Red blood cell culture showing

Staphylococcus infection

Photo by Bill Branson

NASHVILLE—A single-center study has shown that incorporating antimicrobial cloths into an infection-prevention protocol can reduce the incidence of central line-associated bloodstream infections (CLABSIs) in pediatric patients.

After the hospital implemented daily “baths” with disposable cloths containing 2% chlorhexidine gluconate (CHG), its CLABSI incidence fell 59% over a 6-month period.

The details of this experience were presented at the APIC 2015 Annual Conference (abstract 013).

The study was conducted at Riley Hospital for Children at Indiana University Health in Indianapolis. The hospital previously used CHG for daily bathing in the hematology/oncology unit and found it successfully reduced CLABSIs there.

This prompted infection preventionists to consider implementing the practice hospital-wide, regardless of whether patients had central-line catheters.

The infection-prevention team worked with nursing staff, parents, and hospital leadership to adopt daily CHG bathing for all patients and to strengthen adherence to a bundle of prevention practices already in place for patients with central lines.

In addition to daily bathing with CHG-impregnated wipes, the strategies included daily linen changes, assessment of central-line dressings, ensuring use of the appropriate technique for giving medications, and regular tubing and cap changes on the lines.

“We took great care to ensure successful implementation of the new bathing regimen,” said Adam N. Karcz, an infection preventionist at the hospital.

“By educating everyone on the care team, including parents, and standardizing bathing procedures, we were able to dramatically reduce infections and save healthcare dollars in just 6 months.”

Bathing compliance increased from 45% to 81% during the 6-month study period. During the control period—6 months prior to implementation—the 269-bed hospital had 22 CLABSIs. During the implementation period, there were 9 CLABSIs.

The hospital also experienced a 56% drop in the number of methicillin-resistant Staphylococcus aureus (MRSA) infections during this time period.

The reduction in healthcare-associated infections during the implementation period represents a potential cost savings of $297,999.

Red blood cell culture showing

Staphylococcus infection

Photo by Bill Branson

NASHVILLE—A single-center study has shown that incorporating antimicrobial cloths into an infection-prevention protocol can reduce the incidence of central line-associated bloodstream infections (CLABSIs) in pediatric patients.

After the hospital implemented daily “baths” with disposable cloths containing 2% chlorhexidine gluconate (CHG), its CLABSI incidence fell 59% over a 6-month period.

The details of this experience were presented at the APIC 2015 Annual Conference (abstract 013).

The study was conducted at Riley Hospital for Children at Indiana University Health in Indianapolis. The hospital previously used CHG for daily bathing in the hematology/oncology unit and found it successfully reduced CLABSIs there.

This prompted infection preventionists to consider implementing the practice hospital-wide, regardless of whether patients had central-line catheters.

The infection-prevention team worked with nursing staff, parents, and hospital leadership to adopt daily CHG bathing for all patients and to strengthen adherence to a bundle of prevention practices already in place for patients with central lines.

In addition to daily bathing with CHG-impregnated wipes, the strategies included daily linen changes, assessment of central-line dressings, ensuring use of the appropriate technique for giving medications, and regular tubing and cap changes on the lines.

“We took great care to ensure successful implementation of the new bathing regimen,” said Adam N. Karcz, an infection preventionist at the hospital.

“By educating everyone on the care team, including parents, and standardizing bathing procedures, we were able to dramatically reduce infections and save healthcare dollars in just 6 months.”

Bathing compliance increased from 45% to 81% during the 6-month study period. During the control period—6 months prior to implementation—the 269-bed hospital had 22 CLABSIs. During the implementation period, there were 9 CLABSIs.

The hospital also experienced a 56% drop in the number of methicillin-resistant Staphylococcus aureus (MRSA) infections during this time period.

The reduction in healthcare-associated infections during the implementation period represents a potential cost savings of $297,999.

Red blood cell culture showing

Staphylococcus infection

Photo by Bill Branson

NASHVILLE—A single-center study has shown that incorporating antimicrobial cloths into an infection-prevention protocol can reduce the incidence of central line-associated bloodstream infections (CLABSIs) in pediatric patients.

After the hospital implemented daily “baths” with disposable cloths containing 2% chlorhexidine gluconate (CHG), its CLABSI incidence fell 59% over a 6-month period.

The details of this experience were presented at the APIC 2015 Annual Conference (abstract 013).

The study was conducted at Riley Hospital for Children at Indiana University Health in Indianapolis. The hospital previously used CHG for daily bathing in the hematology/oncology unit and found it successfully reduced CLABSIs there.

This prompted infection preventionists to consider implementing the practice hospital-wide, regardless of whether patients had central-line catheters.

The infection-prevention team worked with nursing staff, parents, and hospital leadership to adopt daily CHG bathing for all patients and to strengthen adherence to a bundle of prevention practices already in place for patients with central lines.

In addition to daily bathing with CHG-impregnated wipes, the strategies included daily linen changes, assessment of central-line dressings, ensuring use of the appropriate technique for giving medications, and regular tubing and cap changes on the lines.

“We took great care to ensure successful implementation of the new bathing regimen,” said Adam N. Karcz, an infection preventionist at the hospital.

“By educating everyone on the care team, including parents, and standardizing bathing procedures, we were able to dramatically reduce infections and save healthcare dollars in just 6 months.”

Bathing compliance increased from 45% to 81% during the 6-month study period. During the control period—6 months prior to implementation—the 269-bed hospital had 22 CLABSIs. During the implementation period, there were 9 CLABSIs.

The hospital also experienced a 56% drop in the number of methicillin-resistant Staphylococcus aureus (MRSA) infections during this time period.

The reduction in healthcare-associated infections during the implementation period represents a potential cost savings of $297,999.

Acute Coronary Syndromes

A 53-year-old obese man presented to the ED complaining of pain in his chest, bilateral jaw, and back. He stated that his symptoms had started the previous evening and had increased in severity the morning of presentation. He denied any change in breathing, or any nausea or vomiting. The patient’s medical history was significant for hypertension and chronic back pain. Regarding his social history, the patient noted that he smoked one pack of cigarettes per day; he denied alcohol use.

On physical examination, the patient’s weight was 350 lb, and he was profusely diaphoretic. Vital signs were remarkable for an elevated blood pressure (BP) of 214/106 mm Hg; respiratory rate (RR), heart rate (HR), temperature (T), and oxygen saturation were normal. The head, eyes, ears, nose, and throat examination was normal, and there was no jugular venous distention. The lung and heart examinations were also normal, and the abdominal examination was unremarkable. The patient had 2+ pitting edema in his lower extremities, which he said had been present for the past few weeks. The back examination was unremarkable, and the neurological examination was completely normal, including deep tendon reflexes.

Because of the presence of chest and back pain and history of hypertension, the EP ordered a computed tomography (CT) scan of the chest with intravenous (IV) contrast to rule out aortic dissection. He also administered 0.2 mg of clonidine orally for the elevated BP. Approximately 20 minutes later, the patient was given 2 mg morphine IV for the back pain and another 0.2 mg of clonidine orally. The elevated BP responded to the clonidine, and the patient stated he was feeling better.

The CT scan of the chest was interpreted by radiology services as normal. The patient was then administered 325 mg of aspirin by mouth. Since the EP’s hospital did not have facilities for cardiac catheterization, the EP consulted with a physician at another facility regarding a possible transfer. The consulted physician did not accept the patient for transfer, but instead recommended keeping the patient at the EP’s institution for observation and continuing treatment for the elevated BP and pain. The EP agreed, and diagnosed the patient with a hypertensive emergency and a flare-up of his chronic back pain.

In the ED, the patient’s BP decreased to near normal levels, and he was feeling much improved. Approximately 5.5 hours after his arrival to the ED, he was admitted to a monitored bed under the care of a hospitalist.

A few hours later, the patient began to complain of burning in the epigastric area; analgesics and nitroglycerin were administered and a repeat ECG was ordered. A second troponin level, drawn approximately 6 hours after the original, was found to be significantly elevated. The repeat ECG demonstrated sinus tachycardia with ST-segment depression.

The hospitalist was concerned about an acute coronary syndrome (ACS) and attempted to make contact with the other facility to transfer the patient for an emergent cardiac catheterization. The consulted physician agreed to accept the patient and recommended starting an IV heparin drip and giving clopidogrel bisulfate (Plavix). While arranging for the transfer, the patient suffered a cardiac arrest; resuscitation attempts were unsuccessful. 

The family of the patient sued the hospital, the EP, and the hospitalist, alleging the EP failed to recognize that the initial ECG and elevated troponin level were suggestive of an ACS. They also complained that the morphine, oxygen, nitroglycerin, and aspirin were not started in a timely manner. In addition, the family claimed the decedent should have been immediately transferred to another facility because the defendant’s hospital could not perform cardiac catheterization. They further alleged that the hospitalist failed to perform an independent evaluation of the patient and also failed to obtain a repeat 12-lead ECG sooner. Lastly, the plaintiffs claimed that the hospital’s nursing staff was negligent in failing to provide nursing care for 3 hours prior to the patient being found unresponsive.

The defendant EP asserted that the initial ECG was nondiagnostic and that the initial troponin level, while elevated, was nonspecific. He argued the ED evaluation and care provided was appropriate. Following trial, a defense verdict was returned.

Discussion

Fortunately, the jury ruled correctly in this case. Acute coronary sydromes can be some of the most challenging medical conditions to evaluate and manage in the ED. The EP’s initial cardiac workup and evaluation for a possible acute thoracic aortic dissection were appropriate—an acute thoracic aortic dissection is a true cardiovascular emergency. After interpreting the initial ECG as nondiagnostic (specifically, to rule out evidence of ST-segment elevation, myocardial infarction [MI], or STEMI), obtaining the contrast CT scan of the chest emergently was critically important. This patient had multiple risk factors for aortic dissection: he was a male between the ages of 50 and 55 years old (the mean age for proximal thoracic aortic dissection); he had a history of hypertension; and he was experiencing chest and back pain.¹

Once an acute aortic dissection was excluded, focusing on a cardiac etiology, as the EP did, was appropriate. The only criticism is that this patient probably should have been managed with an IV antihypertensive agent to allow for a more controlled BP reduction; this, however, does not seem to have played any role in the patient’s ultimate outcome.

Acute coronary syndromes are a dynamic process and progress over time. The EP was clearly concerned about an ACS very early in the case, as evidenced by his attempt to transfer the patient to a facility with specialized cardiac capabilities. After not being able to do so, the most appropriate next step was his admission of the patient to a monitored bed with serial cardiac enzymes and ECGs. It is well known that initial evaluation of both ECG and cardiac enzymes can be normal early on in an ACS. Patients with a normal or nonspecific ECG have a 1% to 5% incidence of MI and a 4% to 23% incidence of unstable angina.²

This patient ultimately experienced a non-ST-segment elevation myocardial infarction (NSTEMI). However, this diagnosis did not become evident until several hours after the patient’s admission to the hospital. It is unfortunate the physician consulted by the EP at the onset did not agree to accept this patient. This patient’s best chance for survival was at a facility capable of percutaneous coronary intervention.

Serotonin Syndrome

Acute Coronary Syndromes

A 53-year-old obese man presented to the ED complaining of pain in his chest, bilateral jaw, and back. He stated that his symptoms had started the previous evening and had increased in severity the morning of presentation. He denied any change in breathing, or any nausea or vomiting. The patient’s medical history was significant for hypertension and chronic back pain. Regarding his social history, the patient noted that he smoked one pack of cigarettes per day; he denied alcohol use.

On physical examination, the patient’s weight was 350 lb, and he was profusely diaphoretic. Vital signs were remarkable for an elevated blood pressure (BP) of 214/106 mm Hg; respiratory rate (RR), heart rate (HR), temperature (T), and oxygen saturation were normal. The head, eyes, ears, nose, and throat examination was normal, and there was no jugular venous distention. The lung and heart examinations were also normal, and the abdominal examination was unremarkable. The patient had 2+ pitting edema in his lower extremities, which he said had been present for the past few weeks. The back examination was unremarkable, and the neurological examination was completely normal, including deep tendon reflexes.

Because of the presence of chest and back pain and history of hypertension, the EP ordered a computed tomography (CT) scan of the chest with intravenous (IV) contrast to rule out aortic dissection. He also administered 0.2 mg of clonidine orally for the elevated BP. Approximately 20 minutes later, the patient was given 2 mg morphine IV for the back pain and another 0.2 mg of clonidine orally. The elevated BP responded to the clonidine, and the patient stated he was feeling better.

The CT scan of the chest was interpreted by radiology services as normal. The patient was then administered 325 mg of aspirin by mouth. Since the EP’s hospital did not have facilities for cardiac catheterization, the EP consulted with a physician at another facility regarding a possible transfer. The consulted physician did not accept the patient for transfer, but instead recommended keeping the patient at the EP’s institution for observation and continuing treatment for the elevated BP and pain. The EP agreed, and diagnosed the patient with a hypertensive emergency and a flare-up of his chronic back pain.

In the ED, the patient’s BP decreased to near normal levels, and he was feeling much improved. Approximately 5.5 hours after his arrival to the ED, he was admitted to a monitored bed under the care of a hospitalist.

A few hours later, the patient began to complain of burning in the epigastric area; analgesics and nitroglycerin were administered and a repeat ECG was ordered. A second troponin level, drawn approximately 6 hours after the original, was found to be significantly elevated. The repeat ECG demonstrated sinus tachycardia with ST-segment depression.

The hospitalist was concerned about an acute coronary syndrome (ACS) and attempted to make contact with the other facility to transfer the patient for an emergent cardiac catheterization. The consulted physician agreed to accept the patient and recommended starting an IV heparin drip and giving clopidogrel bisulfate (Plavix). While arranging for the transfer, the patient suffered a cardiac arrest; resuscitation attempts were unsuccessful. 

The family of the patient sued the hospital, the EP, and the hospitalist, alleging the EP failed to recognize that the initial ECG and elevated troponin level were suggestive of an ACS. They also complained that the morphine, oxygen, nitroglycerin, and aspirin were not started in a timely manner. In addition, the family claimed the decedent should have been immediately transferred to another facility because the defendant’s hospital could not perform cardiac catheterization. They further alleged that the hospitalist failed to perform an independent evaluation of the patient and also failed to obtain a repeat 12-lead ECG sooner. Lastly, the plaintiffs claimed that the hospital’s nursing staff was negligent in failing to provide nursing care for 3 hours prior to the patient being found unresponsive.

The defendant EP asserted that the initial ECG was nondiagnostic and that the initial troponin level, while elevated, was nonspecific. He argued the ED evaluation and care provided was appropriate. Following trial, a defense verdict was returned.

Discussion

Fortunately, the jury ruled correctly in this case. Acute coronary sydromes can be some of the most challenging medical conditions to evaluate and manage in the ED. The EP’s initial cardiac workup and evaluation for a possible acute thoracic aortic dissection were appropriate—an acute thoracic aortic dissection is a true cardiovascular emergency. After interpreting the initial ECG as nondiagnostic (specifically, to rule out evidence of ST-segment elevation, myocardial infarction [MI], or STEMI), obtaining the contrast CT scan of the chest emergently was critically important. This patient had multiple risk factors for aortic dissection: he was a male between the ages of 50 and 55 years old (the mean age for proximal thoracic aortic dissection); he had a history of hypertension; and he was experiencing chest and back pain.¹

Once an acute aortic dissection was excluded, focusing on a cardiac etiology, as the EP did, was appropriate. The only criticism is that this patient probably should have been managed with an IV antihypertensive agent to allow for a more controlled BP reduction; this, however, does not seem to have played any role in the patient’s ultimate outcome.

Acute coronary syndromes are a dynamic process and progress over time. The EP was clearly concerned about an ACS very early in the case, as evidenced by his attempt to transfer the patient to a facility with specialized cardiac capabilities. After not being able to do so, the most appropriate next step was his admission of the patient to a monitored bed with serial cardiac enzymes and ECGs. It is well known that initial evaluation of both ECG and cardiac enzymes can be normal early on in an ACS. Patients with a normal or nonspecific ECG have a 1% to 5% incidence of MI and a 4% to 23% incidence of unstable angina.²

This patient ultimately experienced a non-ST-segment elevation myocardial infarction (NSTEMI). However, this diagnosis did not become evident until several hours after the patient’s admission to the hospital. It is unfortunate the physician consulted by the EP at the onset did not agree to accept this patient. This patient’s best chance for survival was at a facility capable of percutaneous coronary intervention.

Serotonin Syndrome

Acute Coronary Syndromes

A 53-year-old obese man presented to the ED complaining of pain in his chest, bilateral jaw, and back. He stated that his symptoms had started the previous evening and had increased in severity the morning of presentation. He denied any change in breathing, or any nausea or vomiting. The patient’s medical history was significant for hypertension and chronic back pain. Regarding his social history, the patient noted that he smoked one pack of cigarettes per day; he denied alcohol use.

On physical examination, the patient’s weight was 350 lb, and he was profusely diaphoretic. Vital signs were remarkable for an elevated blood pressure (BP) of 214/106 mm Hg; respiratory rate (RR), heart rate (HR), temperature (T), and oxygen saturation were normal. The head, eyes, ears, nose, and throat examination was normal, and there was no jugular venous distention. The lung and heart examinations were also normal, and the abdominal examination was unremarkable. The patient had 2+ pitting edema in his lower extremities, which he said had been present for the past few weeks. The back examination was unremarkable, and the neurological examination was completely normal, including deep tendon reflexes.

Because of the presence of chest and back pain and history of hypertension, the EP ordered a computed tomography (CT) scan of the chest with intravenous (IV) contrast to rule out aortic dissection. He also administered 0.2 mg of clonidine orally for the elevated BP. Approximately 20 minutes later, the patient was given 2 mg morphine IV for the back pain and another 0.2 mg of clonidine orally. The elevated BP responded to the clonidine, and the patient stated he was feeling better.

The CT scan of the chest was interpreted by radiology services as normal. The patient was then administered 325 mg of aspirin by mouth. Since the EP’s hospital did not have facilities for cardiac catheterization, the EP consulted with a physician at another facility regarding a possible transfer. The consulted physician did not accept the patient for transfer, but instead recommended keeping the patient at the EP’s institution for observation and continuing treatment for the elevated BP and pain. The EP agreed, and diagnosed the patient with a hypertensive emergency and a flare-up of his chronic back pain.

In the ED, the patient’s BP decreased to near normal levels, and he was feeling much improved. Approximately 5.5 hours after his arrival to the ED, he was admitted to a monitored bed under the care of a hospitalist.

A few hours later, the patient began to complain of burning in the epigastric area; analgesics and nitroglycerin were administered and a repeat ECG was ordered. A second troponin level, drawn approximately 6 hours after the original, was found to be significantly elevated. The repeat ECG demonstrated sinus tachycardia with ST-segment depression.

The hospitalist was concerned about an acute coronary syndrome (ACS) and attempted to make contact with the other facility to transfer the patient for an emergent cardiac catheterization. The consulted physician agreed to accept the patient and recommended starting an IV heparin drip and giving clopidogrel bisulfate (Plavix). While arranging for the transfer, the patient suffered a cardiac arrest; resuscitation attempts were unsuccessful. 

The family of the patient sued the hospital, the EP, and the hospitalist, alleging the EP failed to recognize that the initial ECG and elevated troponin level were suggestive of an ACS. They also complained that the morphine, oxygen, nitroglycerin, and aspirin were not started in a timely manner. In addition, the family claimed the decedent should have been immediately transferred to another facility because the defendant’s hospital could not perform cardiac catheterization. They further alleged that the hospitalist failed to perform an independent evaluation of the patient and also failed to obtain a repeat 12-lead ECG sooner. Lastly, the plaintiffs claimed that the hospital’s nursing staff was negligent in failing to provide nursing care for 3 hours prior to the patient being found unresponsive.

The defendant EP asserted that the initial ECG was nondiagnostic and that the initial troponin level, while elevated, was nonspecific. He argued the ED evaluation and care provided was appropriate. Following trial, a defense verdict was returned.

Discussion

Fortunately, the jury ruled correctly in this case. Acute coronary sydromes can be some of the most challenging medical conditions to evaluate and manage in the ED. The EP’s initial cardiac workup and evaluation for a possible acute thoracic aortic dissection were appropriate—an acute thoracic aortic dissection is a true cardiovascular emergency. After interpreting the initial ECG as nondiagnostic (specifically, to rule out evidence of ST-segment elevation, myocardial infarction [MI], or STEMI), obtaining the contrast CT scan of the chest emergently was critically important. This patient had multiple risk factors for aortic dissection: he was a male between the ages of 50 and 55 years old (the mean age for proximal thoracic aortic dissection); he had a history of hypertension; and he was experiencing chest and back pain.¹

Once an acute aortic dissection was excluded, focusing on a cardiac etiology, as the EP did, was appropriate. The only criticism is that this patient probably should have been managed with an IV antihypertensive agent to allow for a more controlled BP reduction; this, however, does not seem to have played any role in the patient’s ultimate outcome.

Acute coronary syndromes are a dynamic process and progress over time. The EP was clearly concerned about an ACS very early in the case, as evidenced by his attempt to transfer the patient to a facility with specialized cardiac capabilities. After not being able to do so, the most appropriate next step was his admission of the patient to a monitored bed with serial cardiac enzymes and ECGs. It is well known that initial evaluation of both ECG and cardiac enzymes can be normal early on in an ACS. Patients with a normal or nonspecific ECG have a 1% to 5% incidence of MI and a 4% to 23% incidence of unstable angina.²

This patient ultimately experienced a non-ST-segment elevation myocardial infarction (NSTEMI). However, this diagnosis did not become evident until several hours after the patient’s admission to the hospital. It is unfortunate the physician consulted by the EP at the onset did not agree to accept this patient. This patient’s best chance for survival was at a facility capable of percutaneous coronary intervention.

Serotonin Syndrome

Case

A 62-year-old man with a history of hypercholesterolemia and HIV infection presented to the ED for evaluation of diffuse myalgia and tea-colored urine. His medication history included lopinavir/ritonavir (Kaletra) and simvastatin. A week prior to presentation, the patient’s primary care physician had instructed him to increase his daily dose of simvastatin from 40 mg to 80 mg. The patient stated that he had taken simvastatin 80 mg daily for approximately 5 days and then, 2 days prior to presentation, had independently further increased the dose to 160 mg daily.

In the ED, the patient reported feeling fatigued. His initial vital signs were: blood pressure, 129/86 mm Hg; heart rate, 93 beats/minute; respiratory rate, 17 breaths/minute; and temperature, 98.5˚F. Oxygen saturation was 98% on room air. His physical examination was unremarkable. Initial laboratory testing revealed the following: creatine kinase (CK) 350,000 U/L; blood urea nitrogen, 27 mg/dL; creatinine, 0.7 mg/dL; aspartate aminotransferase (AST), 2,950 U/L; and alanine aminotransferase (ALT), 1,305 U/L.

What can cause tea-colored/cola-colored urine and myalgia?

Numerous medications can result in dark-colored urine. These include antimalarial drugs such as chloroquine and primaquine; antibiotics such as metronidazole or nitrofurantoin; and the muscle relaxant methocarbamol. Myalgia and tea-colored urine are the hallmarks of rhabdomyolysis. Rhabdomyolysis involves the destruction of myocytes, which can occur as a result of a long list of processes, including crush injuries, poor oxygenation or perfusion, hypermetabolic states, and direct (or indirect) toxin-mediated myocyte damage.¹ The list of toxic substances that can cause rhabdomyolysis is extensive, and statins are one of the most common drug-induced causes (Table).

Simvastatin is one of seven currently available 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (ie, statins) that are commonly used to treat hypercholesterolemia. Because simvastatin is lipophilic, it can more readily cross cell membranes than nonlipophilic statins such as pravastatin. Simvastatin, therefore, has a propensity to disrupt the cellular integrity of myocytes and hepatocytes.What is the likely cause of this patient’s rhabdomyolysis?

At doses greater than 40 mg daily, simvastatin is associated with myalgia, myositis, and rhabdomyolysis. In December 2011, the US Food and Drug Administration (FDA) released a drug safety announcement recommending the originally approved maximum daily dose of simvastatin 80 mg be limited to patients who have already tolerated that dose for at least 12 months without evidence of muscular injury. The FDA further recommended no new patients be escalated to this dose. According to the FDA, patients taking 80 mg of simvastatin daily are also at increased risk of myopathy. 

The metabolism of simvastatin, in addition to increased dosage of the drug, contributes to its potential for adverse effects. Of the seven available statins, only atorvastatin, lovastatin, and simvastatin are metabolized by the cytochrome P450 3A4 (CYP3A4). Lovastatin and simvastatin appear to have the highest potential for drug-drug interactions when coadministered with drugs that inhibit this enzyme (eg, ritonavir).² The resulting elevation in blood concentration of simvastatin increases the risk of rhabdomyolysis. Other nonlipophilic statins, such as pravastatin, which are mostly eliminated unchanged in the urine and bile, would be preferable for patients taking CYP3A4 inhibitors.

How should patients with rhabdomyolysis be monitored?

