for ischemia and is associated with better outcomes than Wellens syndrome or ST-segment deviation, particularly when the T wave is less than 3 mm deep.¹⁴ In fact, one prospective cohort study found that isolated mild T-wave inversion in patients presenting with acute coronary syndrome is associated with a favorable long-term outcome, similar to that in patients with no electrocardiographic changes.¹⁵

FREQUENTLY MISSED DIAGNOSES MANIFESTING AS ST-SEGMENT DEPRESSION OR T-WAVE INVERSION

True posterior ST-segment elevation myocardial infarction

When accompanied by inferior STEMI, posterior infarction is easily recognized, but it can be difficult to diagnose when it occurs alone, the so-called true posterior STEMI.

In most cases of posterior infarction, the posterior chest leads V₇, V₈, and V₉ reveal ST-segment elevation.¹⁹ One study found that ST-segment depression in the anterior precordial leads was as sensitive as ST-segment elevation in leads V₇ through V₉ in identifying posterior myocardial infarction (sensitivity 80%),²⁰ while other studies found that ST-segment deviation on standard 12-lead electrocardiography has a lower sensitivity (about 60%) in identifying posterior infarction.^18,21

Tall or wide (≥ 0.04-s) R waves in leads V₁ or V₂, particularly when associated with upright T waves, suggest posterior infarction and may further corroborate this diagnosis, but this finding may take up to 24 hours to manifest and is seen in only about 50% of patients with posterior infarction.²¹

Studies have shown that ST-segment elevation on standard 12-lead electrocardiography is found in fewer than 50% of patients with acute left circumflex occlusion and inferoposterior infarction,¹⁸ yet these are cases of “missed” STEMI that indeed benefit from emergency angiography and reperfusion. In addition, studies of non–ST-segment elevation acute coronary syndrome consistently identify patients who have epicardial vessel occlusion (about 15%–20% of cases),¹⁸ yet their initial angiography is usually delayed for hours or days after the initial presentation.

A subgroup analysis from TRITON–TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel Thrombolysis in Myocardial Infarction 38) evaluated patients with isolated anterior ST-segment depression. An occluded “culprit” artery was found 26% of the time, most often the left circumflex artery. Moreover, those patients had a significantly higher rate of death or myocardial infarction at 30-day follow-up than patients without a culprit artery, probably related to delayed revascularization.²²

Recognizing that ST-segment depression that is greatest in leads V₁, V₂, or V₃ represents posterior infarction helps identify a portion of the missed STEMIs in a timely fashion. In addition, in cases of anterior ST-segment depression and in cases of chest pain with nondiagnostic electrocardiography, the recording of ST elevation in leads V₇, V₈, and V₉ is highly sensitive for detecting a true posterior injury.

An anterior ischemic pattern of symmetric T-wave inversion in the precordial leads V₁ through V₄ may also be a sign of acute or chronic right ventricular strain, particularly acute pulmonary embolism. Sinus tachycardia is usually present, but other signs of pulmonary embolism, such as right ventricular hypertrophy and right bundle branch block, may be absent. In fact, T-wave inversion in leads V₁ through V₄ is noted in 19% of patients with nonmassive pulmonary embolism and in 85% of patients with massive pulmonary embolism, and is the most sensitive and specific electrocardiographic finding in massive pulmonary embolism.²³

In addition, acute pulmonary embolism may be associated with T-wave inversion in leads III and aVF,²⁴ and changes of concomitant anterior and inferior ischemia should always raise the question of this diagnosis.

In one retrospective study of patients with acute pulmonary embolism, nonspecific ST-segment or T-wave changes were the most common finding on electrocardiography, noted in 49%.²⁵ Rapid regression of these changes on serial tracings favors pulmonary embolism rather than myocardial infarction.

ST-segment depression reciprocal to a subtle ST-segment elevation

When ST-segment elevation occurs in two contiguous standard leads while ST-segment depression occurs in other leads, and when the ST-segment and T-wave abnormalities are ischemic rather than secondary to depolarization abnormalities, ST-segment elevation is considered the primary ischemic abnormality whereas ST-segment depression is often considered a reciprocal “mirror image” change. This “reciprocal” change may also represent remote ischemia in a distant territory in patients with multivessel coronary disease.^26,27

Reciprocal ST-segment depression is present in all patients with inferior myocardial infarction and in 70% of patients with anterior myocardial infarction.²⁸

Hypokalemia and digitalis effect

DIFFUSE (GLOBAL) T-WAVE INVERSION

Reproduced with permission from Glancy DL, et al. Global T-wave inversion in a 77-year-old woman. Proc (Bayl Univ Med Cent) 2009; 22:81–82.