Statins interfere with the myocyte’s ability to produce adenosine triphosphate, most likely by depleting coenzyme Q—one of the complexes found in the electron transport chain of the mitochondria. Under conditions of a high-energy requirement, myocytes incapable of producing sufficient energy ultimately fail and lyse, releasing cellular contents such as CK and myoglobin.¹ The serum CK activity serves as a marker of muscle injury and should be monitored closely in patients with rhabdomyolysis. Although values above 5,000 U/L has been associated with renal injury,⁴ in healthy patients with access to hydration, renal injury is relatively uncommon with CK activities less than 50,000 U/L. Even though the prediction of renal failure is difficult, a validated nephrotoxicity prediction instrument using the patient’s age, gender, and initial laboratory data (serum creatinine, calcium, CK, phosphate, and bicarbonate) is available.⁵

Although the association between rhabdomyolysis and acute renal injury is well established, the mechanism remains unclear. Myoglobin from skeletal myocytes passes through the glomerulus without causing damage and is reabsorbed in the proximal renal tubular cell. Iron is subsequently released from the porphyrin ring and, in large concentrations, exceeds the binding capacity of the tissue ferritin. Because it is a transition metal, the free iron ion participates in oxidant stress reactions causing direct injury to the renal tubular cells.⁶ Furthermore, myoglobin also combines with renal tubular proteins, a process enhanced by an environment with lower pH, to form casts and cause renal tubular obstruction.

Patients with rhabdomyolysis may also be at risk for aminotransferase elevation, as occurred in the patient presented here. This elevation is most likely due to myocyte injury. In addition, potassium release due to myocyte destruction may cause life-threatening hyperkalemia, and phosphate liberation from these myocytes may cause hypocalcemia. Laboratory monitoring along with an electrocardiogram should be performed as required.

What is the treatment for rhabdomyolysis?

No adequate randomized controlled trials exist to guide the treatment of patients with rhabdomyolysis. As a result, recommendations for management come from retrospective observational studies, animal studies, case reports, and expert opinion.⁷

Once airway, breathing, and circulation have been addressed, patients with statin-induced rhabdomyolysis should be immediately treated with intravenous (IV) fluids to maintain renal perfusion, which helps to limit acute renal injury. Normal saline appears to be the most recommended fluid type, with a goal of maintaining a urine output of approximately 3 to 5 mL/kg/h.^4,7

Some recommendations include the use of a sodium bicarbonate infusion to raise the urine pH, which may help limit the formation of renal casts from myoglobin. The data to support the benefit of sodium bicarbonate, however, is weak.³ A 2013 systematic review indicated that sodium bicarbonate should only be used to treat severe metabolic acidosis in patients with rhabdomyolysis.⁴

In addition to sodium bicarbonate, the use of diuretics is also discouraged by current recommendations. In patients with refractory electrolyte abnormalities or renal failure, hemodialysis may be required. Before disposition of a patient, his or her medication list should be reconciled to reflect statin discontinuation. 

Case Conclusion

The patient received IV normal saline to maintain his urine output at 2 to 3 cc/kg/h. His repeat creatinine was 0.8 mg/dL and remained stable on repeat testing. His CK and AST concentrations trended down during his hospitalization. On hospital day 4, laboratory values were CK, less than 10,000 U/L; AST, 56 U/L; and ALT, 23 U/L. He had normal serum potassium levels and no dysrhythmia on electrocardiogram. His symptoms resolved on hospital day 2, and he was discharged on hospital day 4 with instructions to discontinue simvastatin.

Dr Fernandez is a senior toxicology fellow, department of emergency medicine, New York University School of Medicine. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board.

Case

A 62-year-old man with a history of hypercholesterolemia and HIV infection presented to the ED for evaluation of diffuse myalgia and tea-colored urine. His medication history included lopinavir/ritonavir (Kaletra) and simvastatin. A week prior to presentation, the patient’s primary care physician had instructed him to increase his daily dose of simvastatin from 40 mg to 80 mg. The patient stated that he had taken simvastatin 80 mg daily for approximately 5 days and then, 2 days prior to presentation, had independently further increased the dose to 160 mg daily.

In the ED, the patient reported feeling fatigued. His initial vital signs were: blood pressure, 129/86 mm Hg; heart rate, 93 beats/minute; respiratory rate, 17 breaths/minute; and temperature, 98.5˚F. Oxygen saturation was 98% on room air. His physical examination was unremarkable. Initial laboratory testing revealed the following: creatine kinase (CK) 350,000 U/L; blood urea nitrogen, 27 mg/dL; creatinine, 0.7 mg/dL; aspartate aminotransferase (AST), 2,950 U/L; and alanine aminotransferase (ALT), 1,305 U/L.

What can cause tea-colored/cola-colored urine and myalgia?

Numerous medications can result in dark-colored urine. These include antimalarial drugs such as chloroquine and primaquine; antibiotics such as metronidazole or nitrofurantoin; and the muscle relaxant methocarbamol. Myalgia and tea-colored urine are the hallmarks of rhabdomyolysis. Rhabdomyolysis involves the destruction of myocytes, which can occur as a result of a long list of processes, including crush injuries, poor oxygenation or perfusion, hypermetabolic states, and direct (or indirect) toxin-mediated myocyte damage.¹ The list of toxic substances that can cause rhabdomyolysis is extensive, and statins are one of the most common drug-induced causes (Table).

Simvastatin is one of seven currently available 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (ie, statins) that are commonly used to treat hypercholesterolemia. Because simvastatin is lipophilic, it can more readily cross cell membranes than nonlipophilic statins such as pravastatin. Simvastatin, therefore, has a propensity to disrupt the cellular integrity of myocytes and hepatocytes.What is the likely cause of this patient’s rhabdomyolysis?

At doses greater than 40 mg daily, simvastatin is associated with myalgia, myositis, and rhabdomyolysis. In December 2011, the US Food and Drug Administration (FDA) released a drug safety announcement recommending the originally approved maximum daily dose of simvastatin 80 mg be limited to patients who have already tolerated that dose for at least 12 months without evidence of muscular injury. The FDA further recommended no new patients be escalated to this dose. According to the FDA, patients taking 80 mg of simvastatin daily are also at increased risk of myopathy. 

The metabolism of simvastatin, in addition to increased dosage of the drug, contributes to its potential for adverse effects. Of the seven available statins, only atorvastatin, lovastatin, and simvastatin are metabolized by the cytochrome P450 3A4 (CYP3A4). Lovastatin and simvastatin appear to have the highest potential for drug-drug interactions when coadministered with drugs that inhibit this enzyme (eg, ritonavir).² The resulting elevation in blood concentration of simvastatin increases the risk of rhabdomyolysis. Other nonlipophilic statins, such as pravastatin, which are mostly eliminated unchanged in the urine and bile, would be preferable for patients taking CYP3A4 inhibitors.

How should patients with rhabdomyolysis be monitored?

Statins interfere with the myocyte’s ability to produce adenosine triphosphate, most likely by depleting coenzyme Q—one of the complexes found in the electron transport chain of the mitochondria. Under conditions of a high-energy requirement, myocytes incapable of producing sufficient energy ultimately fail and lyse, releasing cellular contents such as CK and myoglobin.¹ The serum CK activity serves as a marker of muscle injury and should be monitored closely in patients with rhabdomyolysis. Although values above 5,000 U/L has been associated with renal injury,⁴ in healthy patients with access to hydration, renal injury is relatively uncommon with CK activities less than 50,000 U/L. Even though the prediction of renal failure is difficult, a validated nephrotoxicity prediction instrument using the patient’s age, gender, and initial laboratory data (serum creatinine, calcium, CK, phosphate, and bicarbonate) is available.⁵

Although the association between rhabdomyolysis and acute renal injury is well established, the mechanism remains unclear. Myoglobin from skeletal myocytes passes through the glomerulus without causing damage and is reabsorbed in the proximal renal tubular cell. Iron is subsequently released from the porphyrin ring and, in large concentrations, exceeds the binding capacity of the tissue ferritin. Because it is a transition metal, the free iron ion participates in oxidant stress reactions causing direct injury to the renal tubular cells.⁶ Furthermore, myoglobin also combines with renal tubular proteins, a process enhanced by an environment with lower pH, to form casts and cause renal tubular obstruction.

Patients with rhabdomyolysis may also be at risk for aminotransferase elevation, as occurred in the patient presented here. This elevation is most likely due to myocyte injury. In addition, potassium release due to myocyte destruction may cause life-threatening hyperkalemia, and phosphate liberation from these myocytes may cause hypocalcemia. Laboratory monitoring along with an electrocardiogram should be performed as required.

What is the treatment for rhabdomyolysis?

No adequate randomized controlled trials exist to guide the treatment of patients with rhabdomyolysis. As a result, recommendations for management come from retrospective observational studies, animal studies, case reports, and expert opinion.⁷

Once airway, breathing, and circulation have been addressed, patients with statin-induced rhabdomyolysis should be immediately treated with intravenous (IV) fluids to maintain renal perfusion, which helps to limit acute renal injury. Normal saline appears to be the most recommended fluid type, with a goal of maintaining a urine output of approximately 3 to 5 mL/kg/h.^4,7

Some recommendations include the use of a sodium bicarbonate infusion to raise the urine pH, which may help limit the formation of renal casts from myoglobin. The data to support the benefit of sodium bicarbonate, however, is weak.³ A 2013 systematic review indicated that sodium bicarbonate should only be used to treat severe metabolic acidosis in patients with rhabdomyolysis.⁴

In addition to sodium bicarbonate, the use of diuretics is also discouraged by current recommendations. In patients with refractory electrolyte abnormalities or renal failure, hemodialysis may be required. Before disposition of a patient, his or her medication list should be reconciled to reflect statin discontinuation. 

Case Conclusion

The patient received IV normal saline to maintain his urine output at 2 to 3 cc/kg/h. His repeat creatinine was 0.8 mg/dL and remained stable on repeat testing. His CK and AST concentrations trended down during his hospitalization. On hospital day 4, laboratory values were CK, less than 10,000 U/L; AST, 56 U/L; and ALT, 23 U/L. He had normal serum potassium levels and no dysrhythmia on electrocardiogram. His symptoms resolved on hospital day 2, and he was discharged on hospital day 4 with instructions to discontinue simvastatin.

Dr Fernandez is a senior toxicology fellow, department of emergency medicine, New York University School of Medicine. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board.

Case

A 62-year-old man with a history of hypercholesterolemia and HIV infection presented to the ED for evaluation of diffuse myalgia and tea-colored urine. His medication history included lopinavir/ritonavir (Kaletra) and simvastatin. A week prior to presentation, the patient’s primary care physician had instructed him to increase his daily dose of simvastatin from 40 mg to 80 mg. The patient stated that he had taken simvastatin 80 mg daily for approximately 5 days and then, 2 days prior to presentation, had independently further increased the dose to 160 mg daily.

In the ED, the patient reported feeling fatigued. His initial vital signs were: blood pressure, 129/86 mm Hg; heart rate, 93 beats/minute; respiratory rate, 17 breaths/minute; and temperature, 98.5˚F. Oxygen saturation was 98% on room air. His physical examination was unremarkable. Initial laboratory testing revealed the following: creatine kinase (CK) 350,000 U/L; blood urea nitrogen, 27 mg/dL; creatinine, 0.7 mg/dL; aspartate aminotransferase (AST), 2,950 U/L; and alanine aminotransferase (ALT), 1,305 U/L.

What can cause tea-colored/cola-colored urine and myalgia?

Numerous medications can result in dark-colored urine. These include antimalarial drugs such as chloroquine and primaquine; antibiotics such as metronidazole or nitrofurantoin; and the muscle relaxant methocarbamol. Myalgia and tea-colored urine are the hallmarks of rhabdomyolysis. Rhabdomyolysis involves the destruction of myocytes, which can occur as a result of a long list of processes, including crush injuries, poor oxygenation or perfusion, hypermetabolic states, and direct (or indirect) toxin-mediated myocyte damage.¹ The list of toxic substances that can cause rhabdomyolysis is extensive, and statins are one of the most common drug-induced causes (Table).

Simvastatin is one of seven currently available 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (ie, statins) that are commonly used to treat hypercholesterolemia. Because simvastatin is lipophilic, it can more readily cross cell membranes than nonlipophilic statins such as pravastatin. Simvastatin, therefore, has a propensity to disrupt the cellular integrity of myocytes and hepatocytes.What is the likely cause of this patient’s rhabdomyolysis?

At doses greater than 40 mg daily, simvastatin is associated with myalgia, myositis, and rhabdomyolysis. In December 2011, the US Food and Drug Administration (FDA) released a drug safety announcement recommending the originally approved maximum daily dose of simvastatin 80 mg be limited to patients who have already tolerated that dose for at least 12 months without evidence of muscular injury. The FDA further recommended no new patients be escalated to this dose. According to the FDA, patients taking 80 mg of simvastatin daily are also at increased risk of myopathy. 

The metabolism of simvastatin, in addition to increased dosage of the drug, contributes to its potential for adverse effects. Of the seven available statins, only atorvastatin, lovastatin, and simvastatin are metabolized by the cytochrome P450 3A4 (CYP3A4). Lovastatin and simvastatin appear to have the highest potential for drug-drug interactions when coadministered with drugs that inhibit this enzyme (eg, ritonavir).² The resulting elevation in blood concentration of simvastatin increases the risk of rhabdomyolysis. Other nonlipophilic statins, such as pravastatin, which are mostly eliminated unchanged in the urine and bile, would be preferable for patients taking CYP3A4 inhibitors.

How should patients with rhabdomyolysis be monitored?

Statins interfere with the myocyte’s ability to produce adenosine triphosphate, most likely by depleting coenzyme Q—one of the complexes found in the electron transport chain of the mitochondria. Under conditions of a high-energy requirement, myocytes incapable of producing sufficient energy ultimately fail and lyse, releasing cellular contents such as CK and myoglobin.¹ The serum CK activity serves as a marker of muscle injury and should be monitored closely in patients with rhabdomyolysis. Although values above 5,000 U/L has been associated with renal injury,⁴ in healthy patients with access to hydration, renal injury is relatively uncommon with CK activities less than 50,000 U/L. Even though the prediction of renal failure is difficult, a validated nephrotoxicity prediction instrument using the patient’s age, gender, and initial laboratory data (serum creatinine, calcium, CK, phosphate, and bicarbonate) is available.⁵

Although the association between rhabdomyolysis and acute renal injury is well established, the mechanism remains unclear. Myoglobin from skeletal myocytes passes through the glomerulus without causing damage and is reabsorbed in the proximal renal tubular cell. Iron is subsequently released from the porphyrin ring and, in large concentrations, exceeds the binding capacity of the tissue ferritin. Because it is a transition metal, the free iron ion participates in oxidant stress reactions causing direct injury to the renal tubular cells.⁶ Furthermore, myoglobin also combines with renal tubular proteins, a process enhanced by an environment with lower pH, to form casts and cause renal tubular obstruction.

Patients with rhabdomyolysis may also be at risk for aminotransferase elevation, as occurred in the patient presented here. This elevation is most likely due to myocyte injury. In addition, potassium release due to myocyte destruction may cause life-threatening hyperkalemia, and phosphate liberation from these myocytes may cause hypocalcemia. Laboratory monitoring along with an electrocardiogram should be performed as required.

What is the treatment for rhabdomyolysis?

No adequate randomized controlled trials exist to guide the treatment of patients with rhabdomyolysis. As a result, recommendations for management come from retrospective observational studies, animal studies, case reports, and expert opinion.⁷

Once airway, breathing, and circulation have been addressed, patients with statin-induced rhabdomyolysis should be immediately treated with intravenous (IV) fluids to maintain renal perfusion, which helps to limit acute renal injury. Normal saline appears to be the most recommended fluid type, with a goal of maintaining a urine output of approximately 3 to 5 mL/kg/h.^4,7

Some recommendations include the use of a sodium bicarbonate infusion to raise the urine pH, which may help limit the formation of renal casts from myoglobin. The data to support the benefit of sodium bicarbonate, however, is weak.³ A 2013 systematic review indicated that sodium bicarbonate should only be used to treat severe metabolic acidosis in patients with rhabdomyolysis.⁴

In addition to sodium bicarbonate, the use of diuretics is also discouraged by current recommendations. In patients with refractory electrolyte abnormalities or renal failure, hemodialysis may be required. Before disposition of a patient, his or her medication list should be reconciled to reflect statin discontinuation. 

Case Conclusion

The patient received IV normal saline to maintain his urine output at 2 to 3 cc/kg/h. His repeat creatinine was 0.8 mg/dL and remained stable on repeat testing. His CK and AST concentrations trended down during his hospitalization. On hospital day 4, laboratory values were CK, less than 10,000 U/L; AST, 56 U/L; and ALT, 23 U/L. He had normal serum potassium levels and no dysrhythmia on electrocardiogram. His symptoms resolved on hospital day 2, and he was discharged on hospital day 4 with instructions to discontinue simvastatin.

Dr Fernandez is a senior toxicology fellow, department of emergency medicine, New York University School of Medicine. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board.

Patients with loss of bladder control experience discomfort, embarrassment, personal care and health issues, and, often, significant pain, all with a decidedly negative impact on quality of life. Although some patients may find lifestyle modifications, drug therapy, and self-catheterization acceptable and effective, there is a clear need for more options.

Botulinum toxin, or onabotulinumtoxinA, is currently approved by the US Food and Drug Administration (FDA) for neurogenic detrusor overactivity and overactive bladder refractory to drug therapy. Studies so far have shown botulinum toxin injection to be safe and effective for these conditions, and these results have led to interest in off-label uses, eg, for detrusor external sphincter dyssynergia (DESD), motor and sensory urgency, and painful bladder syndrome/interstitial cystitis (Table 1).

Although more data from clinical trials are needed, botulinum toxin injection offers patients a much-needed treatment option.

HOW BOTULINUM TOXIN WORKS

Seven serotypes identified

Discovered in 1897, botulinum toxin is a neurotoxin produced by the gram-positive, rod-shaped anaerobic bacterium Clostridium botulinum¹ and is the most poisonous naturally occurring toxin known.² Seven immunologically distinct antigenic serotypes have been identified (A, B, C1, D, E, F, and G),¹ but only types A and B are available for clinical use.

Most research into potential therapeutic uses has focused on type A, which has the longest duration of action, a clinical advantage.³ Recently, work has been done to further characterize other serotypes and to isolate additional variants of botulinum toxin. For example, serotype E, the predominant serotype associated with foodborne botulism, is being studied in an effort to prevent future outbreaks.⁴

Our discussion focuses on clinical uses of the serotype A botulinum toxin preparation, which we will refer to simply as botulinum toxin.

Studies exploring how it works

Botulinum toxin exerts its effects by binding to peripheral cholinergic terminals, inhibiting release of acetylcholine at the neuromuscular junction. Flaccid paralysis ensues as a result.

Results of animal studies have shed additional light on the specific actions of botulinum toxin A:

• It may alter levels of nerve growth factor and transient receptor potential vanilloid 1 in rats, and this may provide an additional mechanism of reducing bladder detrusor overactivity.⁵
• In addition to blocking acetylcholine release from motor neurons, it inhibits the release of neurotransmitters involved in bladder sensory afferent pathways.⁶
• It inhibits the release of substance P and glutamate, neuropeptides involved in sensory and nociceptive pathways.^6,7
• It promotes apoptosis in prostatic tissue; however, this effect has not been shown in the bladder.³

The time necessary to recover function after botulinum toxin paralysis depends on the subtype of botulinum toxin as well as on the type of nerve terminal. Chemodenervation lasts from 3 to 6 months when the toxin is injected into the neuromuscular junction of skeletal muscle, and considerably longer (up to 1 year) when injected into the autonomic neurons of smooth muscle.^2,6

TREATMENT OF NEUROGENIC DETRUSOR OVERACTIVITY

Neurogenic detrusor overactivity involves involuntary contractions of the bladder resulting from spinal cord injury, multiple sclerosis, and other neurologic conditions. An estimated 273,000 people in the United States have a spinal cord injury, and 81% of them have urologic symptoms ranging from areflexia to overactivity.⁸ From 75% to 100% of patients with multiple sclerosis have urologic symptoms, and detrusor overactivity is the most common.⁹

Detrusor overactivity can cause urinary urgency, urinary frequency, and urgency incontinence, significantly affecting quality of life and leading to skin breakdown, sacral ulcerations, and challenges with personal care.

Anticholinergic drugs have been the mainstay of therapy. If drug therapy failed, the next option was reconstructive surgery, often augmentation cystoplasty. Thus, botulinum toxin injection is an important advance in treatment options.

Studies that showed effectiveness

Botulinum toxin for neurogenic detrusor overactivity was first studied by Schurch et al.¹⁰ In their study, 200 U or 300 U was injected into the trigone of 21 patients with spinal cord injury and urgency incontinence managed with intermittent self-catheterization.¹⁰ At 6 weeks after injection, 17 of the 19 patients seen at follow-up visits were completely continent. Urodynamic evaluation revealed significant increases in maximum cystometric capacity and in volume at first involuntary detrusor contraction, and a decrease in detrusor voiding pressure. Of the 11 patients available for follow-up at 16 and 36 weeks, improvements in measures of incontinence and urodynamic function persisted.

In addition, two small randomized controlled trials^11,12 showed significant increases in cystometric bladder capacity, significant improvement in quality-of-life measures, and reduction in episodes of urgency incontinence.

In 2011 and 2012, two multicenter double-blind randomized controlled trials reported on patients with multiple sclerosis and spinal cord injury with neurogenic detrusor overactivity inadequately managed with drug therapy. The patients were randomized to botulinum toxin injection (200 U or 300 U) or placebo injection.^13,14 The primary end point for both studies was the change from baseline in episodes of urinary incontinence per week at week 6. Secondary end points were maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction, and score on the Incontinence Quality of Life scale.¹⁵

In both studies, the mean number of urinary incontinence episodes per week was 33 at baseline. At week 6, Cruz et al¹⁴ found that patients who received botulinum toxin injection had significantly fewer episodes per week (21.8 fewer with 200 U, 19.4 fewer with 300 U) than those in the placebo group, who had 13.2 fewer episodes per week (P < .01). Ginsberg et al¹³ reported decreases in the mean number of episodes of urinary incontinence of 21, 23, and 9 episodes per week in the 200 U, 300 U, and placebo groups, respectively (P < .001). The patients who received botulinum toxin had statistically significant improvements in maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction, and Incontinence Quality of Life scores compared with placebo (P < .001). Thirty-eight percent of patients in the treatment group were fully continent.^13,14

Safety and adverse effects

The most frequently reported adverse events were urinary tract infection (24% of patients)^13,14 and urinary retention requiring initiation of clean intermittent catheterization. In the study by Cruz et al,¹⁴ these were reported in 30% with 200 U, 42% with 300 U, and 12% with placebo, while in the study by Ginsberg et al¹³ they were reported in 35% with 200 U, 42% with 300 U, and 10% with placebo.

In a study of long-term safety and efficacy of botulinum toxin injection in patients with neurogenic detrusor overactivity, Kennelly et al¹⁶ found that patients undergoing repeat injections had sustained reductions in episodes of incontinence and increases in the maximum cystometric capacity and quality of life scores, with no increase in adverse events over time.¹⁶

But is it cost-effective?

While botulinum toxin injection may be safe and effective for neurogenic detrusor overactivity, is it cost-effective?

Carlson et al¹⁷ used a Markov State Transition model to assess the cost of refractory neurogenic detrusor overactivity in patients receiving botulinum toxin vs best supportive care (incontinence pads, medications, intermittent self-catheterization).¹⁷ They found that the injections were more expensive than supportive care but were cost-effective when considering the reduction in episodes of incontinence, the reduced need for incontinence products, and improvement in measures of quality of life.

What the evidence indicates

Trials of botulinum toxin injection for neurogenic detrusor overactivity have shown that it improves continence, maximum cystometric capacity, detrusor pressures, and quality of life. The main adverse effects are urinary tract infection and urinary retention requiring intermittent self-catheterization.

Although many patients with this condition are already self-catheterizing, the physician must discuss this before botulinum toxin therapy to ensure that the patient or a family member is able to perform catheterization. Studies have shown that patients have an increase in urinary tract infections after botulinum injections. But in these studies, a urinary tract infection was defined as 100,000 colony-forming units or the presence of leukocytosis with or without symptoms. It is important to remember that patients on intermittent catheterization have bacteriuria and should be treated only for symptomatic, not asymptomatic, bacteriuria.

TREATMENT OF IDIOPATHIC OVERACTIVE BLADDER

Patients with idiopathic overactive bladder have urinary urgency accompanied by urgency incontinence, nocturia, or urinary frequency.¹⁸ The prevalence of this condition has been reported to range from 1.7% to 13.3% in men age 30 and older and 7% to 30.3% in women of similar ages. About one-third of women with overactive bladder also have detrusor overactivity.¹⁹ Overactive bladder presents a significant economic and medical burden on the healthcare system, as well as having a negative impact on quality of life.

The FDA approved botulinum toxin injection for treatment of idiopathic overactive bladder in January 2013.

Evidence of effectiveness

Two multicenter randomized controlled trials^20,21 of botulinum toxin 100 U enrolled patients age 18 and older who had more than three episodes of urinary urgency incontinence in a 3-day period or more than eight micturitions per day inadequately managed by anticholinergic drug therapy. Primary end points were the change from baseline in the number of episodes of urinary incontinence per day and the proportion of patients with a positive response on the Treatment Benefit Scale²² at week 12. Secondary end points included episodes of urinary urgency incontinence, micturition, urgency, and nocturia, and scores on health-related quality of life questionnaires (Incontinence Quality of Life scale, King’s Health Questionnaire).

In both studies, patients receiving botulinum toxin had significantly fewer episodes of incontinence compared with placebo (−2.65 vs −0.87; P < .001 and −2.95 vs −1.03; P < .001).^20,21 Reductions from baseline in all other symptoms of overactive bladder, a positive treatment response on the treatment benefit scale, and improvements in quality-of-life scores were also significantly greater with botulinum toxin injection than with placebo (P ≤ .01).

As in the studies of neurogenic detrusor overactivity, the most common adverse effects were urinary tract infection (occurring in 15.5%²⁰ and 24.1%²¹ of patients) and urinary retention requiring self-catheterization (5.4%²⁰ and 6.9%²¹).

The largest study to date of anticholinergic therapy vs botulinum toxin injection²³ in women with urinary urgency incontinence, published in 2012, studied nearly 250 women who had five or more episodes of idiopathic urgency incontinence in a 3-day period. They were randomized either to daily oral therapy (solifenacin 5 mg with possible escalation to 10 mg and, if necessary, a subsequent switch to extended-release trospium 60 mg) plus one intradetrusor injection of saline, or to a daily oral placebo plus one injection of botulinum toxin 100 U.²³

The dropout rate was low in both groups, with 93% of patients in both groups completing the 6-month protocol. Women experienced a mean reduction in urgency incontinence episodes of 3.4 per day (baseline 5) in the anticholinergic group vs 3.3 episodes in the botulinum toxin group (P = .81). However, more patients achieved complete resolution of urinary urgency incontinence in the botulinum toxin group than in the anticholinergic therapy group (27% vs 13%; P = .003). Quality of life improved in both groups without a significant difference between the groups. The botulinum toxin group had higher rates of initiation of self-catheterization (5% vs 0%, P = .01) and urinary tract infection (33% vs 13%, P < .001).²³

Botulinum toxin as a third-line therapy

In May 2014, the American Urological Association updated its guidelines on idiopathic overactive bladder²⁴ to include botulinum toxin injection as standard third-line therapy for patients in whom behavioral and medical management (ie, anticholinergics and beta-3-agonists) failed.

Interpreting the evidence to date

Overall, studies in idiopathic overactive bladder have shown a reduction in episodes of urgency incontinence and other symptoms, with some data also demonstrating a corresponding improvement in quality of life.

As in neurogenic detrusor overactivity, the main risks associated with botulinum toxin injection are urinary tract infection and the need to initiate self-catheterization. Although 94% of patients studied did not require self-catheterization after injection, the patient’s ability to perform self-catheterization should be determined before proceeding with botulinum toxin injections.

DETRUSOR EXTERNAL SPHINCTER DYSSYNERGIA

Botulinum toxin has been used not only to improve bladder storage but also to facilitate bladder emptying, as in patients with DESD, a lack of coordination between the bladder and the urinary sphincter. Normal voiding involves relaxation of the urinary sphincter and contraction of the bladder; in DESD the sphincter contracts and works against the bladder’s ability to empty. This leads not only to difficulty emptying the bladder but also to elevated bladder pressure, which can cause renal damage if untreated.

DESD can be seen after injury between the pontine micturition center, which coordinates activity between the bladder and the sphincter, and the caudal spinal cord. This can occur in spinal cord injury, multiple sclerosis, myelomeningocele, and transverse myelitis and can cause significant morbidity for the patient.

Treatment options include drug therapy, injection of botulinum toxin into the sphincter, clean intermittent catheterization, indwelling catheterization, urethral stenting, sphincterotomy, and reconstructive surgery such as urinary diversion.²⁵

The goals of therapy are to avoid the need for clean intermittent catheterization in patients who have difficulty with manual dexterity, and to avoid the need for surgical procedures such as sphincterotomy and urinary diversion. The efficacy of urethral stenting is low, and medical management can be limited.²⁶

DESD leads to difficulty emptying the bladder, elevated bladder pressure, and, if untreated, renal damage

In the first published report on botulinum toxin for DESD (in 1988),²⁷ of 11 patients with spinal cord injury and DESD who received botulinum toxin injected into the external urethral sphincter, 10 showed signs of sphincter denervation on electromyography and reductions in urethral pressure profiles and postvoid residual volumes. Schurch et al²⁸ and de Sèze et al²⁹ also reported reductions in postvoid residual volume and maximal urethral pressures in patients with spinal cord injury and DESD.

In 2005, Gallien et al³⁰ reported what is still the largest multicenter randomized controlled trial of botulinum toxin injection in DESD. Eighty-six patients with multiple sclerosis, DESD, and chronic urinary retention were randomized to receive either a single transperineal botulinum toxin injection of 100 U plus the alpha-1-blocker alfuzosin, or a placebo injection plus alfuzosin. Botulinum toxin treatment was associated with significantly increased voided volumes and reduced premicturition and maximal detrusor pressures, but no significant decrease in postvoid residual volume.³⁰

More study needed

Despite these findings, a Cochrane Review concluded that, given the limited experience with intrasphincteric injection of botulinum toxin, data from larger randomized controlled trials are needed before making definitive recommendations.²⁵ In the meantime, the clinician must weigh the low morbidity of the procedure against the limited options in the treatment of these patients.

OFF-LABEL UROLOGIC INDICATIONS

Botulinum toxin injection has been studied off-label for painful bladder syndrome/interstitial cystitis and for chronic prostatic pain. Patients with these conditions often describe pain with filling of the bladder, which leads to urinary frequency in an attempt to relieve the pain.

These pain syndromes can be difficult to treat and can have a devastating impact on quality of life. Treatment options include pain management, stress management, physical therapy, intravesical therapies, cystoscopy with hydrodistention, neuromodulation, cyclosporine, urinary diversion surgery, and botulinum toxin injection (an off-label use).³¹

In painful bladder syndrome/interstitial cystitis, botulinum toxin is thought to act on sensory afferent pathways, as well as to inhibit the release of substance P and glutamate, neuropeptides involved in sensory and nociceptive pathways.⁶ In animal studies,³² botulinum toxin was found to inhibit the afferent neural response by inhibiting mechanoreceptor-mediated release of adenosine triphosphate and by causing a decrease in calcitonin gene-related peptide, which helps regulate micturition and mediates painful bladder sensation.

Clinical studies to date in pelvic pain syndromes

Data from clinical studies of botulinum toxin injection for pelvic pain syndromes are limited. Zermann et al³³ performed transurethral perisphincteric injection in 11 men with chronic prostatic pain, 9 of whom reported subjective pain relief, with an average decrease from 7.2 to 1.6 on a visual analogue scale. Postinjection urodynamic studies showed a decrease in functional urethral length, urethral closure pressure, and postvoid residual volume, and an increase in the peak and average flow rates.³³

Abbott et al³⁴ evaluated the effect of botulinum toxin injection into the levator ani in 12 women with chronic pelvic pain and pelvic floor hypertonicity. Pelvic floor manometry showed significant reduction in resting muscle pressures and improvements in dyspareunia and nonmenstrual pain. There were also improvements in quality of life and dyschezia, but these were not statistically significant.

Smith et al³⁵ injected botulinum toxin into the detrusor of 13 women with refractory painful bladder syndrome and interstitial cystitis,³⁵ and 9 women (69%) noted statistically significant improvements in the Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index, daytime frequency, nocturia, pain, and urodynamic parameters (volume at first desire to void, and maximum cystometric capacity).

In a prospective randomized study of patients with refractory painful bladder syndrome and interstitial cystitis, Kuo and Chancellor³⁶ compared suburothelial injection of 200 U or 100 U of botulinum toxin plus hydrodistention against hydrodistention alone.Patients who received botulinum toxin had increased bladder capacity and improved long-term pain relief, but no difference was noted between 200 U and 100 U, and more adverse effects were seen with the higher dose.³⁶

Pinto et al³⁷ treated 16 women with refractory painful bladder syndrome and interstitial cystitis with intratrigonal injections of botulinum toxin and reported improvements in pain scores, symptom scores, urinary frequency, and quality-of-life measures. The effect lasted 9.9 months (± 2.4 months) and persisted with successive injections.³⁷

More study needed

Although these studies show that botulinum toxin injection for pelvic pain syndromes has the potential to improve pain, urinary frequency, bladder sensation, bladder capacity, and quality of life, larger randomized controlled trials are needed.

Again, the treatment options are limited for refractory painful bladder syndrome and interstitial cystitis. Patients may be desperate for relief from their symptoms. Practitioners must manage expectations and properly inform patients of the potential risks of treatments, especially with patients who will easily agree to further treatment with the smallest hope of relief.

INJECTION TECHNIQUES

For general points about the procedure to discuss with patients, see “What to tell patients.”

Cystoscopic detrusor injection

This procedure is usually done on an outpatient basis (eg, office, ambulatory surgery center). With the patient in the lithotomy position, 100 mL of 2% lidocaine is instilled into the bladder and is allowed 15 to 20 minutes to take effect. A flexible or rigid cystoscope can be used. Depending on the indication, the bladder is injected with 100 U to 300 U of botulinum toxin. The ideal depth of injection is 2 mm in the detrusor muscle, with each injection spaced about 1 cm apart. The recommended administration for 100 U is to inject 20 sites with 0.5 U per mL of saline and, for 200 U, to inject 30 sites with about 0.67 U per mL of saline.³⁸ The location of the injections into the detrusor can vary, as long as adequate spacing is assured.

Injection sites vary. Proponents of injecting the trigone argue that as it is an area of greater nerve density, patients will have a better clinical response. Opponents argue that trigonal injection could result in distal ureteral paralysis and subsequent ureteral reflux. However, this theoretical concern has not been observed clinically.

Urethral injection (off-label use)

The urethra can be injected cystoscopically or periurethrally. Cystoscopic injection involves localization of the external sphincter using the rigid cystoscope and collagen needle; a total of 100 U is injected into the sphincter under direct vision, typically at the 3 o’clock and 9 o’clock positions.³⁵ The periurethral technique is an option in women and involves a spinal needle with 100 U to 200 U of botulinum toxin injected into the external sphincter muscle at the 2 o’clock and 10 o’clock positions.

ADVERSE EFFECTS AND CONTRAINDICATIONS

Adverse effects are rare for urologic applications. The injections are localized, with little systemic absorption, and the doses are 1/1,000th of the theorized lethal dose in a 70-kg male.² The maximum recommended dose for a 3-month period is 360 U.

Generalized muscle weakness has been reported in a paraplegic patient and in a tetraplegic patient after detrusor injections.² Interestingly, both patients had return of bladder spasticity within 2 months, prompting speculation about diffusion of botulinum toxin through the bladder wall.²

Repeat injections can cause an immune response in up to 5% of patients.⁶ Patients undergoing repeat injections are at risk of forming neutralizing antibodies that can interfere with the efficacy of botulinum toxin.⁶ In a study by Schulte-Baukloh et al, all patients with antibodies to botulinum toxin had a history of recurrent urinary tract infection.³⁹

Botulinum toxin injection is contraindicated in patients with preexisting neuromuscular disease, such as myasthenia gravis, Eaton-Lambert syndrome, and amyotrophic lateral sclerosis. It should also be avoided in patients who are breastfeeding, pregnant, or using agents that potentiate neuromuscular weakness, such as aminoglycosides.

Patients should be informed that some formulations of botulinum toxin include a stabilizer such as albumin derived from human blood, as this may be of religious or cultural significance.

Patients with loss of bladder control experience discomfort, embarrassment, personal care and health issues, and, often, significant pain, all with a decidedly negative impact on quality of life. Although some patients may find lifestyle modifications, drug therapy, and self-catheterization acceptable and effective, there is a clear need for more options.

Botulinum toxin, or onabotulinumtoxinA, is currently approved by the US Food and Drug Administration (FDA) for neurogenic detrusor overactivity and overactive bladder refractory to drug therapy. Studies so far have shown botulinum toxin injection to be safe and effective for these conditions, and these results have led to interest in off-label uses, eg, for detrusor external sphincter dyssynergia (DESD), motor and sensory urgency, and painful bladder syndrome/interstitial cystitis (Table 1).

Although more data from clinical trials are needed, botulinum toxin injection offers patients a much-needed treatment option.

HOW BOTULINUM TOXIN WORKS

Seven serotypes identified

Discovered in 1897, botulinum toxin is a neurotoxin produced by the gram-positive, rod-shaped anaerobic bacterium Clostridium botulinum¹ and is the most poisonous naturally occurring toxin known.² Seven immunologically distinct antigenic serotypes have been identified (A, B, C1, D, E, F, and G),¹ but only types A and B are available for clinical use.

Most research into potential therapeutic uses has focused on type A, which has the longest duration of action, a clinical advantage.³ Recently, work has been done to further characterize other serotypes and to isolate additional variants of botulinum toxin. For example, serotype E, the predominant serotype associated with foodborne botulism, is being studied in an effort to prevent future outbreaks.⁴

Our discussion focuses on clinical uses of the serotype A botulinum toxin preparation, which we will refer to simply as botulinum toxin.

Studies exploring how it works

Botulinum toxin exerts its effects by binding to peripheral cholinergic terminals, inhibiting release of acetylcholine at the neuromuscular junction. Flaccid paralysis ensues as a result.

Results of animal studies have shed additional light on the specific actions of botulinum toxin A:

• It may alter levels of nerve growth factor and transient receptor potential vanilloid 1 in rats, and this may provide an additional mechanism of reducing bladder detrusor overactivity.⁵
• In addition to blocking acetylcholine release from motor neurons, it inhibits the release of neurotransmitters involved in bladder sensory afferent pathways.⁶
• It inhibits the release of substance P and glutamate, neuropeptides involved in sensory and nociceptive pathways.^6,7
• It promotes apoptosis in prostatic tissue; however, this effect has not been shown in the bladder.³

The time necessary to recover function after botulinum toxin paralysis depends on the subtype of botulinum toxin as well as on the type of nerve terminal. Chemodenervation lasts from 3 to 6 months when the toxin is injected into the neuromuscular junction of skeletal muscle, and considerably longer (up to 1 year) when injected into the autonomic neurons of smooth muscle.^2,6

TREATMENT OF NEUROGENIC DETRUSOR OVERACTIVITY

Neurogenic detrusor overactivity involves involuntary contractions of the bladder resulting from spinal cord injury, multiple sclerosis, and other neurologic conditions. An estimated 273,000 people in the United States have a spinal cord injury, and 81% of them have urologic symptoms ranging from areflexia to overactivity.⁸ From 75% to 100% of patients with multiple sclerosis have urologic symptoms, and detrusor overactivity is the most common.⁹

Detrusor overactivity can cause urinary urgency, urinary frequency, and urgency incontinence, significantly affecting quality of life and leading to skin breakdown, sacral ulcerations, and challenges with personal care.

Anticholinergic drugs have been the mainstay of therapy. If drug therapy failed, the next option was reconstructive surgery, often augmentation cystoplasty. Thus, botulinum toxin injection is an important advance in treatment options.

Studies that showed effectiveness

Botulinum toxin for neurogenic detrusor overactivity was first studied by Schurch et al.¹⁰ In their study, 200 U or 300 U was injected into the trigone of 21 patients with spinal cord injury and urgency incontinence managed with intermittent self-catheterization.¹⁰ At 6 weeks after injection, 17 of the 19 patients seen at follow-up visits were completely continent. Urodynamic evaluation revealed significant increases in maximum cystometric capacity and in volume at first involuntary detrusor contraction, and a decrease in detrusor voiding pressure. Of the 11 patients available for follow-up at 16 and 36 weeks, improvements in measures of incontinence and urodynamic function persisted.

In addition, two small randomized controlled trials^11,12 showed significant increases in cystometric bladder capacity, significant improvement in quality-of-life measures, and reduction in episodes of urgency incontinence.

In 2011 and 2012, two multicenter double-blind randomized controlled trials reported on patients with multiple sclerosis and spinal cord injury with neurogenic detrusor overactivity inadequately managed with drug therapy. The patients were randomized to botulinum toxin injection (200 U or 300 U) or placebo injection.^13,14 The primary end point for both studies was the change from baseline in episodes of urinary incontinence per week at week 6. Secondary end points were maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction, and score on the Incontinence Quality of Life scale.¹⁵

In both studies, the mean number of urinary incontinence episodes per week was 33 at baseline. At week 6, Cruz et al¹⁴ found that patients who received botulinum toxin injection had significantly fewer episodes per week (21.8 fewer with 200 U, 19.4 fewer with 300 U) than those in the placebo group, who had 13.2 fewer episodes per week (P < .01). Ginsberg et al¹³ reported decreases in the mean number of episodes of urinary incontinence of 21, 23, and 9 episodes per week in the 200 U, 300 U, and placebo groups, respectively (P < .001). The patients who received botulinum toxin had statistically significant improvements in maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction, and Incontinence Quality of Life scores compared with placebo (P < .001). Thirty-eight percent of patients in the treatment group were fully continent.^13,14

Safety and adverse effects

The most frequently reported adverse events were urinary tract infection (24% of patients)^13,14 and urinary retention requiring initiation of clean intermittent catheterization. In the study by Cruz et al,¹⁴ these were reported in 30% with 200 U, 42% with 300 U, and 12% with placebo, while in the study by Ginsberg et al¹³ they were reported in 35% with 200 U, 42% with 300 U, and 10% with placebo.

In a study of long-term safety and efficacy of botulinum toxin injection in patients with neurogenic detrusor overactivity, Kennelly et al¹⁶ found that patients undergoing repeat injections had sustained reductions in episodes of incontinence and increases in the maximum cystometric capacity and quality of life scores, with no increase in adverse events over time.¹⁶

But is it cost-effective?

While botulinum toxin injection may be safe and effective for neurogenic detrusor overactivity, is it cost-effective?

Carlson et al¹⁷ used a Markov State Transition model to assess the cost of refractory neurogenic detrusor overactivity in patients receiving botulinum toxin vs best supportive care (incontinence pads, medications, intermittent self-catheterization).¹⁷ They found that the injections were more expensive than supportive care but were cost-effective when considering the reduction in episodes of incontinence, the reduced need for incontinence products, and improvement in measures of quality of life.

What the evidence indicates

Trials of botulinum toxin injection for neurogenic detrusor overactivity have shown that it improves continence, maximum cystometric capacity, detrusor pressures, and quality of life. The main adverse effects are urinary tract infection and urinary retention requiring intermittent self-catheterization.

Although many patients with this condition are already self-catheterizing, the physician must discuss this before botulinum toxin therapy to ensure that the patient or a family member is able to perform catheterization. Studies have shown that patients have an increase in urinary tract infections after botulinum injections. But in these studies, a urinary tract infection was defined as 100,000 colony-forming units or the presence of leukocytosis with or without symptoms. It is important to remember that patients on intermittent catheterization have bacteriuria and should be treated only for symptomatic, not asymptomatic, bacteriuria.

TREATMENT OF IDIOPATHIC OVERACTIVE BLADDER

Patients with idiopathic overactive bladder have urinary urgency accompanied by urgency incontinence, nocturia, or urinary frequency.¹⁸ The prevalence of this condition has been reported to range from 1.7% to 13.3% in men age 30 and older and 7% to 30.3% in women of similar ages. About one-third of women with overactive bladder also have detrusor overactivity.¹⁹ Overactive bladder presents a significant economic and medical burden on the healthcare system, as well as having a negative impact on quality of life.

The FDA approved botulinum toxin injection for treatment of idiopathic overactive bladder in January 2013.

Evidence of effectiveness

Two multicenter randomized controlled trials^20,21 of botulinum toxin 100 U enrolled patients age 18 and older who had more than three episodes of urinary urgency incontinence in a 3-day period or more than eight micturitions per day inadequately managed by anticholinergic drug therapy. Primary end points were the change from baseline in the number of episodes of urinary incontinence per day and the proportion of patients with a positive response on the Treatment Benefit Scale²² at week 12. Secondary end points included episodes of urinary urgency incontinence, micturition, urgency, and nocturia, and scores on health-related quality of life questionnaires (Incontinence Quality of Life scale, King’s Health Questionnaire).

In both studies, patients receiving botulinum toxin had significantly fewer episodes of incontinence compared with placebo (−2.65 vs −0.87; P < .001 and −2.95 vs −1.03; P < .001).^20,21 Reductions from baseline in all other symptoms of overactive bladder, a positive treatment response on the treatment benefit scale, and improvements in quality-of-life scores were also significantly greater with botulinum toxin injection than with placebo (P ≤ .01).

As in the studies of neurogenic detrusor overactivity, the most common adverse effects were urinary tract infection (occurring in 15.5%²⁰ and 24.1%²¹ of patients) and urinary retention requiring self-catheterization (5.4%²⁰ and 6.9%²¹).

The largest study to date of anticholinergic therapy vs botulinum toxin injection²³ in women with urinary urgency incontinence, published in 2012, studied nearly 250 women who had five or more episodes of idiopathic urgency incontinence in a 3-day period. They were randomized either to daily oral therapy (solifenacin 5 mg with possible escalation to 10 mg and, if necessary, a subsequent switch to extended-release trospium 60 mg) plus one intradetrusor injection of saline, or to a daily oral placebo plus one injection of botulinum toxin 100 U.²³

The dropout rate was low in both groups, with 93% of patients in both groups completing the 6-month protocol. Women experienced a mean reduction in urgency incontinence episodes of 3.4 per day (baseline 5) in the anticholinergic group vs 3.3 episodes in the botulinum toxin group (P = .81). However, more patients achieved complete resolution of urinary urgency incontinence in the botulinum toxin group than in the anticholinergic therapy group (27% vs 13%; P = .003). Quality of life improved in both groups without a significant difference between the groups. The botulinum toxin group had higher rates of initiation of self-catheterization (5% vs 0%, P = .01) and urinary tract infection (33% vs 13%, P < .001).²³

Botulinum toxin as a third-line therapy

In May 2014, the American Urological Association updated its guidelines on idiopathic overactive bladder²⁴ to include botulinum toxin injection as standard third-line therapy for patients in whom behavioral and medical management (ie, anticholinergics and beta-3-agonists) failed.

Interpreting the evidence to date

Overall, studies in idiopathic overactive bladder have shown a reduction in episodes of urgency incontinence and other symptoms, with some data also demonstrating a corresponding improvement in quality of life.

As in neurogenic detrusor overactivity, the main risks associated with botulinum toxin injection are urinary tract infection and the need to initiate self-catheterization. Although 94% of patients studied did not require self-catheterization after injection, the patient’s ability to perform self-catheterization should be determined before proceeding with botulinum toxin injections.

DETRUSOR EXTERNAL SPHINCTER DYSSYNERGIA

Botulinum toxin has been used not only to improve bladder storage but also to facilitate bladder emptying, as in patients with DESD, a lack of coordination between the bladder and the urinary sphincter. Normal voiding involves relaxation of the urinary sphincter and contraction of the bladder; in DESD the sphincter contracts and works against the bladder’s ability to empty. This leads not only to difficulty emptying the bladder but also to elevated bladder pressure, which can cause renal damage if untreated.

DESD can be seen after injury between the pontine micturition center, which coordinates activity between the bladder and the sphincter, and the caudal spinal cord. This can occur in spinal cord injury, multiple sclerosis, myelomeningocele, and transverse myelitis and can cause significant morbidity for the patient.

Treatment options include drug therapy, injection of botulinum toxin into the sphincter, clean intermittent catheterization, indwelling catheterization, urethral stenting, sphincterotomy, and reconstructive surgery such as urinary diversion.²⁵

The goals of therapy are to avoid the need for clean intermittent catheterization in patients who have difficulty with manual dexterity, and to avoid the need for surgical procedures such as sphincterotomy and urinary diversion. The efficacy of urethral stenting is low, and medical management can be limited.²⁶

DESD leads to difficulty emptying the bladder, elevated bladder pressure, and, if untreated, renal damage

In the first published report on botulinum toxin for DESD (in 1988),²⁷ of 11 patients with spinal cord injury and DESD who received botulinum toxin injected into the external urethral sphincter, 10 showed signs of sphincter denervation on electromyography and reductions in urethral pressure profiles and postvoid residual volumes. Schurch et al²⁸ and de Sèze et al²⁹ also reported reductions in postvoid residual volume and maximal urethral pressures in patients with spinal cord injury and DESD.

In 2005, Gallien et al³⁰ reported what is still the largest multicenter randomized controlled trial of botulinum toxin injection in DESD. Eighty-six patients with multiple sclerosis, DESD, and chronic urinary retention were randomized to receive either a single transperineal botulinum toxin injection of 100 U plus the alpha-1-blocker alfuzosin, or a placebo injection plus alfuzosin. Botulinum toxin treatment was associated with significantly increased voided volumes and reduced premicturition and maximal detrusor pressures, but no significant decrease in postvoid residual volume.³⁰

More study needed

Despite these findings, a Cochrane Review concluded that, given the limited experience with intrasphincteric injection of botulinum toxin, data from larger randomized controlled trials are needed before making definitive recommendations.²⁵ In the meantime, the clinician must weigh the low morbidity of the procedure against the limited options in the treatment of these patients.

OFF-LABEL UROLOGIC INDICATIONS

Botulinum toxin injection has been studied off-label for painful bladder syndrome/interstitial cystitis and for chronic prostatic pain. Patients with these conditions often describe pain with filling of the bladder, which leads to urinary frequency in an attempt to relieve the pain.

These pain syndromes can be difficult to treat and can have a devastating impact on quality of life. Treatment options include pain management, stress management, physical therapy, intravesical therapies, cystoscopy with hydrodistention, neuromodulation, cyclosporine, urinary diversion surgery, and botulinum toxin injection (an off-label use).³¹

In painful bladder syndrome/interstitial cystitis, botulinum toxin is thought to act on sensory afferent pathways, as well as to inhibit the release of substance P and glutamate, neuropeptides involved in sensory and nociceptive pathways.⁶ In animal studies,³² botulinum toxin was found to inhibit the afferent neural response by inhibiting mechanoreceptor-mediated release of adenosine triphosphate and by causing a decrease in calcitonin gene-related peptide, which helps regulate micturition and mediates painful bladder sensation.