Walder and Spodick³⁶ have found this pattern to be caused most often by myocardial ischemia or neurologic events, particularly intracranial hemorrhage, and it seems more prevalent in women. Other causes include hypertrophic cardiomyopathy, stress-induced cardiomyopathy (takotsubo cardiomyopathy), cocaine abuse, pericarditis, pulmonary embolism, and advanced or complete atrioventricular block.^36,37

The prognosis in patients with global T-wave inversion is determined by the underlying disease, and the striking T-wave changes per se do not imply a poor prognosis.³⁸

OTHER CAUSES OF T-WAVE INVERSION OR ST-SEGMENT DEPRESSION

Various other entities may cause T-wave inversion, notably acute pericarditis or myocarditis, ^41,42 memory T-wave phenomenon,^43,44 and normal variants of repolarization (Table 1, Figure 9).⁴⁵ Additionally, a nonpathologic junctional ST-segment depression may be seen in tachycardia (Figure 10).

Depression of the ST segment and inversion of the T wave are common electrocardiographic abnormalities. Knowing the various ischemic and nonischemic morphologic features is critical for a timely diagnosis of high-risk myocardial ischemia and electrolyte- or drug-related abnormalities. Moreover, it is important to recognize that true posterior infarction or subtle ST-segment elevation infarction may masquerade as ST-segment depression ischemia, and that pulmonary embolism may masquerade as anterior ischemia. These common electrocardiographic abnormalities are summarized in Table 1.

THE ST SEGMENT AND THE T WAVE: A PRIMER

The ST segment corresponds to the plateau phase of ventricular repolarization (phase 2 of the action potential), while the T wave corresponds to the phase of rapid ventricular repolarization (phase 3). ST-segment or T-wave changes may be secondary to abnormalities of depolarization, ie, pre-excitation or abnormalities of QRS voltage or duration.

On the other hand, ST-segment and T-wave abnormalities may be unrelated to any QRS abnormality, in which case they are called primary repolarization abnormalities. These are caused by ischemia, pericarditis, myocarditis, drugs (digoxin, antiarrhythmic drugs), and electrolyte abnormalities, particularly potassium abnormalities.

ST-segment deviation is usually measured at its junction with the end of the QRS complex, ie, the J point, and is referenced against the TP or PR segment.¹ But some prefer to measure the magnitude of the ST-segment deviation 40 to 80 ms after the J point, when all myocardial fibers are expected to have reached the same level of membrane potential and to form an isoelectric ST segment; at the very onset of repolarization, small differences in membrane potential may normally be seen and may cause deviation of the J point and of the early portion of the ST segment.²

Although a diagnosis of ST-segment elevation myocardial infarction (STEMI) that mandates emergency reperfusion therapy requires ST-segment elevation greater than 1 mm in at least two contiguous leads,³ any ST-segment depression or elevation (≥ 0.5 mm, using the usual standard of 1.0 mV = 10 mm) may be abnormal, particularly when the clinical context or the shape of the ST segment suggests ischemia, or when other ischemic signs such as T-wave abnormalities, Q waves, or reciprocal ST-segment changes are concomitantly present. On the other hand, ST-segment depression of up to 0.5 mm in leads V₂ and V₃ and 1 mm in the other leads may be normal.¹

In adults, the T wave normally is inverted in lead aVR; is upright or inverted in leads aVL, III, and V₁; and is upright in leads I, II, aVF, and V₂ through V₆. The T wave is considered inverted when it is deeper than 1 mm; it is considered flat when its peak amplitude is between 1.0 mm and −1.0 mm.¹

As we will discuss, certain features allow the various causes of ST-segment and T-wave abnormalities to be distinguished from one another.

SECONDARY ST-SEGMENT AND T-WAVE ABNORMALITIES

Modified with permission from Hanna EB, Quintal R, Jain N. Cardiology: Handbook for Clinicians. Arlington, VA: Scrubhill Press; 2009:328–354.

• The ST segment and T wave are directed opposite to the QRS: this is called discordance between the QRS complex and the ST-T abnormalities. In the case of right bundle branch block, the ST and T are directed opposite to the terminal portion of the QRS, ie, the part of the QRS deformed by the conduction abnormality.
• The ST segment and T wave are both abnormal and deviate in the same direction, ie, the ST segment is down-sloping and the T wave is inverted in leads with an upright QRS complex, which gives the ST-T complex a “reverse checkmark” asymmetric morphology.
• The ST and T abnormalities are not dynamic, ie, they do not change in the course of several hours to several days.