Clinical studies to date in pelvic pain syndromes

Data from clinical studies of botulinum toxin injection for pelvic pain syndromes are limited. Zermann et al³³ performed transurethral perisphincteric injection in 11 men with chronic prostatic pain, 9 of whom reported subjective pain relief, with an average decrease from 7.2 to 1.6 on a visual analogue scale. Postinjection urodynamic studies showed a decrease in functional urethral length, urethral closure pressure, and postvoid residual volume, and an increase in the peak and average flow rates.³³

Abbott et al³⁴ evaluated the effect of botulinum toxin injection into the levator ani in 12 women with chronic pelvic pain and pelvic floor hypertonicity. Pelvic floor manometry showed significant reduction in resting muscle pressures and improvements in dyspareunia and nonmenstrual pain. There were also improvements in quality of life and dyschezia, but these were not statistically significant.

Smith et al³⁵ injected botulinum toxin into the detrusor of 13 women with refractory painful bladder syndrome and interstitial cystitis,³⁵ and 9 women (69%) noted statistically significant improvements in the Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index, daytime frequency, nocturia, pain, and urodynamic parameters (volume at first desire to void, and maximum cystometric capacity).

In a prospective randomized study of patients with refractory painful bladder syndrome and interstitial cystitis, Kuo and Chancellor³⁶ compared suburothelial injection of 200 U or 100 U of botulinum toxin plus hydrodistention against hydrodistention alone.Patients who received botulinum toxin had increased bladder capacity and improved long-term pain relief, but no difference was noted between 200 U and 100 U, and more adverse effects were seen with the higher dose.³⁶

Pinto et al³⁷ treated 16 women with refractory painful bladder syndrome and interstitial cystitis with intratrigonal injections of botulinum toxin and reported improvements in pain scores, symptom scores, urinary frequency, and quality-of-life measures. The effect lasted 9.9 months (± 2.4 months) and persisted with successive injections.³⁷

More study needed

Although these studies show that botulinum toxin injection for pelvic pain syndromes has the potential to improve pain, urinary frequency, bladder sensation, bladder capacity, and quality of life, larger randomized controlled trials are needed.

Again, the treatment options are limited for refractory painful bladder syndrome and interstitial cystitis. Patients may be desperate for relief from their symptoms. Practitioners must manage expectations and properly inform patients of the potential risks of treatments, especially with patients who will easily agree to further treatment with the smallest hope of relief.

INJECTION TECHNIQUES

For general points about the procedure to discuss with patients, see “What to tell patients.”

Cystoscopic detrusor injection

This procedure is usually done on an outpatient basis (eg, office, ambulatory surgery center). With the patient in the lithotomy position, 100 mL of 2% lidocaine is instilled into the bladder and is allowed 15 to 20 minutes to take effect. A flexible or rigid cystoscope can be used. Depending on the indication, the bladder is injected with 100 U to 300 U of botulinum toxin. The ideal depth of injection is 2 mm in the detrusor muscle, with each injection spaced about 1 cm apart. The recommended administration for 100 U is to inject 20 sites with 0.5 U per mL of saline and, for 200 U, to inject 30 sites with about 0.67 U per mL of saline.³⁸ The location of the injections into the detrusor can vary, as long as adequate spacing is assured.

Injection sites vary. Proponents of injecting the trigone argue that as it is an area of greater nerve density, patients will have a better clinical response. Opponents argue that trigonal injection could result in distal ureteral paralysis and subsequent ureteral reflux. However, this theoretical concern has not been observed clinically.

Urethral injection (off-label use)

The urethra can be injected cystoscopically or periurethrally. Cystoscopic injection involves localization of the external sphincter using the rigid cystoscope and collagen needle; a total of 100 U is injected into the sphincter under direct vision, typically at the 3 o’clock and 9 o’clock positions.³⁵ The periurethral technique is an option in women and involves a spinal needle with 100 U to 200 U of botulinum toxin injected into the external sphincter muscle at the 2 o’clock and 10 o’clock positions.

ADVERSE EFFECTS AND CONTRAINDICATIONS

Adverse effects are rare for urologic applications. The injections are localized, with little systemic absorption, and the doses are 1/1,000th of the theorized lethal dose in a 70-kg male.² The maximum recommended dose for a 3-month period is 360 U.

Generalized muscle weakness has been reported in a paraplegic patient and in a tetraplegic patient after detrusor injections.² Interestingly, both patients had return of bladder spasticity within 2 months, prompting speculation about diffusion of botulinum toxin through the bladder wall.²

Repeat injections can cause an immune response in up to 5% of patients.⁶ Patients undergoing repeat injections are at risk of forming neutralizing antibodies that can interfere with the efficacy of botulinum toxin.⁶ In a study by Schulte-Baukloh et al, all patients with antibodies to botulinum toxin had a history of recurrent urinary tract infection.³⁹

Botulinum toxin injection is contraindicated in patients with preexisting neuromuscular disease, such as myasthenia gravis, Eaton-Lambert syndrome, and amyotrophic lateral sclerosis. It should also be avoided in patients who are breastfeeding, pregnant, or using agents that potentiate neuromuscular weakness, such as aminoglycosides.

Patients should be informed that some formulations of botulinum toxin include a stabilizer such as albumin derived from human blood, as this may be of religious or cultural significance.

Patients with loss of bladder control experience discomfort, embarrassment, personal care and health issues, and, often, significant pain, all with a decidedly negative impact on quality of life. Although some patients may find lifestyle modifications, drug therapy, and self-catheterization acceptable and effective, there is a clear need for more options.

Botulinum toxin, or onabotulinumtoxinA, is currently approved by the US Food and Drug Administration (FDA) for neurogenic detrusor overactivity and overactive bladder refractory to drug therapy. Studies so far have shown botulinum toxin injection to be safe and effective for these conditions, and these results have led to interest in off-label uses, eg, for detrusor external sphincter dyssynergia (DESD), motor and sensory urgency, and painful bladder syndrome/interstitial cystitis (Table 1).

Although more data from clinical trials are needed, botulinum toxin injection offers patients a much-needed treatment option.

HOW BOTULINUM TOXIN WORKS

Seven serotypes identified

Discovered in 1897, botulinum toxin is a neurotoxin produced by the gram-positive, rod-shaped anaerobic bacterium Clostridium botulinum¹ and is the most poisonous naturally occurring toxin known.² Seven immunologically distinct antigenic serotypes have been identified (A, B, C1, D, E, F, and G),¹ but only types A and B are available for clinical use.

Most research into potential therapeutic uses has focused on type A, which has the longest duration of action, a clinical advantage.³ Recently, work has been done to further characterize other serotypes and to isolate additional variants of botulinum toxin. For example, serotype E, the predominant serotype associated with foodborne botulism, is being studied in an effort to prevent future outbreaks.⁴

Our discussion focuses on clinical uses of the serotype A botulinum toxin preparation, which we will refer to simply as botulinum toxin.

Studies exploring how it works

Botulinum toxin exerts its effects by binding to peripheral cholinergic terminals, inhibiting release of acetylcholine at the neuromuscular junction. Flaccid paralysis ensues as a result.

Results of animal studies have shed additional light on the specific actions of botulinum toxin A:

• It may alter levels of nerve growth factor and transient receptor potential vanilloid 1 in rats, and this may provide an additional mechanism of reducing bladder detrusor overactivity.⁵
• In addition to blocking acetylcholine release from motor neurons, it inhibits the release of neurotransmitters involved in bladder sensory afferent pathways.⁶
• It inhibits the release of substance P and glutamate, neuropeptides involved in sensory and nociceptive pathways.^6,7
• It promotes apoptosis in prostatic tissue; however, this effect has not been shown in the bladder.³

The time necessary to recover function after botulinum toxin paralysis depends on the subtype of botulinum toxin as well as on the type of nerve terminal. Chemodenervation lasts from 3 to 6 months when the toxin is injected into the neuromuscular junction of skeletal muscle, and considerably longer (up to 1 year) when injected into the autonomic neurons of smooth muscle.^2,6

TREATMENT OF NEUROGENIC DETRUSOR OVERACTIVITY

Neurogenic detrusor overactivity involves involuntary contractions of the bladder resulting from spinal cord injury, multiple sclerosis, and other neurologic conditions. An estimated 273,000 people in the United States have a spinal cord injury, and 81% of them have urologic symptoms ranging from areflexia to overactivity.⁸ From 75% to 100% of patients with multiple sclerosis have urologic symptoms, and detrusor overactivity is the most common.⁹

Detrusor overactivity can cause urinary urgency, urinary frequency, and urgency incontinence, significantly affecting quality of life and leading to skin breakdown, sacral ulcerations, and challenges with personal care.

Anticholinergic drugs have been the mainstay of therapy. If drug therapy failed, the next option was reconstructive surgery, often augmentation cystoplasty. Thus, botulinum toxin injection is an important advance in treatment options.

Studies that showed effectiveness

Botulinum toxin for neurogenic detrusor overactivity was first studied by Schurch et al.¹⁰ In their study, 200 U or 300 U was injected into the trigone of 21 patients with spinal cord injury and urgency incontinence managed with intermittent self-catheterization.¹⁰ At 6 weeks after injection, 17 of the 19 patients seen at follow-up visits were completely continent. Urodynamic evaluation revealed significant increases in maximum cystometric capacity and in volume at first involuntary detrusor contraction, and a decrease in detrusor voiding pressure. Of the 11 patients available for follow-up at 16 and 36 weeks, improvements in measures of incontinence and urodynamic function persisted.

In addition, two small randomized controlled trials^11,12 showed significant increases in cystometric bladder capacity, significant improvement in quality-of-life measures, and reduction in episodes of urgency incontinence.

In 2011 and 2012, two multicenter double-blind randomized controlled trials reported on patients with multiple sclerosis and spinal cord injury with neurogenic detrusor overactivity inadequately managed with drug therapy. The patients were randomized to botulinum toxin injection (200 U or 300 U) or placebo injection.^13,14 The primary end point for both studies was the change from baseline in episodes of urinary incontinence per week at week 6. Secondary end points were maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction, and score on the Incontinence Quality of Life scale.¹⁵

In both studies, the mean number of urinary incontinence episodes per week was 33 at baseline. At week 6, Cruz et al¹⁴ found that patients who received botulinum toxin injection had significantly fewer episodes per week (21.8 fewer with 200 U, 19.4 fewer with 300 U) than those in the placebo group, who had 13.2 fewer episodes per week (P < .01). Ginsberg et al¹³ reported decreases in the mean number of episodes of urinary incontinence of 21, 23, and 9 episodes per week in the 200 U, 300 U, and placebo groups, respectively (P < .001). The patients who received botulinum toxin had statistically significant improvements in maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction, and Incontinence Quality of Life scores compared with placebo (P < .001). Thirty-eight percent of patients in the treatment group were fully continent.^13,14

Safety and adverse effects

The most frequently reported adverse events were urinary tract infection (24% of patients)^13,14 and urinary retention requiring initiation of clean intermittent catheterization. In the study by Cruz et al,¹⁴ these were reported in 30% with 200 U, 42% with 300 U, and 12% with placebo, while in the study by Ginsberg et al¹³ they were reported in 35% with 200 U, 42% with 300 U, and 10% with placebo.

In a study of long-term safety and efficacy of botulinum toxin injection in patients with neurogenic detrusor overactivity, Kennelly et al¹⁶ found that patients undergoing repeat injections had sustained reductions in episodes of incontinence and increases in the maximum cystometric capacity and quality of life scores, with no increase in adverse events over time.¹⁶

But is it cost-effective?

While botulinum toxin injection may be safe and effective for neurogenic detrusor overactivity, is it cost-effective?

Carlson et al¹⁷ used a Markov State Transition model to assess the cost of refractory neurogenic detrusor overactivity in patients receiving botulinum toxin vs best supportive care (incontinence pads, medications, intermittent self-catheterization).¹⁷ They found that the injections were more expensive than supportive care but were cost-effective when considering the reduction in episodes of incontinence, the reduced need for incontinence products, and improvement in measures of quality of life.

What the evidence indicates

Trials of botulinum toxin injection for neurogenic detrusor overactivity have shown that it improves continence, maximum cystometric capacity, detrusor pressures, and quality of life. The main adverse effects are urinary tract infection and urinary retention requiring intermittent self-catheterization.

Although many patients with this condition are already self-catheterizing, the physician must discuss this before botulinum toxin therapy to ensure that the patient or a family member is able to perform catheterization. Studies have shown that patients have an increase in urinary tract infections after botulinum injections. But in these studies, a urinary tract infection was defined as 100,000 colony-forming units or the presence of leukocytosis with or without symptoms. It is important to remember that patients on intermittent catheterization have bacteriuria and should be treated only for symptomatic, not asymptomatic, bacteriuria.

TREATMENT OF IDIOPATHIC OVERACTIVE BLADDER

Patients with idiopathic overactive bladder have urinary urgency accompanied by urgency incontinence, nocturia, or urinary frequency.¹⁸ The prevalence of this condition has been reported to range from 1.7% to 13.3% in men age 30 and older and 7% to 30.3% in women of similar ages. About one-third of women with overactive bladder also have detrusor overactivity.¹⁹ Overactive bladder presents a significant economic and medical burden on the healthcare system, as well as having a negative impact on quality of life.

The FDA approved botulinum toxin injection for treatment of idiopathic overactive bladder in January 2013.

Evidence of effectiveness

Two multicenter randomized controlled trials^20,21 of botulinum toxin 100 U enrolled patients age 18 and older who had more than three episodes of urinary urgency incontinence in a 3-day period or more than eight micturitions per day inadequately managed by anticholinergic drug therapy. Primary end points were the change from baseline in the number of episodes of urinary incontinence per day and the proportion of patients with a positive response on the Treatment Benefit Scale²² at week 12. Secondary end points included episodes of urinary urgency incontinence, micturition, urgency, and nocturia, and scores on health-related quality of life questionnaires (Incontinence Quality of Life scale, King’s Health Questionnaire).

In both studies, patients receiving botulinum toxin had significantly fewer episodes of incontinence compared with placebo (−2.65 vs −0.87; P < .001 and −2.95 vs −1.03; P < .001).^20,21 Reductions from baseline in all other symptoms of overactive bladder, a positive treatment response on the treatment benefit scale, and improvements in quality-of-life scores were also significantly greater with botulinum toxin injection than with placebo (P ≤ .01).

As in the studies of neurogenic detrusor overactivity, the most common adverse effects were urinary tract infection (occurring in 15.5%²⁰ and 24.1%²¹ of patients) and urinary retention requiring self-catheterization (5.4%²⁰ and 6.9%²¹).

The largest study to date of anticholinergic therapy vs botulinum toxin injection²³ in women with urinary urgency incontinence, published in 2012, studied nearly 250 women who had five or more episodes of idiopathic urgency incontinence in a 3-day period. They were randomized either to daily oral therapy (solifenacin 5 mg with possible escalation to 10 mg and, if necessary, a subsequent switch to extended-release trospium 60 mg) plus one intradetrusor injection of saline, or to a daily oral placebo plus one injection of botulinum toxin 100 U.²³

The dropout rate was low in both groups, with 93% of patients in both groups completing the 6-month protocol. Women experienced a mean reduction in urgency incontinence episodes of 3.4 per day (baseline 5) in the anticholinergic group vs 3.3 episodes in the botulinum toxin group (P = .81). However, more patients achieved complete resolution of urinary urgency incontinence in the botulinum toxin group than in the anticholinergic therapy group (27% vs 13%; P = .003). Quality of life improved in both groups without a significant difference between the groups. The botulinum toxin group had higher rates of initiation of self-catheterization (5% vs 0%, P = .01) and urinary tract infection (33% vs 13%, P < .001).²³

Botulinum toxin as a third-line therapy

In May 2014, the American Urological Association updated its guidelines on idiopathic overactive bladder²⁴ to include botulinum toxin injection as standard third-line therapy for patients in whom behavioral and medical management (ie, anticholinergics and beta-3-agonists) failed.

Interpreting the evidence to date

Overall, studies in idiopathic overactive bladder have shown a reduction in episodes of urgency incontinence and other symptoms, with some data also demonstrating a corresponding improvement in quality of life.

As in neurogenic detrusor overactivity, the main risks associated with botulinum toxin injection are urinary tract infection and the need to initiate self-catheterization. Although 94% of patients studied did not require self-catheterization after injection, the patient’s ability to perform self-catheterization should be determined before proceeding with botulinum toxin injections.

DETRUSOR EXTERNAL SPHINCTER DYSSYNERGIA

Botulinum toxin has been used not only to improve bladder storage but also to facilitate bladder emptying, as in patients with DESD, a lack of coordination between the bladder and the urinary sphincter. Normal voiding involves relaxation of the urinary sphincter and contraction of the bladder; in DESD the sphincter contracts and works against the bladder’s ability to empty. This leads not only to difficulty emptying the bladder but also to elevated bladder pressure, which can cause renal damage if untreated.

DESD can be seen after injury between the pontine micturition center, which coordinates activity between the bladder and the sphincter, and the caudal spinal cord. This can occur in spinal cord injury, multiple sclerosis, myelomeningocele, and transverse myelitis and can cause significant morbidity for the patient.

Treatment options include drug therapy, injection of botulinum toxin into the sphincter, clean intermittent catheterization, indwelling catheterization, urethral stenting, sphincterotomy, and reconstructive surgery such as urinary diversion.²⁵

The goals of therapy are to avoid the need for clean intermittent catheterization in patients who have difficulty with manual dexterity, and to avoid the need for surgical procedures such as sphincterotomy and urinary diversion. The efficacy of urethral stenting is low, and medical management can be limited.²⁶

DESD leads to difficulty emptying the bladder, elevated bladder pressure, and, if untreated, renal damage

In the first published report on botulinum toxin for DESD (in 1988),²⁷ of 11 patients with spinal cord injury and DESD who received botulinum toxin injected into the external urethral sphincter, 10 showed signs of sphincter denervation on electromyography and reductions in urethral pressure profiles and postvoid residual volumes. Schurch et al²⁸ and de Sèze et al²⁹ also reported reductions in postvoid residual volume and maximal urethral pressures in patients with spinal cord injury and DESD.

In 2005, Gallien et al³⁰ reported what is still the largest multicenter randomized controlled trial of botulinum toxin injection in DESD. Eighty-six patients with multiple sclerosis, DESD, and chronic urinary retention were randomized to receive either a single transperineal botulinum toxin injection of 100 U plus the alpha-1-blocker alfuzosin, or a placebo injection plus alfuzosin. Botulinum toxin treatment was associated with significantly increased voided volumes and reduced premicturition and maximal detrusor pressures, but no significant decrease in postvoid residual volume.³⁰

More study needed

Despite these findings, a Cochrane Review concluded that, given the limited experience with intrasphincteric injection of botulinum toxin, data from larger randomized controlled trials are needed before making definitive recommendations.²⁵ In the meantime, the clinician must weigh the low morbidity of the procedure against the limited options in the treatment of these patients.

OFF-LABEL UROLOGIC INDICATIONS

Botulinum toxin injection has been studied off-label for painful bladder syndrome/interstitial cystitis and for chronic prostatic pain. Patients with these conditions often describe pain with filling of the bladder, which leads to urinary frequency in an attempt to relieve the pain.

These pain syndromes can be difficult to treat and can have a devastating impact on quality of life. Treatment options include pain management, stress management, physical therapy, intravesical therapies, cystoscopy with hydrodistention, neuromodulation, cyclosporine, urinary diversion surgery, and botulinum toxin injection (an off-label use).³¹

In painful bladder syndrome/interstitial cystitis, botulinum toxin is thought to act on sensory afferent pathways, as well as to inhibit the release of substance P and glutamate, neuropeptides involved in sensory and nociceptive pathways.⁶ In animal studies,³² botulinum toxin was found to inhibit the afferent neural response by inhibiting mechanoreceptor-mediated release of adenosine triphosphate and by causing a decrease in calcitonin gene-related peptide, which helps regulate micturition and mediates painful bladder sensation.

Clinical studies to date in pelvic pain syndromes

Data from clinical studies of botulinum toxin injection for pelvic pain syndromes are limited. Zermann et al³³ performed transurethral perisphincteric injection in 11 men with chronic prostatic pain, 9 of whom reported subjective pain relief, with an average decrease from 7.2 to 1.6 on a visual analogue scale. Postinjection urodynamic studies showed a decrease in functional urethral length, urethral closure pressure, and postvoid residual volume, and an increase in the peak and average flow rates.³³

Abbott et al³⁴ evaluated the effect of botulinum toxin injection into the levator ani in 12 women with chronic pelvic pain and pelvic floor hypertonicity. Pelvic floor manometry showed significant reduction in resting muscle pressures and improvements in dyspareunia and nonmenstrual pain. There were also improvements in quality of life and dyschezia, but these were not statistically significant.

Smith et al³⁵ injected botulinum toxin into the detrusor of 13 women with refractory painful bladder syndrome and interstitial cystitis,³⁵ and 9 women (69%) noted statistically significant improvements in the Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index, daytime frequency, nocturia, pain, and urodynamic parameters (volume at first desire to void, and maximum cystometric capacity).

In a prospective randomized study of patients with refractory painful bladder syndrome and interstitial cystitis, Kuo and Chancellor³⁶ compared suburothelial injection of 200 U or 100 U of botulinum toxin plus hydrodistention against hydrodistention alone.Patients who received botulinum toxin had increased bladder capacity and improved long-term pain relief, but no difference was noted between 200 U and 100 U, and more adverse effects were seen with the higher dose.³⁶

Pinto et al³⁷ treated 16 women with refractory painful bladder syndrome and interstitial cystitis with intratrigonal injections of botulinum toxin and reported improvements in pain scores, symptom scores, urinary frequency, and quality-of-life measures. The effect lasted 9.9 months (± 2.4 months) and persisted with successive injections.³⁷

More study needed

Although these studies show that botulinum toxin injection for pelvic pain syndromes has the potential to improve pain, urinary frequency, bladder sensation, bladder capacity, and quality of life, larger randomized controlled trials are needed.

Again, the treatment options are limited for refractory painful bladder syndrome and interstitial cystitis. Patients may be desperate for relief from their symptoms. Practitioners must manage expectations and properly inform patients of the potential risks of treatments, especially with patients who will easily agree to further treatment with the smallest hope of relief.

INJECTION TECHNIQUES

For general points about the procedure to discuss with patients, see “What to tell patients.”

Cystoscopic detrusor injection

This procedure is usually done on an outpatient basis (eg, office, ambulatory surgery center). With the patient in the lithotomy position, 100 mL of 2% lidocaine is instilled into the bladder and is allowed 15 to 20 minutes to take effect. A flexible or rigid cystoscope can be used. Depending on the indication, the bladder is injected with 100 U to 300 U of botulinum toxin. The ideal depth of injection is 2 mm in the detrusor muscle, with each injection spaced about 1 cm apart. The recommended administration for 100 U is to inject 20 sites with 0.5 U per mL of saline and, for 200 U, to inject 30 sites with about 0.67 U per mL of saline.³⁸ The location of the injections into the detrusor can vary, as long as adequate spacing is assured.

Injection sites vary. Proponents of injecting the trigone argue that as it is an area of greater nerve density, patients will have a better clinical response. Opponents argue that trigonal injection could result in distal ureteral paralysis and subsequent ureteral reflux. However, this theoretical concern has not been observed clinically.

Urethral injection (off-label use)

The urethra can be injected cystoscopically or periurethrally. Cystoscopic injection involves localization of the external sphincter using the rigid cystoscope and collagen needle; a total of 100 U is injected into the sphincter under direct vision, typically at the 3 o’clock and 9 o’clock positions.³⁵ The periurethral technique is an option in women and involves a spinal needle with 100 U to 200 U of botulinum toxin injected into the external sphincter muscle at the 2 o’clock and 10 o’clock positions.

ADVERSE EFFECTS AND CONTRAINDICATIONS

Adverse effects are rare for urologic applications. The injections are localized, with little systemic absorption, and the doses are 1/1,000th of the theorized lethal dose in a 70-kg male.² The maximum recommended dose for a 3-month period is 360 U.

Generalized muscle weakness has been reported in a paraplegic patient and in a tetraplegic patient after detrusor injections.² Interestingly, both patients had return of bladder spasticity within 2 months, prompting speculation about diffusion of botulinum toxin through the bladder wall.²

Repeat injections can cause an immune response in up to 5% of patients.⁶ Patients undergoing repeat injections are at risk of forming neutralizing antibodies that can interfere with the efficacy of botulinum toxin.⁶ In a study by Schulte-Baukloh et al, all patients with antibodies to botulinum toxin had a history of recurrent urinary tract infection.³⁹

Botulinum toxin injection is contraindicated in patients with preexisting neuromuscular disease, such as myasthenia gravis, Eaton-Lambert syndrome, and amyotrophic lateral sclerosis. It should also be avoided in patients who are breastfeeding, pregnant, or using agents that potentiate neuromuscular weakness, such as aminoglycosides.

Patients should be informed that some formulations of botulinum toxin include a stabilizer such as albumin derived from human blood, as this may be of religious or cultural significance.

Ceftaroline fosamil (Teflaro), introduced to the US market in October 2010, is the first beta-lactam agent with clinically useful activity against methicillin-resistant Staphylococcus aureus (MRSA). Currently, it is approved by the US Food and Drug Administration (FDA) to treat acute bacterial skin and skin-structure infections and community-acquired bacterial pneumonia caused by susceptible microorganisms.

In an era of increasing drug resistance and limited numbers of antimicrobials in the drug-production pipeline, ceftaroline is a step forward in fulfilling the Infectious Diseases Society of America’s “10 × ’20 Initiative” to increase support for drug research and manufacturing, with the goal of producing 10 new antimicrobial drugs by the year 2020.¹ Ceftaroline was the first of several antibiotics to receive FDA approval in response to this initiative. It was followed by dalbavancin (May 2014), tedizolid phosphate (June 2014), oritavancin (August 2014), ceftolozane-tazobactam (December 2014), and ceftazidime-avibactam (February 2015). These antibiotic agents are aimed at treating infections caused by drug-resistant gram-positive and gram-negative microorganisms. It is important to understand and optimize the use of these new antibiotic agents in order to decrease the risk of emerging antibiotic resistance and superinfections (eg, Clostridium difficile infection) caused by antibiotic overuse or misuse.

This article provides an overview of ceftaroline’s mechanisms of action and resistance, spectrum of activity, pharmacokinetic properties, adverse effects, and current place in therapy.

AN ERA OF MULTIDRUG-RESISTANT MICROORGANISMS

Increasing rates of antimicrobial resistance threaten the efficacy of antimicrobial drugs in the daily practice of medicine. The World Health Organization has labeled antimicrobial resistance one of the three greatest threats to human health. Global efforts are under way to stimulate development of new antimicrobial agents and to decrease rates of antimicrobial resistance.

Staphylococcus aureus: A threat, even with vancomycin

Between 1998 and 2005, S aureus was one of the most common inpatient and outpatient isolates reported by clinical laboratories throughout the United States.²

Treatment of S aureus infection is complicated by a variety of resistance mechanisms that have evolved over time. In fact, the first resistant isolate of S aureus emerged not long after penicillin’s debut into clinical practice, and now the majority of strains are resistant to penicillin.

Methicillin was designed to overcome this beta-lactamase resistance and became the treatment of choice for penicillin-resistant S aureus isolates. However, MRSA isolates soon emerged because of the organism’s acquisition of penicillin-binding protein PBP2a via the mecA gene, leading to decreased binding affinity of methicillin.³

Since then, several agents active against MRSA (vancomycin, daptomycin, linezolid, tigecycline) have been introduced and continue to be widely used. While vancomycin is considered the first-line option for a variety of MRSA infections, its use has been threatened because of the emergence of vancomycin-intermediate-resistant S aureus (VISA), S aureus strains displaying vancomycin heteroresistance (hVISA), and vancomycin-resistant S aureus (VRSA) strains.⁴

VISA and hVISA isolates emerged through sequential mutations that lead to autolytic activity and cell-wall thickening. In contrast, the mechanism of resistance in VRSA is by acquisition of the vanA resistance gene, which alters the binding site of vancomycin from d-alanine-d-alanine to d-alanine-d-lactate.⁵

Streptococcus pneumoniae resistance: A continuing problem

The prevalence of drug resistance in S pneumoniae has risen since the late 1990s. A 2013 report from the SENTRY Antimicrobial Surveillance Program stated that almost 20% of S pneumoniae isolates were resistant to amoxicillin-clavulanate, and similar trends have been observed for penicillin (14.8%) and ceftriaxone (11.7%).⁶

S pneumoniae resistance is acquired through modifications of the penicillin-binding proteins, namely PBP1a, PBP2b, PBP2x, and, less frequently, PBP2a. These modifications lead to decreased binding affinity for most beta-lactams.⁷

Clinical impact of multidrug-resistant S aureus and S pneumoniae

In 2011, the US Centers for Disease Control and Prevention reported an estimated 80,000 severe MRSA infections and 11,000 MRSA-related deaths in the United States.⁸ In the same report, drug-resistant S pneumoniae was estimated to be responsible for almost 1.2 million illnesses and 7,000 deaths per year, leading to upwards of $96 million in related medical costs.

While invasive drug-resistant S pneumoniae infections usually affect patients at the extremes of age (under age 5 and over age 65), they have had a serious impact on patients of all ages.⁸

In light of the increasing prevalence of multidrug-resistant organisms, newer antimicrobial agents with novel mechanisms of action are needed.

CEFTAROLINE: A BETA-LACTAM WITH ANTI-MRSA ACTIVITY

The cephalosporins, a class of beta-lactam antibiotics, were originally derived from the fungus Cephalosporium (now called Acremonium). There are now many agents in this class, each containing a nucleus consisting of a beta-lactam ring fused to a six-member dihydrothiazine ring, and two side chains that can be modified to affect antibacterial activity and pharmacokinetic properties.

Cephalosporins are typically categorized into “generations.” With some exceptions, the first- and second-generation agents have good activity against gram-positive microorganisms, including methicillin-susceptible S aureus—but not against MRSA. The third- and fourth-generation cephalosporins have better gram-negative activity, with many agents having activity against the gram-negative bacterium Pseudomonas aeruginosa.

Enterococcal isolates are intrinsically resistant to cephalosporins. Additionally, cephalosporins are not active against anaerobic bacteria, except for a subset of structurally unique second-generation cephalosporins, ie, cefotetan and cefoxitin.

Ceftaroline was synthesized with specific manipulations of the side chains to provide enhanced activity against MRSA and multidrug-resistant S pneumoniae isolates, making it the first available beta-lactam with this ability.

Mechanism of action

Ceftaroline binds to penicillin-binding proteins, inhibiting transpeptidation. This interaction blocks the final stage of peptidoglycan synthesis and inhibits bacterial cell wall formation, ultimately leading to cellular autolysis and microorganism death. Ceftaroline binds with high affinity to PBP2a and PBP2x, expanding its activity to encompass MRSA and penicillin-resistant S pneumoniae isolates.⁹

Spectrum of activity

Ceftaroline has in vitro activity against many gram-positive and gram-negative bacteria,^10–13 including (Table 1):

• Methicillin-susceptible and methicillin-resistant staphylococci
• VISA, VRSA, and hVISA
• Daptomycin-nonsusceptible S aureus
• Streptococcal species, including penicillin-resistant S pneumoniae
• Enterobacteriaceae, including Klebsiella pneumoniae, Klebsiella oxytoca, Escherichia coli, Citrobacter koseri, Citrobacter freundii, Enterobacter cloacae, Enterobacter aerogenes, Moraxella catarrhalis, Morganella morganii, and Proteus mirabilis.

Of note, ceftaroline is not active against Pseudomonas species, Enterococcus species, or Bacteroides fragilis. In addition, it is not active against the “atypical” respiratory pathogens Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila.

Ceftaroline resistance

Gram-negative organisms appear to develop resistance to ceftaroline at rates similar to those observed with the other oxyimino-cephalosporins (eg, ceftriaxone). Ceftaroline is inactive against gram-negative organisms producing extended-spectrum beta-lactamases, including K pneumoniae carbapenemase and metallo-beta-lactamases.¹⁴ In addition, it induces the expression of AmpC beta-lactamases.

Although currently uncommon, resistance to ceftaroline has also been reported in S aureus strains.¹⁵ The mechanism of resistance is decreased binding affinity for PBP2a due to amino acid substitutions on the nonpenicillin-binding domains.¹⁵

Pharmacokinetic profile

An understanding of pharmacokinetics is key in optimizing the dose of antimicrobials so that the drugs are used most effectively and pathogens do not develop resistance to them.

Ceftaroline fosamil is a prodrug that, upon intravenous administration, is rapidly converted by phosphatase enzymes to its active moiety, ceftaroline. Its pharmacokinetic profile is summarized in Table 2.^16,17 Its volume of distribution is similar to that of the fourth-generation cephalosporin cefepime.

Ceftaroline is then hydrolyzed into its inactive metabolite, ceftaroline M-1. It undergoes little hepatic metabolism and lacks properties to make it a substrate, inhibitor, or inducer of the CYP450 enzyme system and therefore is not likely to cause notable CYP450-related drug-drug interactions.

Like most other beta-lactams, ceftaroline is primarily excreted by the kidneys. Furthermore, an estimated 21% of a dose is eliminated with each intermittent hemodialysis session. Therefore, renal and intermittent hemodialysis dose adjustments are necessary. The estimated elimination half-life is 2.6 hours, necessitating dosing two to three times daily, depending on the indication and infectious inoculum.

Ceftaroline dosing

Ceftaroline is available only in a parenteral preparation and is typically given at a dose of 600 mg every 12 hours.¹⁰ The intravenous infusion is given over 1 hour.

The current stability data require reconstituted ceftaroline to be used within 6 hours at room temperature and within 24 hours if refrigerated.¹⁰

Ceftaroline requires dosing adjustments for patients with renal insufficiency. Per the manufacturer, renal dosing adjustments are based on the creatinine clearance rate, as estimated by the Cockroft-Gault formula:

• Creatinine clearance > 50 mL/min: no dosage adjustment necessary
• Creatinine clearance > 30 to ≤ 50 mL/min: give 400 mg every 12 hours
• Creatinine clearance ≥ 15 to ≤ 30 mL/min: give 300 mg every 12 hours
• Creatinine clearance < 15 mL/min or on intermittent dialysis: give 200 mg every 12 hours.

Ongoing clinical trials are investigating a higher-dosing strategy of 600 mg every 8 hours for patients with community-acquired bacterial pneumonia at risk of MRSA bacteremia.¹⁸

CLINICAL TRIALS LEADING TO CEFTAROLINE’S APPROVAL

Ceftaroline was approved for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin-structure infections due to susceptible pathogens on the basis of phase 3 comparator trials.

Community-acquired bacterial pneumonia: The FOCUS 1 and 2 trials

The efficacy and safety of ceftaroline in the treatment of community-acquired bacterial pneumonia was studied in two randomized, double-blind, noninferiority trials, known as Ceftaroline Community-acquired Pneumonia vs Ceftriaxone (FOCUS) 1 and FOCUS 2.^19,20

Patients were adults and not critically ill, as was reflected by their being in Pneumonia Outcomes Research Team (PORT) risk class III or IV (with class V indicating the highest risk of death). Therefore, the results may not be completely applicable to critically ill patients or those not admitted to the hospital. Of note, patients were excluded from the trials if they had infections known or thought to be due to MRSA or to atypical organisms.²¹ Baseline characteristics and patient demographics were similar between study groups in both trials.

A bacterial pathogen was identified in 26.1% of the patients included in the modified intent-to-treat analysis of the pooled data of the trials; the most common pathogens were S pneumoniae, methicillin-sensitive S aureus, Haemophilus influenzae, K pneumoniae, and E coli.²¹

Treatment. Patients received either ceftaroline 600 mg every 12 hours (or a lower dose based on renal function) or ceftriaxone 1 g every 24 hours. In addition, in the FOCUS 1 trial, patients in both treatment groups received clarithromycin 500 mg every 12 hours for the first day.¹⁹

Results. In both trials and in the integrated analysis, ceftaroline was noninferior to ceftriaxone (Table 3).²² In the integrated analysis of both trials, compared with the ceftriaxone group, the ceftaroline group had a higher clinical cure rate among patients classified as PORT risk class III (86.8% vs 79.2%, weighted treatment difference 12.6%, 95% confidence interval [CI] 1.3–13.8) and among patients who had not received prior antibiotic treatment (85.5% vs 74.9%, weighted treatment difference 11.2%, 95% CI 4.5–18.0).²¹

Acute bacterial skin and skin-structure infections: The CANVAS 1 and 2 trials

The efficacy and safety of ceftaroline in the treatment of complicated acute bacterial skin and skin-structure infections was studied in two randomized, double-blind trials: Ceftaroline Versus Vancomycin in Skin and Skin Structure Infections (CANVAS) 1 and CANVAS 2.^23,24

Patients. Adult patients with a diagnosis of community-acquired skin and skin-structure infections warranting at least 5 days of intravenous antimicrobial therapy were included in the trials. Important protocol exclusions were patients with diabetic foot ulcers, decubitus ulcers, burns, ulcers associated with peripheral vascular disease accompanied by osteomyelitis, and suspected P aeruginosa infections.²⁵ This limits the external validity of ceftaroline use in the aforementioned excluded patient populations.

Patients in each treatment group of the trials had similar demographic characteristics. The most common infections were cellulitis, major abscess requiring surgical intervention, wound infection, and infected ulcer. Bacteremia was present in 4.2% of patients in the ceftaroline group and in 3.8% of patients in the vancomycin-aztreonam group. The most common pathogen was S aureus. Methicillin resistance was present in 40% of the ceftaroline group and 34% of the control group.

Treatment. Patients received either ceftaroline 600 mg every 12 hours or the combination of vancomycin 1 g plus aztreonam 1 g given 12 hours, for 5 to 14 days.

Results. As assessed at a “test-of-cure” visit 8 to 15 days after the last dose of study medication, the efficacy of ceftaroline was similar to that of vancomycin-aztreonam, meeting the set noninferiority goal (Table 4).²⁵ Moreover, if assessed on day 2 or 3 (a new end point recommended by the FDA), the rate of cessation of erythema spread and absence of fever was higher in the ceftaroline group than in the vancomycin-aztreonam group.²⁶ However, this end point was not in the original trial protocol.

CEFTAROLINE FOR OTHER INDICATIONS

As noted, ceftaroline has been approved for treating community-acquired bacterial pneumonia and acute bacterial skin and skin-structure infections. In addition, it has been used in several studies in animals, and case reports of non-FDA approved indications including endocarditis and osteomyelitis have been published. Clinical trials are evaluating its use in pediatric patients, as well as for community-acquired bacterial pneumonia with risk for MRSA and for MRSA bacteremia.

Endocarditis

Animal studies have demonstrated ceftaroline to have bactericidal activity against MRSA and hVISA in endocarditis.²⁷

A few case series have been published describing ceftaroline’s use as salvage therapy for persistent MRSA bacteremia and endocarditis. For example, Ho et al²⁸ reported using it in three patients who had endocarditis as a source of their persistent bacteremia. All three patients had resolution of their MRSA bloodstream infection following ceftaroline therapy. The dosage was 600 mg every 8 hours, which is higher than in the manufacturer’s prescribing information.

Lin et al²⁹ reported using ceftaroline in five patients with either possible or probable endocarditis. Three of the five patients had clinical cure as defined by resolution or improvement of all signs and symptoms of infection, and not requiring further antimicrobial therapy.²⁹

More data from clinical trials would be beneficial in defining ceftaroline’s role in treating endocarditis caused by susceptible microorganisms.

Osteomyelitis

In animal studies of osteomyelitis, ceftaroline exhibited activity against MRSA in infected bone and joint fluid. Compared with vancomycin and linezolid, ceftaroline was associated with more significant decreases in bacterial load in the infected joint fluid, bone marrow, and bone.³⁰

Lin et al²⁹ gave ceftaroline to two patients with bone and joint infections, both of whom had received other therapies that had failed. The doses of ceftaroline were higher than those recommended in the prescribing information; clinical cure was noted in both cases following the switch.

These data come from case series, and more study of ceftaroline’s role in the treatment of osteomyelitis infections is warranted.

Meningitis

The use of ceftaroline in meningitis has been studied in rabbits. While ceftaroline penetrated into the cerebrospinal fluid in only negligible amounts in healthy rabbits (3% penetration), its penetration improved to 15% in animals with inflamed meninges. Ceftaroline cerebrospinal fluid levels in inflamed meninges were sufficient to provide bactericidal activity against penicillin-sensitive and resistant S pneumoniae strains as well as K pneumoniae and E coli strains.^31,32

REPORTED ADVERSE EFFECTS OF CEFTAROLINE

Overall, ceftaroline was well tolerated in clinical trials, and its safety profile was similar to those of the comparator agents (ceftriaxone and vancomycin-aztreonam).

As with the other cephalosporins, hypersensitivity reactions have been reported with ceftaroline. In the clinical trials, 3% of patients developed a rash with ceftaroline.^33,34 Patients with a history of beta-lactam allergy were excluded from the trials, so the rate of cross-reactivity with penicillins and with other cephalosporins is unknown.

In the phase 3 clinical trials, gastrointestinal side effects including diarrhea (5%), nausea (4%), and vomiting (2%) were reported with ceftaroline. C difficile-associated diarrhea has also been reported.³³

As with other cephalosporins, ceftaroline can cause a false-positive result on the Coombs test. Approximately 11% of ceftaroline-treated patients in phase 3 clinical trials had a positive Coombs test, but hemolytic anemia did not occur in any patients.^33,34

Discontinuation of ceftaroline due to an adverse reaction was reported in 2.7% of patients receiving the drug during phase 3 trials, compared with 3.7% with comparator agents.

WHEN SHOULD CEFTAROLINE BE USED IN DAILY PRACTICE?

Ceftaroline has been shown to be at least as effective as ceftriaxone in treating community-acquired bacterial pneumonia, and at least as effective as vancomycin-aztreonam in treating acute bacterial skin and skin-structure infections. The 2014 Infectious Diseases Society of America’s guidelines for the diagnosis and management of skin and soft-tissue infections recommend ceftaroline as an option for empiric therapy for purulent skin and soft-tissue infections.³⁵

The guidelines on community-acquired pneumonia have not been updated since 2007, which was before ceftaroline was approved. However, these guidelines are currently undergoing revision and may provide insight on ceftaroline’s place in the treatment of community-acquired bacterial pneumonia.³⁶

Currently, ceftaroline’s routine use for these indications should be balanced by its higher cost ($150 for a 600-mg dose) compared with ceftriaxone ($5 for a 1-g dose) or vancomycin ($25 for a 1-g dose). The drug’s in vitro activity against drug-resistant pneumococci and S aureus, including MRSA, hVISA, and VISA may help fill an unmet need or provide a safer and more tolerable alternative to currently available therapies.

However, ceftaroline’s lack of activity against P aeruginosa and carbapenem-resistant Enterobacteriaceae does not meet the public health threat needs stemming from these multidrug-resistant microorganisms. Ongoing clinical trials in patients with more serious MRSA infections will provide important information about ceftaroline’s role as an anti-MRSA agent.

While the discovery of antimicrobials has had one of the greatest impacts on medicine, continued antibiotic use is threatened by the emergence of drug-resistant pathogens. Therefore, it is as important as ever to be good stewards of our currently available antimicrobials. Developing usage and dosing criteria for antimicrobials based on available data and literature is a step forward in optimizing the use of antibiotics—a precious medical resource.

Ceftaroline fosamil (Teflaro), introduced to the US market in October 2010, is the first beta-lactam agent with clinically useful activity against methicillin-resistant Staphylococcus aureus (MRSA). Currently, it is approved by the US Food and Drug Administration (FDA) to treat acute bacterial skin and skin-structure infections and community-acquired bacterial pneumonia caused by susceptible microorganisms.

In an era of increasing drug resistance and limited numbers of antimicrobials in the drug-production pipeline, ceftaroline is a step forward in fulfilling the Infectious Diseases Society of America’s “10 × ’20 Initiative” to increase support for drug research and manufacturing, with the goal of producing 10 new antimicrobial drugs by the year 2020.¹ Ceftaroline was the first of several antibiotics to receive FDA approval in response to this initiative. It was followed by dalbavancin (May 2014), tedizolid phosphate (June 2014), oritavancin (August 2014), ceftolozane-tazobactam (December 2014), and ceftazidime-avibactam (February 2015). These antibiotic agents are aimed at treating infections caused by drug-resistant gram-positive and gram-negative microorganisms. It is important to understand and optimize the use of these new antibiotic agents in order to decrease the risk of emerging antibiotic resistance and superinfections (eg, Clostridium difficile infection) caused by antibiotic overuse or misuse.

This article provides an overview of ceftaroline’s mechanisms of action and resistance, spectrum of activity, pharmacokinetic properties, adverse effects, and current place in therapy.

AN ERA OF MULTIDRUG-RESISTANT MICROORGANISMS

Increasing rates of antimicrobial resistance threaten the efficacy of antimicrobial drugs in the daily practice of medicine. The World Health Organization has labeled antimicrobial resistance one of the three greatest threats to human health. Global efforts are under way to stimulate development of new antimicrobial agents and to decrease rates of antimicrobial resistance.

Staphylococcus aureus: A threat, even with vancomycin

Between 1998 and 2005, S aureus was one of the most common inpatient and outpatient isolates reported by clinical laboratories throughout the United States.²

Treatment of S aureus infection is complicated by a variety of resistance mechanisms that have evolved over time. In fact, the first resistant isolate of S aureus emerged not long after penicillin’s debut into clinical practice, and now the majority of strains are resistant to penicillin.

Methicillin was designed to overcome this beta-lactamase resistance and became the treatment of choice for penicillin-resistant S aureus isolates. However, MRSA isolates soon emerged because of the organism’s acquisition of penicillin-binding protein PBP2a via the mecA gene, leading to decreased binding affinity of methicillin.³

Since then, several agents active against MRSA (vancomycin, daptomycin, linezolid, tigecycline) have been introduced and continue to be widely used. While vancomycin is considered the first-line option for a variety of MRSA infections, its use has been threatened because of the emergence of vancomycin-intermediate-resistant S aureus (VISA), S aureus strains displaying vancomycin heteroresistance (hVISA), and vancomycin-resistant S aureus (VRSA) strains.⁴

VISA and hVISA isolates emerged through sequential mutations that lead to autolytic activity and cell-wall thickening. In contrast, the mechanism of resistance in VRSA is by acquisition of the vanA resistance gene, which alters the binding site of vancomycin from d-alanine-d-alanine to d-alanine-d-lactate.⁵

Streptococcus pneumoniae resistance: A continuing problem

The prevalence of drug resistance in S pneumoniae has risen since the late 1990s. A 2013 report from the SENTRY Antimicrobial Surveillance Program stated that almost 20% of S pneumoniae isolates were resistant to amoxicillin-clavulanate, and similar trends have been observed for penicillin (14.8%) and ceftriaxone (11.7%).⁶

S pneumoniae resistance is acquired through modifications of the penicillin-binding proteins, namely PBP1a, PBP2b, PBP2x, and, less frequently, PBP2a. These modifications lead to decreased binding affinity for most beta-lactams.⁷

Clinical impact of multidrug-resistant S aureus and S pneumoniae

In 2011, the US Centers for Disease Control and Prevention reported an estimated 80,000 severe MRSA infections and 11,000 MRSA-related deaths in the United States.⁸ In the same report, drug-resistant S pneumoniae was estimated to be responsible for almost 1.2 million illnesses and 7,000 deaths per year, leading to upwards of $96 million in related medical costs.

While invasive drug-resistant S pneumoniae infections usually affect patients at the extremes of age (under age 5 and over age 65), they have had a serious impact on patients of all ages.⁸

In light of the increasing prevalence of multidrug-resistant organisms, newer antimicrobial agents with novel mechanisms of action are needed.

CEFTAROLINE: A BETA-LACTAM WITH ANTI-MRSA ACTIVITY

The cephalosporins, a class of beta-lactam antibiotics, were originally derived from the fungus Cephalosporium (now called Acremonium). There are now many agents in this class, each containing a nucleus consisting of a beta-lactam ring fused to a six-member dihydrothiazine ring, and two side chains that can be modified to affect antibacterial activity and pharmacokinetic properties.

Cephalosporins are typically categorized into “generations.” With some exceptions, the first- and second-generation agents have good activity against gram-positive microorganisms, including methicillin-susceptible S aureus—but not against MRSA. The third- and fourth-generation cephalosporins have better gram-negative activity, with many agents having activity against the gram-negative bacterium Pseudomonas aeruginosa.

Enterococcal isolates are intrinsically resistant to cephalosporins. Additionally, cephalosporins are not active against anaerobic bacteria, except for a subset of structurally unique second-generation cephalosporins, ie, cefotetan and cefoxitin.

Ceftaroline was synthesized with specific manipulations of the side chains to provide enhanced activity against MRSA and multidrug-resistant S pneumoniae isolates, making it the first available beta-lactam with this ability.

Mechanism of action

Ceftaroline binds to penicillin-binding proteins, inhibiting transpeptidation. This interaction blocks the final stage of peptidoglycan synthesis and inhibits bacterial cell wall formation, ultimately leading to cellular autolysis and microorganism death. Ceftaroline binds with high affinity to PBP2a and PBP2x, expanding its activity to encompass MRSA and penicillin-resistant S pneumoniae isolates.⁹

Spectrum of activity

Ceftaroline has in vitro activity against many gram-positive and gram-negative bacteria,^10–13 including (Table 1):

• Methicillin-susceptible and methicillin-resistant staphylococci
• VISA, VRSA, and hVISA
• Daptomycin-nonsusceptible S aureus
• Streptococcal species, including penicillin-resistant S pneumoniae
• Enterobacteriaceae, including Klebsiella pneumoniae, Klebsiella oxytoca, Escherichia coli, Citrobacter koseri, Citrobacter freundii, Enterobacter cloacae, Enterobacter aerogenes, Moraxella catarrhalis, Morganella morganii, and Proteus mirabilis.

Of note, ceftaroline is not active against Pseudomonas species, Enterococcus species, or Bacteroides fragilis. In addition, it is not active against the “atypical” respiratory pathogens Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila.

Ceftaroline resistance

Gram-negative organisms appear to develop resistance to ceftaroline at rates similar to those observed with the other oxyimino-cephalosporins (eg, ceftriaxone). Ceftaroline is inactive against gram-negative organisms producing extended-spectrum beta-lactamases, including K pneumoniae carbapenemase and metallo-beta-lactamases.¹⁴ In addition, it induces the expression of AmpC beta-lactamases.

Although currently uncommon, resistance to ceftaroline has also been reported in S aureus strains.¹⁵ The mechanism of resistance is decreased binding affinity for PBP2a due to amino acid substitutions on the nonpenicillin-binding domains.¹⁵

Pharmacokinetic profile

An understanding of pharmacokinetics is key in optimizing the dose of antimicrobials so that the drugs are used most effectively and pathogens do not develop resistance to them.

Ceftaroline fosamil is a prodrug that, upon intravenous administration, is rapidly converted by phosphatase enzymes to its active moiety, ceftaroline. Its pharmacokinetic profile is summarized in Table 2.^16,17 Its volume of distribution is similar to that of the fourth-generation cephalosporin cefepime.

Ceftaroline is then hydrolyzed into its inactive metabolite, ceftaroline M-1. It undergoes little hepatic metabolism and lacks properties to make it a substrate, inhibitor, or inducer of the CYP450 enzyme system and therefore is not likely to cause notable CYP450-related drug-drug interactions.