Thus, in cases of left ventricular hypertrophy or left bundle branch block, since the QRS complex is upright in the left lateral leads I, aVL, V₅, and V₆, the ST segment is characteristically depressed and the T wave is inverted in these leads (Figure 2). In cases of right ventricular hypertrophy or right bundle branch block, T waves are characteristically inverted in the right precordial leads V₁, V₂, and V₃.

Left bundle branch block is always associated with secondary ST-T abnormalities, the absence of which suggests associated ischemia. Left and right ventricular hypertrophy, on the other hand, are not always associated with ST-T abnormalities, but when these are present, they correlate with more severe hypertrophy or ventricular systolic dysfunction,⁴ and have been called strain pattern. In addition, while these morphologic features are consistent with secondary abnormalities, they do not rule out ischemia in a patient with angina.

Some exceptions to these typical morphologic features:

• Right ventricular hypertrophy and right bundle branch block may be associated with isolated T-wave inversion without ST-segment depression in precordial leads V₁, V₂, and V₃.
• Left ventricular hypertrophy may be associated with symmetric T-wave inversion without ST-segment depression or with a horizontally depressed ST segment. This may be the case in up to one-third of ST-T abnormalities secondary to left ventricular hypertrophy and is seen in hypertrophic cardiomyopathy, particularly the apical variant, in leads V₃ through V₆.⁵

ISCHEMIC ST-SEGMENT DEPRESSION, T-WAVE INVERSION, OR BOTH

ST-segment depression or T-wave inversion is consistent with ischemia if any of the following is true:

• The ST-segment depression or T-wave inversion is directed in the same direction as the QRS complex: this is called concordance between the QRS complex and the ST or T abnormality (Figure 1B).
• The ST segment is depressed but the T wave is upright (Figure 1C).
• The T wave has a positive-negative biphasic pattern (Figure 1D).
• The T wave is symmetrically inverted and has a pointed configuration, while the ST segment is not deviated or is upwardly bowed (coved) or horizontally depressed (Figure 1E).
• The magnitude of ST-segment depression progresses or regresses on serial tracings, or ST-segment depression progresses to T-wave abnormality during ischemia-free intervals (dynamic ST-segment depression).

Unlike ST-segment elevation, ST-segment depression does not localize ischemia.⁶ However, the extent and the magnitude of ST-segment depression correlate with the extent and the severity of ischemia. In fact, ST-segment depression in eight or more leads, combined with ST-segment elevation in leads aVR and V₁ and occurring during ischemic pain, is associated with a 75% predictive accuracy for left main coronary artery or three-vessel disease (Figure 3).^7,8 This finding may also be seen in cases of tight proximal stenosis of the left anterior descending coronary artery.⁹

Wellens syndrome

Wellens and his colleagues showed that 75% of patients who developed these T-wave abnormalities and who were treated medically without angiographic investigation went on to develop extensive anterior wall myocardial infarction within a mean of 8.5 days.¹⁰

In a later investigation of 1,260 patients presenting with unstable angina, 180 patients (14%) had this characteristic T-wave pattern.¹¹ All of the latter patients had stenosis of 50% or more in the proximal left anterior descending artery, and 18% had total occlusion of the left anterior descending artery.

Thus, although medical management may provide symptomatic improvement at first, early coronary angiography and revascularization should be strongly considered in anyone with Wellens syndrome because it usually predicts impending anterior myocardial infarction.

Wellens syndrome is characterized by two patterns of T-wave changes. In 75% of cases, T waves are deeply (≥ 5 mm) and symmetrically inverted in leads V₂ through V₄ (Figures 1E, 4B). In 25% of cases, the T wave has a characteristic positive-negative biphasic morphology in leads V₂ through V₄ (Figures 1D, 4A).¹⁰ In both patterns, the ST segment is isoelectric or minimally elevated (< 1 mm) with a straight or convex morphology, the down-slope of the T wave is sharp, and the QT interval is often prolonged. These abnormalities are characteristically seen hours to days after the ischemic chest pain resolves. In fact, the ischemic episode is usually associated with transient ST-segment elevation or depression that progresses to the T-wave abnormality after the pain subsides.¹¹

In Wellens’ original description, only 12% of patients had increases in their creatine kinase levels, and these were small. Therefore, the electrocardiogram may be the only indication of an impending large anterior infarction in a chest-pain-free patient.¹²