Like most other beta-lactams, ceftaroline is primarily excreted by the kidneys. Furthermore, an estimated 21% of a dose is eliminated with each intermittent hemodialysis session. Therefore, renal and intermittent hemodialysis dose adjustments are necessary. The estimated elimination half-life is 2.6 hours, necessitating dosing two to three times daily, depending on the indication and infectious inoculum.

Ceftaroline dosing

Ceftaroline is available only in a parenteral preparation and is typically given at a dose of 600 mg every 12 hours.¹⁰ The intravenous infusion is given over 1 hour.

The current stability data require reconstituted ceftaroline to be used within 6 hours at room temperature and within 24 hours if refrigerated.¹⁰

Ceftaroline requires dosing adjustments for patients with renal insufficiency. Per the manufacturer, renal dosing adjustments are based on the creatinine clearance rate, as estimated by the Cockroft-Gault formula:

• Creatinine clearance > 50 mL/min: no dosage adjustment necessary
• Creatinine clearance > 30 to ≤ 50 mL/min: give 400 mg every 12 hours
• Creatinine clearance ≥ 15 to ≤ 30 mL/min: give 300 mg every 12 hours
• Creatinine clearance < 15 mL/min or on intermittent dialysis: give 200 mg every 12 hours.

Ongoing clinical trials are investigating a higher-dosing strategy of 600 mg every 8 hours for patients with community-acquired bacterial pneumonia at risk of MRSA bacteremia.¹⁸

CLINICAL TRIALS LEADING TO CEFTAROLINE’S APPROVAL

Ceftaroline was approved for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin-structure infections due to susceptible pathogens on the basis of phase 3 comparator trials.

Community-acquired bacterial pneumonia: The FOCUS 1 and 2 trials

The efficacy and safety of ceftaroline in the treatment of community-acquired bacterial pneumonia was studied in two randomized, double-blind, noninferiority trials, known as Ceftaroline Community-acquired Pneumonia vs Ceftriaxone (FOCUS) 1 and FOCUS 2.^19,20

Patients were adults and not critically ill, as was reflected by their being in Pneumonia Outcomes Research Team (PORT) risk class III or IV (with class V indicating the highest risk of death). Therefore, the results may not be completely applicable to critically ill patients or those not admitted to the hospital. Of note, patients were excluded from the trials if they had infections known or thought to be due to MRSA or to atypical organisms.²¹ Baseline characteristics and patient demographics were similar between study groups in both trials.

A bacterial pathogen was identified in 26.1% of the patients included in the modified intent-to-treat analysis of the pooled data of the trials; the most common pathogens were S pneumoniae, methicillin-sensitive S aureus, Haemophilus influenzae, K pneumoniae, and E coli.²¹

Treatment. Patients received either ceftaroline 600 mg every 12 hours (or a lower dose based on renal function) or ceftriaxone 1 g every 24 hours. In addition, in the FOCUS 1 trial, patients in both treatment groups received clarithromycin 500 mg every 12 hours for the first day.¹⁹

Results. In both trials and in the integrated analysis, ceftaroline was noninferior to ceftriaxone (Table 3).²² In the integrated analysis of both trials, compared with the ceftriaxone group, the ceftaroline group had a higher clinical cure rate among patients classified as PORT risk class III (86.8% vs 79.2%, weighted treatment difference 12.6%, 95% confidence interval [CI] 1.3–13.8) and among patients who had not received prior antibiotic treatment (85.5% vs 74.9%, weighted treatment difference 11.2%, 95% CI 4.5–18.0).²¹

Acute bacterial skin and skin-structure infections: The CANVAS 1 and 2 trials

The efficacy and safety of ceftaroline in the treatment of complicated acute bacterial skin and skin-structure infections was studied in two randomized, double-blind trials: Ceftaroline Versus Vancomycin in Skin and Skin Structure Infections (CANVAS) 1 and CANVAS 2.^23,24

Patients. Adult patients with a diagnosis of community-acquired skin and skin-structure infections warranting at least 5 days of intravenous antimicrobial therapy were included in the trials. Important protocol exclusions were patients with diabetic foot ulcers, decubitus ulcers, burns, ulcers associated with peripheral vascular disease accompanied by osteomyelitis, and suspected P aeruginosa infections.²⁵ This limits the external validity of ceftaroline use in the aforementioned excluded patient populations.

Patients in each treatment group of the trials had similar demographic characteristics. The most common infections were cellulitis, major abscess requiring surgical intervention, wound infection, and infected ulcer. Bacteremia was present in 4.2% of patients in the ceftaroline group and in 3.8% of patients in the vancomycin-aztreonam group. The most common pathogen was S aureus. Methicillin resistance was present in 40% of the ceftaroline group and 34% of the control group.

Treatment. Patients received either ceftaroline 600 mg every 12 hours or the combination of vancomycin 1 g plus aztreonam 1 g given 12 hours, for 5 to 14 days.

Results. As assessed at a “test-of-cure” visit 8 to 15 days after the last dose of study medication, the efficacy of ceftaroline was similar to that of vancomycin-aztreonam, meeting the set noninferiority goal (Table 4).²⁵ Moreover, if assessed on day 2 or 3 (a new end point recommended by the FDA), the rate of cessation of erythema spread and absence of fever was higher in the ceftaroline group than in the vancomycin-aztreonam group.²⁶ However, this end point was not in the original trial protocol.

CEFTAROLINE FOR OTHER INDICATIONS

As noted, ceftaroline has been approved for treating community-acquired bacterial pneumonia and acute bacterial skin and skin-structure infections. In addition, it has been used in several studies in animals, and case reports of non-FDA approved indications including endocarditis and osteomyelitis have been published. Clinical trials are evaluating its use in pediatric patients, as well as for community-acquired bacterial pneumonia with risk for MRSA and for MRSA bacteremia.

Endocarditis

Animal studies have demonstrated ceftaroline to have bactericidal activity against MRSA and hVISA in endocarditis.²⁷

A few case series have been published describing ceftaroline’s use as salvage therapy for persistent MRSA bacteremia and endocarditis. For example, Ho et al²⁸ reported using it in three patients who had endocarditis as a source of their persistent bacteremia. All three patients had resolution of their MRSA bloodstream infection following ceftaroline therapy. The dosage was 600 mg every 8 hours, which is higher than in the manufacturer’s prescribing information.

Lin et al²⁹ reported using ceftaroline in five patients with either possible or probable endocarditis. Three of the five patients had clinical cure as defined by resolution or improvement of all signs and symptoms of infection, and not requiring further antimicrobial therapy.²⁹

More data from clinical trials would be beneficial in defining ceftaroline’s role in treating endocarditis caused by susceptible microorganisms.

Osteomyelitis

In animal studies of osteomyelitis, ceftaroline exhibited activity against MRSA in infected bone and joint fluid. Compared with vancomycin and linezolid, ceftaroline was associated with more significant decreases in bacterial load in the infected joint fluid, bone marrow, and bone.³⁰

Lin et al²⁹ gave ceftaroline to two patients with bone and joint infections, both of whom had received other therapies that had failed. The doses of ceftaroline were higher than those recommended in the prescribing information; clinical cure was noted in both cases following the switch.

These data come from case series, and more study of ceftaroline’s role in the treatment of osteomyelitis infections is warranted.

Meningitis

The use of ceftaroline in meningitis has been studied in rabbits. While ceftaroline penetrated into the cerebrospinal fluid in only negligible amounts in healthy rabbits (3% penetration), its penetration improved to 15% in animals with inflamed meninges. Ceftaroline cerebrospinal fluid levels in inflamed meninges were sufficient to provide bactericidal activity against penicillin-sensitive and resistant S pneumoniae strains as well as K pneumoniae and E coli strains.^31,32

REPORTED ADVERSE EFFECTS OF CEFTAROLINE

Overall, ceftaroline was well tolerated in clinical trials, and its safety profile was similar to those of the comparator agents (ceftriaxone and vancomycin-aztreonam).

As with the other cephalosporins, hypersensitivity reactions have been reported with ceftaroline. In the clinical trials, 3% of patients developed a rash with ceftaroline.^33,34 Patients with a history of beta-lactam allergy were excluded from the trials, so the rate of cross-reactivity with penicillins and with other cephalosporins is unknown.

In the phase 3 clinical trials, gastrointestinal side effects including diarrhea (5%), nausea (4%), and vomiting (2%) were reported with ceftaroline. C difficile-associated diarrhea has also been reported.³³

As with other cephalosporins, ceftaroline can cause a false-positive result on the Coombs test. Approximately 11% of ceftaroline-treated patients in phase 3 clinical trials had a positive Coombs test, but hemolytic anemia did not occur in any patients.^33,34

Discontinuation of ceftaroline due to an adverse reaction was reported in 2.7% of patients receiving the drug during phase 3 trials, compared with 3.7% with comparator agents.

WHEN SHOULD CEFTAROLINE BE USED IN DAILY PRACTICE?

Ceftaroline has been shown to be at least as effective as ceftriaxone in treating community-acquired bacterial pneumonia, and at least as effective as vancomycin-aztreonam in treating acute bacterial skin and skin-structure infections. The 2014 Infectious Diseases Society of America’s guidelines for the diagnosis and management of skin and soft-tissue infections recommend ceftaroline as an option for empiric therapy for purulent skin and soft-tissue infections.³⁵

The guidelines on community-acquired pneumonia have not been updated since 2007, which was before ceftaroline was approved. However, these guidelines are currently undergoing revision and may provide insight on ceftaroline’s place in the treatment of community-acquired bacterial pneumonia.³⁶

Currently, ceftaroline’s routine use for these indications should be balanced by its higher cost ($150 for a 600-mg dose) compared with ceftriaxone ($5 for a 1-g dose) or vancomycin ($25 for a 1-g dose). The drug’s in vitro activity against drug-resistant pneumococci and S aureus, including MRSA, hVISA, and VISA may help fill an unmet need or provide a safer and more tolerable alternative to currently available therapies.

However, ceftaroline’s lack of activity against P aeruginosa and carbapenem-resistant Enterobacteriaceae does not meet the public health threat needs stemming from these multidrug-resistant microorganisms. Ongoing clinical trials in patients with more serious MRSA infections will provide important information about ceftaroline’s role as an anti-MRSA agent.

While the discovery of antimicrobials has had one of the greatest impacts on medicine, continued antibiotic use is threatened by the emergence of drug-resistant pathogens. Therefore, it is as important as ever to be good stewards of our currently available antimicrobials. Developing usage and dosing criteria for antimicrobials based on available data and literature is a step forward in optimizing the use of antibiotics—a precious medical resource.

Ceftaroline fosamil (Teflaro), introduced to the US market in October 2010, is the first beta-lactam agent with clinically useful activity against methicillin-resistant Staphylococcus aureus (MRSA). Currently, it is approved by the US Food and Drug Administration (FDA) to treat acute bacterial skin and skin-structure infections and community-acquired bacterial pneumonia caused by susceptible microorganisms.

In an era of increasing drug resistance and limited numbers of antimicrobials in the drug-production pipeline, ceftaroline is a step forward in fulfilling the Infectious Diseases Society of America’s “10 × ’20 Initiative” to increase support for drug research and manufacturing, with the goal of producing 10 new antimicrobial drugs by the year 2020.¹ Ceftaroline was the first of several antibiotics to receive FDA approval in response to this initiative. It was followed by dalbavancin (May 2014), tedizolid phosphate (June 2014), oritavancin (August 2014), ceftolozane-tazobactam (December 2014), and ceftazidime-avibactam (February 2015). These antibiotic agents are aimed at treating infections caused by drug-resistant gram-positive and gram-negative microorganisms. It is important to understand and optimize the use of these new antibiotic agents in order to decrease the risk of emerging antibiotic resistance and superinfections (eg, Clostridium difficile infection) caused by antibiotic overuse or misuse.

This article provides an overview of ceftaroline’s mechanisms of action and resistance, spectrum of activity, pharmacokinetic properties, adverse effects, and current place in therapy.

AN ERA OF MULTIDRUG-RESISTANT MICROORGANISMS

Increasing rates of antimicrobial resistance threaten the efficacy of antimicrobial drugs in the daily practice of medicine. The World Health Organization has labeled antimicrobial resistance one of the three greatest threats to human health. Global efforts are under way to stimulate development of new antimicrobial agents and to decrease rates of antimicrobial resistance.

Staphylococcus aureus: A threat, even with vancomycin

Between 1998 and 2005, S aureus was one of the most common inpatient and outpatient isolates reported by clinical laboratories throughout the United States.²

Treatment of S aureus infection is complicated by a variety of resistance mechanisms that have evolved over time. In fact, the first resistant isolate of S aureus emerged not long after penicillin’s debut into clinical practice, and now the majority of strains are resistant to penicillin.

Methicillin was designed to overcome this beta-lactamase resistance and became the treatment of choice for penicillin-resistant S aureus isolates. However, MRSA isolates soon emerged because of the organism’s acquisition of penicillin-binding protein PBP2a via the mecA gene, leading to decreased binding affinity of methicillin.³

Since then, several agents active against MRSA (vancomycin, daptomycin, linezolid, tigecycline) have been introduced and continue to be widely used. While vancomycin is considered the first-line option for a variety of MRSA infections, its use has been threatened because of the emergence of vancomycin-intermediate-resistant S aureus (VISA), S aureus strains displaying vancomycin heteroresistance (hVISA), and vancomycin-resistant S aureus (VRSA) strains.⁴

VISA and hVISA isolates emerged through sequential mutations that lead to autolytic activity and cell-wall thickening. In contrast, the mechanism of resistance in VRSA is by acquisition of the vanA resistance gene, which alters the binding site of vancomycin from d-alanine-d-alanine to d-alanine-d-lactate.⁵

Streptococcus pneumoniae resistance: A continuing problem

The prevalence of drug resistance in S pneumoniae has risen since the late 1990s. A 2013 report from the SENTRY Antimicrobial Surveillance Program stated that almost 20% of S pneumoniae isolates were resistant to amoxicillin-clavulanate, and similar trends have been observed for penicillin (14.8%) and ceftriaxone (11.7%).⁶

S pneumoniae resistance is acquired through modifications of the penicillin-binding proteins, namely PBP1a, PBP2b, PBP2x, and, less frequently, PBP2a. These modifications lead to decreased binding affinity for most beta-lactams.⁷

Clinical impact of multidrug-resistant S aureus and S pneumoniae

In 2011, the US Centers for Disease Control and Prevention reported an estimated 80,000 severe MRSA infections and 11,000 MRSA-related deaths in the United States.⁸ In the same report, drug-resistant S pneumoniae was estimated to be responsible for almost 1.2 million illnesses and 7,000 deaths per year, leading to upwards of $96 million in related medical costs.

While invasive drug-resistant S pneumoniae infections usually affect patients at the extremes of age (under age 5 and over age 65), they have had a serious impact on patients of all ages.⁸

In light of the increasing prevalence of multidrug-resistant organisms, newer antimicrobial agents with novel mechanisms of action are needed.

CEFTAROLINE: A BETA-LACTAM WITH ANTI-MRSA ACTIVITY

The cephalosporins, a class of beta-lactam antibiotics, were originally derived from the fungus Cephalosporium (now called Acremonium). There are now many agents in this class, each containing a nucleus consisting of a beta-lactam ring fused to a six-member dihydrothiazine ring, and two side chains that can be modified to affect antibacterial activity and pharmacokinetic properties.

Cephalosporins are typically categorized into “generations.” With some exceptions, the first- and second-generation agents have good activity against gram-positive microorganisms, including methicillin-susceptible S aureus—but not against MRSA. The third- and fourth-generation cephalosporins have better gram-negative activity, with many agents having activity against the gram-negative bacterium Pseudomonas aeruginosa.

Enterococcal isolates are intrinsically resistant to cephalosporins. Additionally, cephalosporins are not active against anaerobic bacteria, except for a subset of structurally unique second-generation cephalosporins, ie, cefotetan and cefoxitin.

Ceftaroline was synthesized with specific manipulations of the side chains to provide enhanced activity against MRSA and multidrug-resistant S pneumoniae isolates, making it the first available beta-lactam with this ability.

Mechanism of action

Ceftaroline binds to penicillin-binding proteins, inhibiting transpeptidation. This interaction blocks the final stage of peptidoglycan synthesis and inhibits bacterial cell wall formation, ultimately leading to cellular autolysis and microorganism death. Ceftaroline binds with high affinity to PBP2a and PBP2x, expanding its activity to encompass MRSA and penicillin-resistant S pneumoniae isolates.⁹

Spectrum of activity

Ceftaroline has in vitro activity against many gram-positive and gram-negative bacteria,^10–13 including (Table 1):

• Methicillin-susceptible and methicillin-resistant staphylococci
• VISA, VRSA, and hVISA
• Daptomycin-nonsusceptible S aureus
• Streptococcal species, including penicillin-resistant S pneumoniae
• Enterobacteriaceae, including Klebsiella pneumoniae, Klebsiella oxytoca, Escherichia coli, Citrobacter koseri, Citrobacter freundii, Enterobacter cloacae, Enterobacter aerogenes, Moraxella catarrhalis, Morganella morganii, and Proteus mirabilis.

Of note, ceftaroline is not active against Pseudomonas species, Enterococcus species, or Bacteroides fragilis. In addition, it is not active against the “atypical” respiratory pathogens Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila.

Ceftaroline resistance

Gram-negative organisms appear to develop resistance to ceftaroline at rates similar to those observed with the other oxyimino-cephalosporins (eg, ceftriaxone). Ceftaroline is inactive against gram-negative organisms producing extended-spectrum beta-lactamases, including K pneumoniae carbapenemase and metallo-beta-lactamases.¹⁴ In addition, it induces the expression of AmpC beta-lactamases.

Although currently uncommon, resistance to ceftaroline has also been reported in S aureus strains.¹⁵ The mechanism of resistance is decreased binding affinity for PBP2a due to amino acid substitutions on the nonpenicillin-binding domains.¹⁵

Pharmacokinetic profile

An understanding of pharmacokinetics is key in optimizing the dose of antimicrobials so that the drugs are used most effectively and pathogens do not develop resistance to them.

Ceftaroline fosamil is a prodrug that, upon intravenous administration, is rapidly converted by phosphatase enzymes to its active moiety, ceftaroline. Its pharmacokinetic profile is summarized in Table 2.^16,17 Its volume of distribution is similar to that of the fourth-generation cephalosporin cefepime.

Ceftaroline is then hydrolyzed into its inactive metabolite, ceftaroline M-1. It undergoes little hepatic metabolism and lacks properties to make it a substrate, inhibitor, or inducer of the CYP450 enzyme system and therefore is not likely to cause notable CYP450-related drug-drug interactions.

Like most other beta-lactams, ceftaroline is primarily excreted by the kidneys. Furthermore, an estimated 21% of a dose is eliminated with each intermittent hemodialysis session. Therefore, renal and intermittent hemodialysis dose adjustments are necessary. The estimated elimination half-life is 2.6 hours, necessitating dosing two to three times daily, depending on the indication and infectious inoculum.

Ceftaroline dosing

Ceftaroline is available only in a parenteral preparation and is typically given at a dose of 600 mg every 12 hours.¹⁰ The intravenous infusion is given over 1 hour.

The current stability data require reconstituted ceftaroline to be used within 6 hours at room temperature and within 24 hours if refrigerated.¹⁰

Ceftaroline requires dosing adjustments for patients with renal insufficiency. Per the manufacturer, renal dosing adjustments are based on the creatinine clearance rate, as estimated by the Cockroft-Gault formula:

• Creatinine clearance > 50 mL/min: no dosage adjustment necessary
• Creatinine clearance > 30 to ≤ 50 mL/min: give 400 mg every 12 hours
• Creatinine clearance ≥ 15 to ≤ 30 mL/min: give 300 mg every 12 hours
• Creatinine clearance < 15 mL/min or on intermittent dialysis: give 200 mg every 12 hours.

Ongoing clinical trials are investigating a higher-dosing strategy of 600 mg every 8 hours for patients with community-acquired bacterial pneumonia at risk of MRSA bacteremia.¹⁸

CLINICAL TRIALS LEADING TO CEFTAROLINE’S APPROVAL

Ceftaroline was approved for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin-structure infections due to susceptible pathogens on the basis of phase 3 comparator trials.

Community-acquired bacterial pneumonia: The FOCUS 1 and 2 trials

The efficacy and safety of ceftaroline in the treatment of community-acquired bacterial pneumonia was studied in two randomized, double-blind, noninferiority trials, known as Ceftaroline Community-acquired Pneumonia vs Ceftriaxone (FOCUS) 1 and FOCUS 2.^19,20

Patients were adults and not critically ill, as was reflected by their being in Pneumonia Outcomes Research Team (PORT) risk class III or IV (with class V indicating the highest risk of death). Therefore, the results may not be completely applicable to critically ill patients or those not admitted to the hospital. Of note, patients were excluded from the trials if they had infections known or thought to be due to MRSA or to atypical organisms.²¹ Baseline characteristics and patient demographics were similar between study groups in both trials.

A bacterial pathogen was identified in 26.1% of the patients included in the modified intent-to-treat analysis of the pooled data of the trials; the most common pathogens were S pneumoniae, methicillin-sensitive S aureus, Haemophilus influenzae, K pneumoniae, and E coli.²¹

Treatment. Patients received either ceftaroline 600 mg every 12 hours (or a lower dose based on renal function) or ceftriaxone 1 g every 24 hours. In addition, in the FOCUS 1 trial, patients in both treatment groups received clarithromycin 500 mg every 12 hours for the first day.¹⁹

Results. In both trials and in the integrated analysis, ceftaroline was noninferior to ceftriaxone (Table 3).²² In the integrated analysis of both trials, compared with the ceftriaxone group, the ceftaroline group had a higher clinical cure rate among patients classified as PORT risk class III (86.8% vs 79.2%, weighted treatment difference 12.6%, 95% confidence interval [CI] 1.3–13.8) and among patients who had not received prior antibiotic treatment (85.5% vs 74.9%, weighted treatment difference 11.2%, 95% CI 4.5–18.0).²¹

Acute bacterial skin and skin-structure infections: The CANVAS 1 and 2 trials

The efficacy and safety of ceftaroline in the treatment of complicated acute bacterial skin and skin-structure infections was studied in two randomized, double-blind trials: Ceftaroline Versus Vancomycin in Skin and Skin Structure Infections (CANVAS) 1 and CANVAS 2.^23,24

Patients. Adult patients with a diagnosis of community-acquired skin and skin-structure infections warranting at least 5 days of intravenous antimicrobial therapy were included in the trials. Important protocol exclusions were patients with diabetic foot ulcers, decubitus ulcers, burns, ulcers associated with peripheral vascular disease accompanied by osteomyelitis, and suspected P aeruginosa infections.²⁵ This limits the external validity of ceftaroline use in the aforementioned excluded patient populations.

Patients in each treatment group of the trials had similar demographic characteristics. The most common infections were cellulitis, major abscess requiring surgical intervention, wound infection, and infected ulcer. Bacteremia was present in 4.2% of patients in the ceftaroline group and in 3.8% of patients in the vancomycin-aztreonam group. The most common pathogen was S aureus. Methicillin resistance was present in 40% of the ceftaroline group and 34% of the control group.

Treatment. Patients received either ceftaroline 600 mg every 12 hours or the combination of vancomycin 1 g plus aztreonam 1 g given 12 hours, for 5 to 14 days.

Results. As assessed at a “test-of-cure” visit 8 to 15 days after the last dose of study medication, the efficacy of ceftaroline was similar to that of vancomycin-aztreonam, meeting the set noninferiority goal (Table 4).²⁵ Moreover, if assessed on day 2 or 3 (a new end point recommended by the FDA), the rate of cessation of erythema spread and absence of fever was higher in the ceftaroline group than in the vancomycin-aztreonam group.²⁶ However, this end point was not in the original trial protocol.

CEFTAROLINE FOR OTHER INDICATIONS

As noted, ceftaroline has been approved for treating community-acquired bacterial pneumonia and acute bacterial skin and skin-structure infections. In addition, it has been used in several studies in animals, and case reports of non-FDA approved indications including endocarditis and osteomyelitis have been published. Clinical trials are evaluating its use in pediatric patients, as well as for community-acquired bacterial pneumonia with risk for MRSA and for MRSA bacteremia.

Endocarditis

Animal studies have demonstrated ceftaroline to have bactericidal activity against MRSA and hVISA in endocarditis.²⁷

A few case series have been published describing ceftaroline’s use as salvage therapy for persistent MRSA bacteremia and endocarditis. For example, Ho et al²⁸ reported using it in three patients who had endocarditis as a source of their persistent bacteremia. All three patients had resolution of their MRSA bloodstream infection following ceftaroline therapy. The dosage was 600 mg every 8 hours, which is higher than in the manufacturer’s prescribing information.

Lin et al²⁹ reported using ceftaroline in five patients with either possible or probable endocarditis. Three of the five patients had clinical cure as defined by resolution or improvement of all signs and symptoms of infection, and not requiring further antimicrobial therapy.²⁹

More data from clinical trials would be beneficial in defining ceftaroline’s role in treating endocarditis caused by susceptible microorganisms.

Osteomyelitis

In animal studies of osteomyelitis, ceftaroline exhibited activity against MRSA in infected bone and joint fluid. Compared with vancomycin and linezolid, ceftaroline was associated with more significant decreases in bacterial load in the infected joint fluid, bone marrow, and bone.³⁰

Lin et al²⁹ gave ceftaroline to two patients with bone and joint infections, both of whom had received other therapies that had failed. The doses of ceftaroline were higher than those recommended in the prescribing information; clinical cure was noted in both cases following the switch.

These data come from case series, and more study of ceftaroline’s role in the treatment of osteomyelitis infections is warranted.

Meningitis

The use of ceftaroline in meningitis has been studied in rabbits. While ceftaroline penetrated into the cerebrospinal fluid in only negligible amounts in healthy rabbits (3% penetration), its penetration improved to 15% in animals with inflamed meninges. Ceftaroline cerebrospinal fluid levels in inflamed meninges were sufficient to provide bactericidal activity against penicillin-sensitive and resistant S pneumoniae strains as well as K pneumoniae and E coli strains.^31,32

REPORTED ADVERSE EFFECTS OF CEFTAROLINE

Overall, ceftaroline was well tolerated in clinical trials, and its safety profile was similar to those of the comparator agents (ceftriaxone and vancomycin-aztreonam).

As with the other cephalosporins, hypersensitivity reactions have been reported with ceftaroline. In the clinical trials, 3% of patients developed a rash with ceftaroline.^33,34 Patients with a history of beta-lactam allergy were excluded from the trials, so the rate of cross-reactivity with penicillins and with other cephalosporins is unknown.

In the phase 3 clinical trials, gastrointestinal side effects including diarrhea (5%), nausea (4%), and vomiting (2%) were reported with ceftaroline. C difficile-associated diarrhea has also been reported.³³

As with other cephalosporins, ceftaroline can cause a false-positive result on the Coombs test. Approximately 11% of ceftaroline-treated patients in phase 3 clinical trials had a positive Coombs test, but hemolytic anemia did not occur in any patients.^33,34

Discontinuation of ceftaroline due to an adverse reaction was reported in 2.7% of patients receiving the drug during phase 3 trials, compared with 3.7% with comparator agents.

WHEN SHOULD CEFTAROLINE BE USED IN DAILY PRACTICE?

Ceftaroline has been shown to be at least as effective as ceftriaxone in treating community-acquired bacterial pneumonia, and at least as effective as vancomycin-aztreonam in treating acute bacterial skin and skin-structure infections. The 2014 Infectious Diseases Society of America’s guidelines for the diagnosis and management of skin and soft-tissue infections recommend ceftaroline as an option for empiric therapy for purulent skin and soft-tissue infections.³⁵

The guidelines on community-acquired pneumonia have not been updated since 2007, which was before ceftaroline was approved. However, these guidelines are currently undergoing revision and may provide insight on ceftaroline’s place in the treatment of community-acquired bacterial pneumonia.³⁶

Currently, ceftaroline’s routine use for these indications should be balanced by its higher cost ($150 for a 600-mg dose) compared with ceftriaxone ($5 for a 1-g dose) or vancomycin ($25 for a 1-g dose). The drug’s in vitro activity against drug-resistant pneumococci and S aureus, including MRSA, hVISA, and VISA may help fill an unmet need or provide a safer and more tolerable alternative to currently available therapies.

However, ceftaroline’s lack of activity against P aeruginosa and carbapenem-resistant Enterobacteriaceae does not meet the public health threat needs stemming from these multidrug-resistant microorganisms. Ongoing clinical trials in patients with more serious MRSA infections will provide important information about ceftaroline’s role as an anti-MRSA agent.

While the discovery of antimicrobials has had one of the greatest impacts on medicine, continued antibiotic use is threatened by the emergence of drug-resistant pathogens. Therefore, it is as important as ever to be good stewards of our currently available antimicrobials. Developing usage and dosing criteria for antimicrobials based on available data and literature is a step forward in optimizing the use of antibiotics—a precious medical resource.

In the first report evaluating the impact of a clinical guideline that calls for the use of postoperative continuous electroencephalography (CEEG) on infants after they’ve had cardiopulmonary bypass surgery, investigators at Children’s Hospital of Philadelphia and the University of Pennsylvania validated the clinical utility of routine CEEG monitoring and found that clinical assessment for seizures without CEEG is not a reliable marker for diagnosis and treatment.

In a report online in the Journal of Thoracic and Cardiovascular Surgery (J. Thorac. Cardiovasc. Surg. 2015 [doi:10.1016/j.jtcvs.2015.03.045]), Dr. Maryam Naim and colleagues said that CEEG identified electroencephalographic seizures in 8% of newborns after cardiopulmonary bypass surgery. The study, conducted over 18 months, evaluated 172 newborns, none older than 1 month, with 161 (94%) having undergone postoperative CEEG. They had CEEG within 6 hours of their return to the cardiac intensive care unit.

Courtesy of JTCVS/AATS

The study classified electroencephalographic seizures as EEG-only (also termed nonconvulsive seizures, with no observable clinical signs either at bedside or via video) or electroclinical seizures. Dr. Naim and colleagues said the majority of seizures they identified with CEEG would not have been noticed otherwise as they had no clinically obvious signs or symptoms.

The American Clinical Neurophysiology Society (ACNS) recommends that cardiac surgeons consider continuous CEEG monitoring in high-risk neonates with congenital heart disease (CHD) after bypass surgery, but Dr. Naim and coauthors raised the question of whether seizure incidence would justify routine CEEG for all neonates with CHD who’ve had bypass surgery, especially as health systems place greater emphasis on quality improvement programs and cost-effective strategies. The authors said that neonates with all types of congenital heart disease had seizures.

“In adult populations, CEEG has not been shown to significantly increase hospital costs, but cost-effectiveness analyses have not been performed in neonates with CHD,” the authors said.

So they attempted to identify at-risk populations of newborns who would benefit most from routine CEEG monitoring. In a multivariable model that the investigators used, both delayed sternal closure and longer deep hypothermic circulatory arrest (DHCA) during surgery seemed predictive of seizures, but the odds ratios for both were low, “suggesting the statistically significant findings may not be very useful in focusing CEEG implementation on a high-risk group.”

Previous studies have reported that identifying and treating seizures in newborns who have had bypass surgery may reduce secondary brain injury and improve outcomes (Pediatrics 2008;121:e759-67), and the Boston Circulatory Arrest Study showed an association between postoperative seizures and lower reading and math scores and lower cognitive and functional skills later in life (Circulation 2011;124:1361-1369). The authors cited other studies that showed older, critically ill children with “high seizure burdens” have had worse outcomes. (Critical Care Medicine 2013;31:215-23; Neurology 2014;82:396-404; Brain 2014;137:1429-38). They also pointed out increased risk if the seizure is not treated. “While occurrence of a seizure is a marker of brain injury, there may also be secondary injury if the seizure activity is not terminated,” Dr. Naim and coauthors said.

The investigators concluded that postoperative CEEG to identify seizures “is warranted,” and while they found some newborns may be at greater risk of postbypass seizures than others, they advocated for “widespread” monitoring strategies.

Their work also questioned the effectiveness of non-CEEG assessment. In the study, clinicians identified bedside events indicative of seizures – what the study termed “push-button events” – in 32 newborns, or about 18% of patients, but none of the events had an EEG correlate, so they were considered nonepileptic. When the authors looked more closely at those “push-button” events, they found they ranged from abnormal body movement in 14 and hypertension in 7 to tachycardia and abnormal face movements, among other characterizations, in lesser numbers.

“Furthermore, push-button events by bedside clinicians, including abnormal movements and hypertensive episodes concerning for possible seizures, did not have any EEG correlate, indicating that bedside clinical assessment for seizures without CEEG monitoring is unreliable,” Dr. Naim and colleagues said.

As to whether identifying and treating postbypass seizures in young newborns with CHD will improve long-term neurodevelopment in these children, the authors acknowledged that further study is needed.

They reported having no financial disclosures.

In the first report evaluating the impact of a clinical guideline that calls for the use of postoperative continuous electroencephalography (CEEG) on infants after they’ve had cardiopulmonary bypass surgery, investigators at Children’s Hospital of Philadelphia and the University of Pennsylvania validated the clinical utility of routine CEEG monitoring and found that clinical assessment for seizures without CEEG is not a reliable marker for diagnosis and treatment.

In a report online in the Journal of Thoracic and Cardiovascular Surgery (J. Thorac. Cardiovasc. Surg. 2015 [doi:10.1016/j.jtcvs.2015.03.045]), Dr. Maryam Naim and colleagues said that CEEG identified electroencephalographic seizures in 8% of newborns after cardiopulmonary bypass surgery. The study, conducted over 18 months, evaluated 172 newborns, none older than 1 month, with 161 (94%) having undergone postoperative CEEG. They had CEEG within 6 hours of their return to the cardiac intensive care unit.

Courtesy of JTCVS/AATS

The study classified electroencephalographic seizures as EEG-only (also termed nonconvulsive seizures, with no observable clinical signs either at bedside or via video) or electroclinical seizures. Dr. Naim and colleagues said the majority of seizures they identified with CEEG would not have been noticed otherwise as they had no clinically obvious signs or symptoms.

The American Clinical Neurophysiology Society (ACNS) recommends that cardiac surgeons consider continuous CEEG monitoring in high-risk neonates with congenital heart disease (CHD) after bypass surgery, but Dr. Naim and coauthors raised the question of whether seizure incidence would justify routine CEEG for all neonates with CHD who’ve had bypass surgery, especially as health systems place greater emphasis on quality improvement programs and cost-effective strategies. The authors said that neonates with all types of congenital heart disease had seizures.

“In adult populations, CEEG has not been shown to significantly increase hospital costs, but cost-effectiveness analyses have not been performed in neonates with CHD,” the authors said.

So they attempted to identify at-risk populations of newborns who would benefit most from routine CEEG monitoring. In a multivariable model that the investigators used, both delayed sternal closure and longer deep hypothermic circulatory arrest (DHCA) during surgery seemed predictive of seizures, but the odds ratios for both were low, “suggesting the statistically significant findings may not be very useful in focusing CEEG implementation on a high-risk group.”

Previous studies have reported that identifying and treating seizures in newborns who have had bypass surgery may reduce secondary brain injury and improve outcomes (Pediatrics 2008;121:e759-67), and the Boston Circulatory Arrest Study showed an association between postoperative seizures and lower reading and math scores and lower cognitive and functional skills later in life (Circulation 2011;124:1361-1369). The authors cited other studies that showed older, critically ill children with “high seizure burdens” have had worse outcomes. (Critical Care Medicine 2013;31:215-23; Neurology 2014;82:396-404; Brain 2014;137:1429-38). They also pointed out increased risk if the seizure is not treated. “While occurrence of a seizure is a marker of brain injury, there may also be secondary injury if the seizure activity is not terminated,” Dr. Naim and coauthors said.

The investigators concluded that postoperative CEEG to identify seizures “is warranted,” and while they found some newborns may be at greater risk of postbypass seizures than others, they advocated for “widespread” monitoring strategies.

Their work also questioned the effectiveness of non-CEEG assessment. In the study, clinicians identified bedside events indicative of seizures – what the study termed “push-button events” – in 32 newborns, or about 18% of patients, but none of the events had an EEG correlate, so they were considered nonepileptic. When the authors looked more closely at those “push-button” events, they found they ranged from abnormal body movement in 14 and hypertension in 7 to tachycardia and abnormal face movements, among other characterizations, in lesser numbers.

“Furthermore, push-button events by bedside clinicians, including abnormal movements and hypertensive episodes concerning for possible seizures, did not have any EEG correlate, indicating that bedside clinical assessment for seizures without CEEG monitoring is unreliable,” Dr. Naim and colleagues said.

As to whether identifying and treating postbypass seizures in young newborns with CHD will improve long-term neurodevelopment in these children, the authors acknowledged that further study is needed.

They reported having no financial disclosures.

In the first report evaluating the impact of a clinical guideline that calls for the use of postoperative continuous electroencephalography (CEEG) on infants after they’ve had cardiopulmonary bypass surgery, investigators at Children’s Hospital of Philadelphia and the University of Pennsylvania validated the clinical utility of routine CEEG monitoring and found that clinical assessment for seizures without CEEG is not a reliable marker for diagnosis and treatment.

In a report online in the Journal of Thoracic and Cardiovascular Surgery (J. Thorac. Cardiovasc. Surg. 2015 [doi:10.1016/j.jtcvs.2015.03.045]), Dr. Maryam Naim and colleagues said that CEEG identified electroencephalographic seizures in 8% of newborns after cardiopulmonary bypass surgery. The study, conducted over 18 months, evaluated 172 newborns, none older than 1 month, with 161 (94%) having undergone postoperative CEEG. They had CEEG within 6 hours of their return to the cardiac intensive care unit.

Courtesy of JTCVS/AATS

The study classified electroencephalographic seizures as EEG-only (also termed nonconvulsive seizures, with no observable clinical signs either at bedside or via video) or electroclinical seizures. Dr. Naim and colleagues said the majority of seizures they identified with CEEG would not have been noticed otherwise as they had no clinically obvious signs or symptoms.

The American Clinical Neurophysiology Society (ACNS) recommends that cardiac surgeons consider continuous CEEG monitoring in high-risk neonates with congenital heart disease (CHD) after bypass surgery, but Dr. Naim and coauthors raised the question of whether seizure incidence would justify routine CEEG for all neonates with CHD who’ve had bypass surgery, especially as health systems place greater emphasis on quality improvement programs and cost-effective strategies. The authors said that neonates with all types of congenital heart disease had seizures.

“In adult populations, CEEG has not been shown to significantly increase hospital costs, but cost-effectiveness analyses have not been performed in neonates with CHD,” the authors said.

So they attempted to identify at-risk populations of newborns who would benefit most from routine CEEG monitoring. In a multivariable model that the investigators used, both delayed sternal closure and longer deep hypothermic circulatory arrest (DHCA) during surgery seemed predictive of seizures, but the odds ratios for both were low, “suggesting the statistically significant findings may not be very useful in focusing CEEG implementation on a high-risk group.”

Previous studies have reported that identifying and treating seizures in newborns who have had bypass surgery may reduce secondary brain injury and improve outcomes (Pediatrics 2008;121:e759-67), and the Boston Circulatory Arrest Study showed an association between postoperative seizures and lower reading and math scores and lower cognitive and functional skills later in life (Circulation 2011;124:1361-1369). The authors cited other studies that showed older, critically ill children with “high seizure burdens” have had worse outcomes. (Critical Care Medicine 2013;31:215-23; Neurology 2014;82:396-404; Brain 2014;137:1429-38). They also pointed out increased risk if the seizure is not treated. “While occurrence of a seizure is a marker of brain injury, there may also be secondary injury if the seizure activity is not terminated,” Dr. Naim and coauthors said.

The investigators concluded that postoperative CEEG to identify seizures “is warranted,” and while they found some newborns may be at greater risk of postbypass seizures than others, they advocated for “widespread” monitoring strategies.

Their work also questioned the effectiveness of non-CEEG assessment. In the study, clinicians identified bedside events indicative of seizures – what the study termed “push-button events” – in 32 newborns, or about 18% of patients, but none of the events had an EEG correlate, so they were considered nonepileptic. When the authors looked more closely at those “push-button” events, they found they ranged from abnormal body movement in 14 and hypertension in 7 to tachycardia and abnormal face movements, among other characterizations, in lesser numbers.

“Furthermore, push-button events by bedside clinicians, including abnormal movements and hypertensive episodes concerning for possible seizures, did not have any EEG correlate, indicating that bedside clinical assessment for seizures without CEEG monitoring is unreliable,” Dr. Naim and colleagues said.

As to whether identifying and treating postbypass seizures in young newborns with CHD will improve long-term neurodevelopment in these children, the authors acknowledged that further study is needed.

They reported having no financial disclosures.

In the 1980s, human immunodeficiency virus (HIV) infection was considered untreatable and predictably lethal. Today, with highly effective antiretroviral therapy, it has become a chronic condition in which patients have a life expectancy comparable to that in the general population.

This change has led to new challenges for primary care physicians, many of whom now find themselves either the sole medical provider for or the comanager of aging HIV-infected patients. Given that about one-fifth of new HIV diagnoses are now in people over the age of 50, it is crucial that primary care providers be able to recognize and diagnose the disease in this population. In addition, they need to effectively manage the polypharmacy and subsequent drug interactions prevalent in older HIV-infected patients. Finally, the clinician must address comorbid diseases common in the elderly, specifically neurologic, cardiovascular, metabolic, and endocrine disorders, as well as performing routine cancer screening.

Take-home point

• As the number of people age 50 and older with HIV infection increases, primary care providers must be able to both recognize and manage the condition.

RISING PREVALENCE OF HIV IN THE ELDERLY

Globally, about 2.5 million people received a new diagnosis of HIV infection in 2011, and about 35 million people worldwide are currently living with it.¹ An estimated 1.1 million Americans are living with HIV, and of these, about 16% do not know they are infected.²

HIV patients who adhere to treatment and achieve a CD4 count above 350 and a low viral load have a normal life expectancy

Antiretroviral therapy has greatly improved the life expectancy of HIV-infected patients, and the number of HIV-infected people over age 50 continues to rise. A successfully treated HIV-positive person with a CD4 count higher than 350 × 10⁶/L and a suppressed viral load now has a normal life expectancy.³ In 2011, nearly 20% of newly diagnosed HIV-infected people in the United States were over age 50, as were nearly 25% of those with a new diagnosis of acquired immune deficiency syndrome (AIDS).⁴ This year (2015), we expect that more than half of all HIV-infected people in the United States will be over age 50.⁵

The rising prevalence of HIV infection in this age group has prompted reevaluation of screening guidelines. The US Preventive Services Task Force recommends screening for HIV in all people ages 15 to 65, and also after age 65 in people at ongoing risk of infection.⁶ The American College of Physicians has suggested that the range for routine HIV screening be expanded to age 75.⁷ The cost-effectiveness of expanded and more frequent HIV testing appears to justify it.⁸

Take-home points

• An HIV-infected patient who is compliant with an appropriate antiretroviral regimen and has a CD4 count higher than 350 × 10⁶/L and a suppressed viral load now has a normal life expectancy.
• Today, nearly 20% of newly diagnosed HIV-infected people and more than 50% of all HIV-infected people in the United States are over the age of 50.
• The age range for routine screening for HIV infection should be expanded.

HIGH-RISK GROUPS AMONG THE ELDERLY

Early in the HIV epidemic, older patients acquired HIV from blood transfusions received because of hemophilia and other disorders. However, this rapidly ceased after blood banks began screening blood products. Today, people over age 50 who acquire HIV have many of the same risk factors as younger people.

Men who have sex with men are the largest subgroup of HIV-infected people in the United States, even among those over age 50. In particular, white men who have sex with men now constitute the largest demographic group among the HIV-infected elderly.⁴

Intravenous drug users make up about 15% of older people with HIV.

Women who have sex with infected men or with men at risk of HIV infection make up the largest group of older women with HIV.⁴

Sex and the older person

Many older HIV-infected people remain sexually active and continue to engage in unprotected sexual intercourse far into advanced age. According to one survey, 53% of Americans ages 65 to 74 are engaging in sexual activity regularly; however, they are not using protective measures with up to 91% of casual partners and 70% of new partners.^9,10 Many widowed and divorced people are dating again, and they may be unfamiliar with condom use or may be reluctant to use condoms because condoms can often make it difficult to maintain an erection.

Drugs for erectile dysfunction are making it easier for the elderly to engage in both vaginal and anal intercourse, but often without a condom.⁹ Older women who no longer worry about getting pregnant may be less likely to insist their partners use a condom and to practice safe sex. In addition, age-related thinning and dryness can cause vaginal tears, increasing the risk of HIV transmission.¹¹

Take-home points

• People older than 50 have risk factors for HIV similar to those in younger people.
• Men who have sex with men compose the largest group of HIV-infected individuals in the elderly population.
• Unprotected sexual intercourse is common in the elderly for several reasons: unfamiliarity with condom use, difficulty maintaining an erection, lack of concern about possible pregnancy, and vaginal thinning and dryness in women.

UNDERDIAGNOSIS AND LATE DIAGNOSIS IN THE ELDERLY

The cumulative number of AIDS cases in adults age 50 and older increased nearly ninefold from 1990 to the end of 2009. Even more worrisome, one-half of HIV-positive adults over age 50 are diagnosed with AIDS simultaneously or within 1 year of their HIV diagnosis.⁴ This late diagnosis—and therefore late initiation of treatment—is associated with poorer health outcomes and more rapid disease progression.¹²

HIV infection in older adults often goes undiagnosed, for several reasons.

Providers may underestimate the risk in this population and therefore may not discuss HIV transmission or perform testing. Despite a US Centers for Disease Control and Prevention recommendation that people ages 13 to 64 be tested at least once, and more often if sexually active, only 35% of adults ages 45 to 64 have ever been tested for HIV infection.¹³

Age greater than 50 has been strongly associated with higher rates of non–AIDS-related cancers and cardiovascular disease

Older patients may not perceive themselves to be at risk of HIV infection because of lack of insight and information about its prevention and transmission. They are also less likely than younger adults to discuss their sexual habits or drug use with providers.¹⁴ In addition, compared with the young sexually active population, very little HIV prevention education is targeted to older people.¹⁵ Social stigmatization is also a concern for many HIV-infected elderly, as a perceived negative reputation within their community may prevent them from seeking care and disclosing their HIV status.

Take-home points

Reasons that HIV infection is underdiagnosed in the elderly include lack of:

• Provider recognition
• Insight and information about HIV prevention and transmission
• HIV-prevention education targeting the elderly
• Disclosure because of the social stigma of HIV infection.

HIV ACCELERATES AGING, AGING REDUCES IMMUNITY

Many HIV-positive people can expect to live as long as people in the general population, but those who are diagnosed late and thus are started on antiretroviral therapy later in the course of their infection have a reduced life expectancy. Longevity depends on both restoring the CD4 count to near-normal and suppressing the viral load to undetectable levels.^3,16 This is especially important for older adults, as HIV may accelerate aging, and aging itself may speed the progression of HIV disease, so that therapy may result in delayed or only partial restoration of immunity.

Older age at the time of HIV infection is a strong predictor of accelerated HIV disease progression in the absence of therapy.¹⁷ Left untreated, older patients with HIV lose CD4 cells and progress to AIDS and death faster than younger patients. The deleterious effects of chronic immune activation in the course of HIV infection, combined with the immune senescence of aging, are thought to promote this accelerated course.¹⁸

Recent data indicate that starting antiretroviral therapy early can help prevent the CD4-cell impairment that occurs with aging.¹⁹ However, in adults over age 50, the capacity to restore the CD4 count with antiretroviral therapy apears to be reduced, despite demonstrated viral load suppression and better adherence.²⁰ Although mean adherence rates appear higher in older HIV-infected patients, they are worse in those with neurocognitive impairment, highlighting the importance of evaluating neurocognition in this population.²¹

Decreased immune recovery and the subsequent increased risk of serious AIDS events are factors that now favor starting antiretroviral therapy in all HIV patients over age 50, regardless of CD4 count.

Take-home points

• Without treatment, HIV infection in older patients progresses more rapidly to AIDS and death than in younger patients.
• HIV-positive people over age 50 who have never received antiretroviral therapy should be strongly considered for it, regardless of the CD4 count.

SO MANY DRUGS, SO MANY INTERACTIONS

Since HIV patients are now living longer thanks to antiretroviral therapy, they are now experiencing more disease- and treatment-related problems. This has led to an increased likelihood of polypharmacy, defined here as the use of six or more medications.

In general, polypharmacy in the elderly is associated with adverse drug events, drug interactions, inappropriate medication use, delirium, falls, fractures, and poor medication adherence.^22,23 But it becomes even more of a problem in HIV-infected elderly patients, as various drug interactions can alter the effectiveness of the antiretroviral regimen and can result in drug toxicity.

The most common classes of medications used in the elderly are antihypertensives, lipid-lowering agents, antiplatelet medications, antidepressants, anxiolytics, sedatives, and analgesics, and many of these have notable interactions with current antiretroviral regimens.^24,25 Most medications, including antiretrovirals, are cleared by the liver or kidneys, and the function of these organs often decreases with age, resulting in impaired elimination and in drug accumulation.

Information on drug interactions is readily available from the US Department of Health and Human Services,²⁶ drug interaction databases,^27,28 and drug interaction software. The combination of antiretroviral therapy and preexisting polypharmacy significantly increases the risk of serious interactions, which can lead to drug toxicity, poorer adherence with antiretroviral therapy, loss of efficacy of the coadministered medication, or resurgence of HIV infection due to drug-drug interactions affecting the metabolism and ultimate efficacy of the antiretroviral therapy. An increased awareness of common drug-drug interactions can prevent coadministration of potentially harmful medications in elderly HIV patients.

Important interactions between antiretroviral drugs and other drug classes are summarized in Table 1.^25–28 Most notably:

• Simvastatin and lovastatin are contraindicated with any protease inhibitor.
• Proton pump inhibitors are not recommended for patients taking ritonavir-boosted atazanavir. If a proton pump inhibitor is necessary, the daily dose should not exceed 20 mg of omeprazole or its equivalent in patients who have never taken a protease inhibitor, and it should be taken 12 hours before boosted atazanavir.²⁶
• Corticosteroids, whether systemic, inhaled, or intranasal (eg, fluticasone, budesonide), should be avoided in combination with any protease inhibitor, as they can cause iatrogenic Cushing syndrome and also pose the risk of adrenal crisis during acute illness.²⁷

Take-home points

• In cases of preexisting polypharmacy, antiretroviral therapy can lead to significant drug toxicity, poor adherence to medications, and resurgence of HIV infection.
• Increased provider awareness of common drug-drug interactions can prevent the prescribing of potentially harmful drug combinations to HIV-infected elderly patients.