T waves that are symmetrically but less deeply inverted than Wellens-type T waves may still represent ischemia. However, this finding is less specific for ischemia and is associated with better outcomes than Wellens syndrome or ST-segment deviation, particularly when the T wave is less than 3 mm deep.¹⁴ In fact, one prospective cohort study found that isolated mild T-wave inversion in patients presenting with acute coronary syndrome is associated with a favorable long-term outcome, similar to that in patients with no electrocardiographic changes.¹⁵

FREQUENTLY MISSED DIAGNOSES MANIFESTING AS ST-SEGMENT DEPRESSION OR T-WAVE INVERSION

True posterior ST-segment elevation myocardial infarction

When accompanied by inferior STEMI, posterior infarction is easily recognized, but it can be difficult to diagnose when it occurs alone, the so-called true posterior STEMI.

In most cases of posterior infarction, the posterior chest leads V₇, V₈, and V₉ reveal ST-segment elevation.¹⁹ One study found that ST-segment depression in the anterior precordial leads was as sensitive as ST-segment elevation in leads V₇ through V₉ in identifying posterior myocardial infarction (sensitivity 80%),²⁰ while other studies found that ST-segment deviation on standard 12-lead electrocardiography has a lower sensitivity (about 60%) in identifying posterior infarction.^18,21

Tall or wide (≥ 0.04-s) R waves in leads V₁ or V₂, particularly when associated with upright T waves, suggest posterior infarction and may further corroborate this diagnosis, but this finding may take up to 24 hours to manifest and is seen in only about 50% of patients with posterior infarction.²¹

Studies have shown that ST-segment elevation on standard 12-lead electrocardiography is found in fewer than 50% of patients with acute left circumflex occlusion and inferoposterior infarction,¹⁸ yet these are cases of “missed” STEMI that indeed benefit from emergency angiography and reperfusion. In addition, studies of non–ST-segment elevation acute coronary syndrome consistently identify patients who have epicardial vessel occlusion (about 15%–20% of cases),¹⁸ yet their initial angiography is usually delayed for hours or days after the initial presentation.

A subgroup analysis from TRITON–TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel Thrombolysis in Myocardial Infarction 38) evaluated patients with isolated anterior ST-segment depression. An occluded “culprit” artery was found 26% of the time, most often the left circumflex artery. Moreover, those patients had a significantly higher rate of death or myocardial infarction at 30-day follow-up than patients without a culprit artery, probably related to delayed revascularization.²²

Recognizing that ST-segment depression that is greatest in leads V₁, V₂, or V₃ represents posterior infarction helps identify a portion of the missed STEMIs in a timely fashion. In addition, in cases of anterior ST-segment depression and in cases of chest pain with nondiagnostic electrocardiography, the recording of ST elevation in leads V₇, V₈, and V₉ is highly sensitive for detecting a true posterior injury.

An anterior ischemic pattern of symmetric T-wave inversion in the precordial leads V₁ through V₄ may also be a sign of acute or chronic right ventricular strain, particularly acute pulmonary embolism. Sinus tachycardia is usually present, but other signs of pulmonary embolism, such as right ventricular hypertrophy and right bundle branch block, may be absent. In fact, T-wave inversion in leads V₁ through V₄ is noted in 19% of patients with nonmassive pulmonary embolism and in 85% of patients with massive pulmonary embolism, and is the most sensitive and specific electrocardiographic finding in massive pulmonary embolism.²³

In addition, acute pulmonary embolism may be associated with T-wave inversion in leads III and aVF,²⁴ and changes of concomitant anterior and inferior ischemia should always raise the question of this diagnosis.

In one retrospective study of patients with acute pulmonary embolism, nonspecific ST-segment or T-wave changes were the most common finding on electrocardiography, noted in 49%.²⁵ Rapid regression of these changes on serial tracings favors pulmonary embolism rather than myocardial infarction.

ST-segment depression reciprocal to a subtle ST-segment elevation

When ST-segment elevation occurs in two contiguous standard leads while ST-segment depression occurs in other leads, and when the ST-segment and T-wave abnormalities are ischemic rather than secondary to depolarization abnormalities, ST-segment elevation is considered the primary ischemic abnormality whereas ST-segment depression is often considered a reciprocal “mirror image” change. This “reciprocal” change may also represent remote ischemia in a distant territory in patients with multivessel coronary disease.^26,27

Reciprocal ST-segment depression is present in all patients with inferior myocardial infarction and in 70% of patients with anterior myocardial infarction.²⁸

Hypokalemia and digitalis effect