COMORBIDITIES

In recent years, more than half of the deaths in HIV patients on antiretroviral therapy have been from noninfectious comorbidities such as cardiovascular disease, bone disease, and renal failure, which often coexist and are associated with advanced age.²⁹ In fact, both older age and each additional year of antiretroviral therapy are independent predictors of polypathology (simultaneous occurrence of two or more defined diseases).³⁰ The Antiretroviral Therapy Cohort Collaboration found that age greater than 50 was strongly associated with increasing rates of non–AIDS-related malignancy and cardiovascular disease.³¹

CARDIOVASCULAR DISEASE

With the increasing life expectancy of HIV-infected adults on antiretroviral therapy, cardiovascular disease has become an important concern. HIV-infected adults appear to have a significantly greater risk of myocardial infarction and coronary artery disease than age-matched HIV-negative individuals.³² Strikingly, being older than 50 itself increases the risk of hospitalization for cardiovascular disease fivefold (incidence rate ratio 5.01, 95% confidence interval 3.41–7.38).³³ In addition, HIV infection is associated with a risk of acute myocardial infarction 50% higher than that explained by recognized risk factors.³⁴

This high prevalence of coronary artery disease is likely from a combination of factors, including increasing age and the chronic inflammation and immune activation associated with HIV infection.³⁵ An association between untreated HIV disease and markers of risk for cardiovascular disease has been identified.^36,37

HIV is associated with a 50% higher risk of acute myocardial infarction beyond traditional risk factors

In addition, antiretroviral therapy is associated with dyslipidemia, which is most pronounced with protease inhibitor regimens. Whether specific lipid changes associated with individual antiretroviral drugs affect cardiovascular risk remains uncertain. In the Data Collection on Adverse Events of Anti-HIV Drugs studies,³⁸ only cumulative exposure to indinavir, lopinavir-ritonavir, and didanosine was associated with an increased risk of myocardial infarction.³⁸

Traditional risk factors such as obesity, tobacco use, and genetic predisposition also apply to HIV-infected people.³⁹ In fact, the prevalence of traditional risk factors such as smoking and dyslipidemia is generally higher in HIV-infected people than in the general population, although this situation may be improving.⁴⁰

Science needs to elucidate the relationship between traditional and nontraditional risk factors for cardiovascular disease in older HIV-infected adults. In the meantime, older patients with HIV require aggressive management of modifiable risk factors.

Tools for assessing cardiovascular risk include the Framingham risk score⁴¹ and the Data Collection on Adverse Events of Anti-HIV Drugs 5-year risk calculator.⁴² The European AIDS Clinical Society guidelines recommend considering changing the antiretroviral regimen if the patient’s 10-year risk of cardiovascular disease is more than 20%.⁴³ Recommended strategies for reducing cardiovascular risk in elderly patients with HIV infection include counseling about smoking cessation and weight loss at every clinic visit and optimally controlling dyslipidemia and hypertension using nationally accepted standardized guidelines.⁴⁴

Take-home points

• HIV infection is associated with a 50% higher risk of acute myocardial infarction beyond that explained by traditional risk factors.
• Chronic inflammation, immune activation, and dyslipidemia associated with antiretroviral therapy all contribute to cardiovascular disease in HIV-infected patients.
• HIV-infected elderly patients require aggressive management of modifiable risk factors for cardiovascular disease.

ENDOCRINE DISEASE

Diabetes mellitus

The estimated prevalence of diabetes mellitus is 3% in HIV-infected people who have never received antiretroviral therapy, but glucose intolerance increases to the range of 10% to 25% in those who have started it.⁴⁵ Glucose disorders are associated with traditional risk factors as well as with HIV-associated factors such as lipodystrophy and antiretroviral therapy, specifically long-term use of protease inhibitors.⁴⁶ Although increasing age and obesity clearly play a role in the development of diabetes mellitus in this population, HIV-specific factors may also allow diabetes to develop at a lower level of adiposity than in people without HIV infection.⁴⁷

Strategies for preventing type 2 diabetes mellitus in HIV-infected patients focus on avoiding excessive weight gain, especially after starting antiretroviral therapy; regularly screening for diabetes using hemoglobin A_1c, both before and after starting antiretroviral therapy; and continuing to check hemoglobin A_1c every 6 months. The target hemoglobin A_1c should be less than 7.0%. This threshold should be increased to 8% in frail elderly adults if their anticipated life expectancy is less than 5 years, given their higher risk of hypoglycemia, polypharmacy, and drug interactions.⁴⁸ In addition, as in HIV-negative patients, diabetes screening should be performed if systolic blood pressure exceeds 135/80 mm Hg.

Insulin sensitizers such as metformin and thiazolidinediones should be considered for treating diabetes in HIV-infected patients if no contraindications exist. Consideration may also be given to switching the antiretroviral regimen from a protease inhibitor-based regimen to a nonnucleoside reverse transcriptase inhibitor-based regimen.⁴⁸

Take-home points

• Glucose intolerance has been associated with HIV-specific factors, including lipodystrophy and antiretroviral therapy.
• Avoiding excessive weight gain, use of insulin-sensitizing medications, and alteration in antiretroviral regimens should be considered for the treatment of diabetes mellitus in HIV infection.

Osteoporosis

Osteoporotic bone disease disproportionately affects patients with advanced HIV infection compared with patients of similar age.⁴⁹ Bone mineral density is lower and the fracture rate is higher in HIV-infected individuals.

The pathogenesis of bone disease appears to be multifactorial. Traditional risk factors include hypogonadism, smoking, alcohol use, and low body weight, while HIV-related risk factors include chronic immune activation and antiretroviral therapy.⁵⁰

Several antiretroviral regimens have been linked to clinically significant bone loss, including both tenofovir-based and protease inhibitor-based regimens.⁵¹ Most studies have shown that bone mineral density decreases by 2% to 6% in the first 2 years after starting these regimens⁵²; however, long-term effects on bone loss are unknown.

Questions remain. For example, what are the exact mechanisms that lead to the acute decrease in bone mineral density after starting antiretroviral therapy? And why is vitamin D deficiency is so prevalent in HIV infection, with low vitamin D levels seen in up to 60% to 75% of elderly HIV-infected patients?⁵³

Osteoporosis and vitamin D deficiency appear to be more prevalent with HIV infection

Both the Work Group for the HIV and Aging Consensus Project⁵⁴ and the European AIDS Clinical Society⁴³ recommend screening for and treating causes of secondary low bone mineral density in HIV-infected men over age 50 and postmenopausal HIV-infected women. These causes include vitamin D deficiency. As of 2013, the National Osteoporosis Foundation guidelines include HIV infection and antiretroviral therapy as osteoporosis risk factors that should trigger screening for low bone mineral density with dual-energy x-ray absorptiometry (DXA).⁵⁵

As in the general population, the preferred treatment for low bone mineral density in people with HIV is a bisphosphonate, in addition to ensuring adequate calcium and vitamin D intake. It is important to repeat DXA imaging every 2 years and to reassess the need for continued bisphosphonate therapy after 3 to 5 years because of a possible increased risk of fracture with prolonged use.

Take-home points

• Osteoporosis and vitamin D deficiency both appear to be more prevalent with HIV infection.
• HIV infection and antiretroviral therapy are risk factors that should prompt DXA screening to evaluate for osteoporosis.

NEUROCOGNITIVE DISORDERS

HIV-associated neurocognitive disorders are common, with an estimated 50% of HIV-infected patients experiencing some degree of cognitive loss and some progressing to dementia.⁵⁶ Unfortunately, studies suggest that cognitive disorders can occur despite good HIV control with antiretroviral therapy, with one report demonstrating that 84% of patients with cognitive complaints and 64% without complaints were affected by an HIV-associated neurocognitive disorder.⁵⁷

HIV-associated dementia is often subcortical, with fluctuating symptoms such as psychomotor retardation, difficulty multitasking, and apathy. In contrast to dementia syndromes such as Alzheimer disease, relentless progression is less common in HIV-infected patients who receive antiretroviral therapy.

The Mini-Mental State Examination should not be used to screen for HIV-associated neurocognitive disorders, as it does not assess the domains that are typically impaired. The Montreal Cognitive Assessment has been suggested as the best screening instrument in elderly HIV-infected patients; it is available at no cost at www.mocatest.org.⁵⁸

As HIV-associated neurocognitive disorder is a diagnosis of exclusion, an evaluation for alternative diagnoses such as syphilis, hypothyroidism, and depression is recommended. If an HIV-associated neurocognitive disorder is diagnosed, referral to specialty care should be considered, as interventions such as lumbar puncture to assess cerebrospinal fluid viral escape and changing the antiretroviral regimen to improve central nervous system penetration are possible options under study.

Patients with poorly controlled HIV and a depressed CD4 count are at risk of a number of central nervous system complications in addition to HIV-associated neurocognitive disorders, eg, central nervous system toxoplasmosis, cryptococcal meningitis, progressive multifocal leukoencephalopathy, and primary central nervous system lymphoma. Adherence to an effective antiretroviral regimen is the primary prevention strategy.

Take-home points

• HIV-associated neurocognitive disorders and dementia can occur despite appropriate HIV control and adherence to antiretroviral therapy.
• Adherence to antiretroviral therapy is the primary prevention against most central nervous system complications in HIV infection.

GERIATRIC SYNDROMES

The aging HIV-infected adult may also be at increased risk of geriatric syndromes.

HIV-infected men are 4.5 to 10 times more likely than age-matched controls to be frail

In particular, a frailty-related phenotype of weight loss, exhaustion, slowness, and low physical activity was more common in HIV-infected elderly than in noninfected elderly.⁵⁹ HIV-infected men are 4.5 to 10 times more likely than age-matched controls to be frail, and the likelihood of frailty increases with age, duration of HIV infection, having a CD4 count lower than 350 × 10⁶/L, and having uncontrolled HIV replication.^60,61

Other geriatric syndromes such as falls, urinary incontinence, and functional impairment have been identified in 25% to 56% of older HIV-infected patients.⁶² Indeed, the combination of HIV and older age may adversely affect performance of instrumental activities of daily living.⁶³ Also, as previously mentioned, nondisclosure, fear of HIV-related social stigmatization, and a desire to be self-reliant are all factors that perpetuate the social isolation that is common among the HIV-infected elderly.

For these reasons, a comprehensive approach involving a geriatrician, an infectious disease specialist, and community social workers is needed to manage the care of this aging population.

Take-home point

• Geriatric syndromes have an important impact on health in aging HIV patients.

CANCER SCREENING IN HIV PATIENTS

People with HIV have an elevated risk of cancer. Specifically, compared with the general population, their risk is:

• 3,640 times higher for Kaposi sarcoma
• 77 times higher for non-Hodgkin lymphomas
• 6 times higher for cervical cancer.^64,65

These cancers are considered “AIDS-defining,” and fortunately, the development of effective antiretroviral therapy in the 1990s has led to a marked reduction in their incidence. However, the aging HIV population is now experiencing a rise in the incidence of non–AIDS-defining cancers, such as cancers of the lung, liver, kidney, anus, head and neck, and skin, as well as Hodgkin lymphoma.⁶⁶ Table 2 shows the standardized incidence ratio of selected non–AIDS-defining cancers in HIV-infected patients as reported in several large international studies.^65,67,68 The etiology for the increased risk of non–AIDS-defining cancers in the HIV-infected population is not clear, but possible explanations include the virus itself, antiretroviral therapy, and co-infection with other viruses such as hepatitis B, hepatitis C, and Epstein-Barr virus.

Guidelines for cancer screening vary by organization, and the American Cancer Society, the National Cancer Institute, and the US Preventive Services Task Force do not have formal screening guidelines for the most common non–AIDS-defining cancers. The European AIDS Clinical Society, however, has proposed some screening recommendations for selected malignancies.⁴³

In general, screening recommendations are similar to those for HIV-negative patients. A specific difference for HIV-infected patients is in cervical cancer screening. HIV-infected women should undergo a Papanicolaou smear at 6-month intervals during the first year after diagnosis of HIV infection and, if the results are normal, annually thereafter. There is no consensus as to whether human papillomavirus testing should be performed routinely on HIV-infected women.

At the time of this writing, there are no recommendations for routine screening for anal cancer, although some specialists recommend anal cytologic screening for HIV-positive men and women, and an annual digital anal examination may be useful to detect masses that could be anal cancer.⁶⁹

Take-home points

• The incidence of non–AIDS-defining cancers is rising in the aging HIV population.
• There are currently no formal recommendations for routine screening for anal cancer.

FINAL WORD

Because patients with HIV are living longer as a result of newer effective combination antiretroviral therapies, physicians face a new challenge of managing conditions in these patients that are traditionally associated with aging. Providers will need to improve their understanding of drug-drug interactions and polypharmacy issues and be able to address the complex medical and psychosocial issues in this growing population. As patients with HIV on effective antiretroviral therapy grow older, the burden of comorbid medical disease will continue to increase.

In the 1980s, human immunodeficiency virus (HIV) infection was considered untreatable and predictably lethal. Today, with highly effective antiretroviral therapy, it has become a chronic condition in which patients have a life expectancy comparable to that in the general population.

This change has led to new challenges for primary care physicians, many of whom now find themselves either the sole medical provider for or the comanager of aging HIV-infected patients. Given that about one-fifth of new HIV diagnoses are now in people over the age of 50, it is crucial that primary care providers be able to recognize and diagnose the disease in this population. In addition, they need to effectively manage the polypharmacy and subsequent drug interactions prevalent in older HIV-infected patients. Finally, the clinician must address comorbid diseases common in the elderly, specifically neurologic, cardiovascular, metabolic, and endocrine disorders, as well as performing routine cancer screening.

Take-home point

• As the number of people age 50 and older with HIV infection increases, primary care providers must be able to both recognize and manage the condition.

RISING PREVALENCE OF HIV IN THE ELDERLY

Globally, about 2.5 million people received a new diagnosis of HIV infection in 2011, and about 35 million people worldwide are currently living with it.¹ An estimated 1.1 million Americans are living with HIV, and of these, about 16% do not know they are infected.²

HIV patients who adhere to treatment and achieve a CD4 count above 350 and a low viral load have a normal life expectancy

Antiretroviral therapy has greatly improved the life expectancy of HIV-infected patients, and the number of HIV-infected people over age 50 continues to rise. A successfully treated HIV-positive person with a CD4 count higher than 350 × 10⁶/L and a suppressed viral load now has a normal life expectancy.³ In 2011, nearly 20% of newly diagnosed HIV-infected people in the United States were over age 50, as were nearly 25% of those with a new diagnosis of acquired immune deficiency syndrome (AIDS).⁴ This year (2015), we expect that more than half of all HIV-infected people in the United States will be over age 50.⁵

The rising prevalence of HIV infection in this age group has prompted reevaluation of screening guidelines. The US Preventive Services Task Force recommends screening for HIV in all people ages 15 to 65, and also after age 65 in people at ongoing risk of infection.⁶ The American College of Physicians has suggested that the range for routine HIV screening be expanded to age 75.⁷ The cost-effectiveness of expanded and more frequent HIV testing appears to justify it.⁸

Take-home points

• An HIV-infected patient who is compliant with an appropriate antiretroviral regimen and has a CD4 count higher than 350 × 10⁶/L and a suppressed viral load now has a normal life expectancy.
• Today, nearly 20% of newly diagnosed HIV-infected people and more than 50% of all HIV-infected people in the United States are over the age of 50.
• The age range for routine screening for HIV infection should be expanded.

HIGH-RISK GROUPS AMONG THE ELDERLY

Early in the HIV epidemic, older patients acquired HIV from blood transfusions received because of hemophilia and other disorders. However, this rapidly ceased after blood banks began screening blood products. Today, people over age 50 who acquire HIV have many of the same risk factors as younger people.

Men who have sex with men are the largest subgroup of HIV-infected people in the United States, even among those over age 50. In particular, white men who have sex with men now constitute the largest demographic group among the HIV-infected elderly.⁴

Intravenous drug users make up about 15% of older people with HIV.

Women who have sex with infected men or with men at risk of HIV infection make up the largest group of older women with HIV.⁴

Sex and the older person

Many older HIV-infected people remain sexually active and continue to engage in unprotected sexual intercourse far into advanced age. According to one survey, 53% of Americans ages 65 to 74 are engaging in sexual activity regularly; however, they are not using protective measures with up to 91% of casual partners and 70% of new partners.^9,10 Many widowed and divorced people are dating again, and they may be unfamiliar with condom use or may be reluctant to use condoms because condoms can often make it difficult to maintain an erection.

Drugs for erectile dysfunction are making it easier for the elderly to engage in both vaginal and anal intercourse, but often without a condom.⁹ Older women who no longer worry about getting pregnant may be less likely to insist their partners use a condom and to practice safe sex. In addition, age-related thinning and dryness can cause vaginal tears, increasing the risk of HIV transmission.¹¹

Take-home points

• People older than 50 have risk factors for HIV similar to those in younger people.
• Men who have sex with men compose the largest group of HIV-infected individuals in the elderly population.
• Unprotected sexual intercourse is common in the elderly for several reasons: unfamiliarity with condom use, difficulty maintaining an erection, lack of concern about possible pregnancy, and vaginal thinning and dryness in women.

UNDERDIAGNOSIS AND LATE DIAGNOSIS IN THE ELDERLY

The cumulative number of AIDS cases in adults age 50 and older increased nearly ninefold from 1990 to the end of 2009. Even more worrisome, one-half of HIV-positive adults over age 50 are diagnosed with AIDS simultaneously or within 1 year of their HIV diagnosis.⁴ This late diagnosis—and therefore late initiation of treatment—is associated with poorer health outcomes and more rapid disease progression.¹²

HIV infection in older adults often goes undiagnosed, for several reasons.

Providers may underestimate the risk in this population and therefore may not discuss HIV transmission or perform testing. Despite a US Centers for Disease Control and Prevention recommendation that people ages 13 to 64 be tested at least once, and more often if sexually active, only 35% of adults ages 45 to 64 have ever been tested for HIV infection.¹³

Age greater than 50 has been strongly associated with higher rates of non–AIDS-related cancers and cardiovascular disease

Older patients may not perceive themselves to be at risk of HIV infection because of lack of insight and information about its prevention and transmission. They are also less likely than younger adults to discuss their sexual habits or drug use with providers.¹⁴ In addition, compared with the young sexually active population, very little HIV prevention education is targeted to older people.¹⁵ Social stigmatization is also a concern for many HIV-infected elderly, as a perceived negative reputation within their community may prevent them from seeking care and disclosing their HIV status.

Take-home points

Reasons that HIV infection is underdiagnosed in the elderly include lack of:

• Provider recognition
• Insight and information about HIV prevention and transmission
• HIV-prevention education targeting the elderly
• Disclosure because of the social stigma of HIV infection.

HIV ACCELERATES AGING, AGING REDUCES IMMUNITY

Many HIV-positive people can expect to live as long as people in the general population, but those who are diagnosed late and thus are started on antiretroviral therapy later in the course of their infection have a reduced life expectancy. Longevity depends on both restoring the CD4 count to near-normal and suppressing the viral load to undetectable levels.^3,16 This is especially important for older adults, as HIV may accelerate aging, and aging itself may speed the progression of HIV disease, so that therapy may result in delayed or only partial restoration of immunity.

Older age at the time of HIV infection is a strong predictor of accelerated HIV disease progression in the absence of therapy.¹⁷ Left untreated, older patients with HIV lose CD4 cells and progress to AIDS and death faster than younger patients. The deleterious effects of chronic immune activation in the course of HIV infection, combined with the immune senescence of aging, are thought to promote this accelerated course.¹⁸

Recent data indicate that starting antiretroviral therapy early can help prevent the CD4-cell impairment that occurs with aging.¹⁹ However, in adults over age 50, the capacity to restore the CD4 count with antiretroviral therapy apears to be reduced, despite demonstrated viral load suppression and better adherence.²⁰ Although mean adherence rates appear higher in older HIV-infected patients, they are worse in those with neurocognitive impairment, highlighting the importance of evaluating neurocognition in this population.²¹

Decreased immune recovery and the subsequent increased risk of serious AIDS events are factors that now favor starting antiretroviral therapy in all HIV patients over age 50, regardless of CD4 count.

Take-home points

• Without treatment, HIV infection in older patients progresses more rapidly to AIDS and death than in younger patients.
• HIV-positive people over age 50 who have never received antiretroviral therapy should be strongly considered for it, regardless of the CD4 count.

SO MANY DRUGS, SO MANY INTERACTIONS

Since HIV patients are now living longer thanks to antiretroviral therapy, they are now experiencing more disease- and treatment-related problems. This has led to an increased likelihood of polypharmacy, defined here as the use of six or more medications.

In general, polypharmacy in the elderly is associated with adverse drug events, drug interactions, inappropriate medication use, delirium, falls, fractures, and poor medication adherence.^22,23 But it becomes even more of a problem in HIV-infected elderly patients, as various drug interactions can alter the effectiveness of the antiretroviral regimen and can result in drug toxicity.

The most common classes of medications used in the elderly are antihypertensives, lipid-lowering agents, antiplatelet medications, antidepressants, anxiolytics, sedatives, and analgesics, and many of these have notable interactions with current antiretroviral regimens.^24,25 Most medications, including antiretrovirals, are cleared by the liver or kidneys, and the function of these organs often decreases with age, resulting in impaired elimination and in drug accumulation.

Information on drug interactions is readily available from the US Department of Health and Human Services,²⁶ drug interaction databases,^27,28 and drug interaction software. The combination of antiretroviral therapy and preexisting polypharmacy significantly increases the risk of serious interactions, which can lead to drug toxicity, poorer adherence with antiretroviral therapy, loss of efficacy of the coadministered medication, or resurgence of HIV infection due to drug-drug interactions affecting the metabolism and ultimate efficacy of the antiretroviral therapy. An increased awareness of common drug-drug interactions can prevent coadministration of potentially harmful medications in elderly HIV patients.

Important interactions between antiretroviral drugs and other drug classes are summarized in Table 1.^25–28 Most notably:

• Simvastatin and lovastatin are contraindicated with any protease inhibitor.
• Proton pump inhibitors are not recommended for patients taking ritonavir-boosted atazanavir. If a proton pump inhibitor is necessary, the daily dose should not exceed 20 mg of omeprazole or its equivalent in patients who have never taken a protease inhibitor, and it should be taken 12 hours before boosted atazanavir.²⁶
• Corticosteroids, whether systemic, inhaled, or intranasal (eg, fluticasone, budesonide), should be avoided in combination with any protease inhibitor, as they can cause iatrogenic Cushing syndrome and also pose the risk of adrenal crisis during acute illness.²⁷

Take-home points

• In cases of preexisting polypharmacy, antiretroviral therapy can lead to significant drug toxicity, poor adherence to medications, and resurgence of HIV infection.
• Increased provider awareness of common drug-drug interactions can prevent the prescribing of potentially harmful drug combinations to HIV-infected elderly patients.

COMORBIDITIES

In recent years, more than half of the deaths in HIV patients on antiretroviral therapy have been from noninfectious comorbidities such as cardiovascular disease, bone disease, and renal failure, which often coexist and are associated with advanced age.²⁹ In fact, both older age and each additional year of antiretroviral therapy are independent predictors of polypathology (simultaneous occurrence of two or more defined diseases).³⁰ The Antiretroviral Therapy Cohort Collaboration found that age greater than 50 was strongly associated with increasing rates of non–AIDS-related malignancy and cardiovascular disease.³¹

CARDIOVASCULAR DISEASE

With the increasing life expectancy of HIV-infected adults on antiretroviral therapy, cardiovascular disease has become an important concern. HIV-infected adults appear to have a significantly greater risk of myocardial infarction and coronary artery disease than age-matched HIV-negative individuals.³² Strikingly, being older than 50 itself increases the risk of hospitalization for cardiovascular disease fivefold (incidence rate ratio 5.01, 95% confidence interval 3.41–7.38).³³ In addition, HIV infection is associated with a risk of acute myocardial infarction 50% higher than that explained by recognized risk factors.³⁴

This high prevalence of coronary artery disease is likely from a combination of factors, including increasing age and the chronic inflammation and immune activation associated with HIV infection.³⁵ An association between untreated HIV disease and markers of risk for cardiovascular disease has been identified.^36,37

HIV is associated with a 50% higher risk of acute myocardial infarction beyond traditional risk factors

In addition, antiretroviral therapy is associated with dyslipidemia, which is most pronounced with protease inhibitor regimens. Whether specific lipid changes associated with individual antiretroviral drugs affect cardiovascular risk remains uncertain. In the Data Collection on Adverse Events of Anti-HIV Drugs studies,³⁸ only cumulative exposure to indinavir, lopinavir-ritonavir, and didanosine was associated with an increased risk of myocardial infarction.³⁸

Traditional risk factors such as obesity, tobacco use, and genetic predisposition also apply to HIV-infected people.³⁹ In fact, the prevalence of traditional risk factors such as smoking and dyslipidemia is generally higher in HIV-infected people than in the general population, although this situation may be improving.⁴⁰

Science needs to elucidate the relationship between traditional and nontraditional risk factors for cardiovascular disease in older HIV-infected adults. In the meantime, older patients with HIV require aggressive management of modifiable risk factors.

Tools for assessing cardiovascular risk include the Framingham risk score⁴¹ and the Data Collection on Adverse Events of Anti-HIV Drugs 5-year risk calculator.⁴² The European AIDS Clinical Society guidelines recommend considering changing the antiretroviral regimen if the patient’s 10-year risk of cardiovascular disease is more than 20%.⁴³ Recommended strategies for reducing cardiovascular risk in elderly patients with HIV infection include counseling about smoking cessation and weight loss at every clinic visit and optimally controlling dyslipidemia and hypertension using nationally accepted standardized guidelines.⁴⁴

Take-home points

• HIV infection is associated with a 50% higher risk of acute myocardial infarction beyond that explained by traditional risk factors.
• Chronic inflammation, immune activation, and dyslipidemia associated with antiretroviral therapy all contribute to cardiovascular disease in HIV-infected patients.
• HIV-infected elderly patients require aggressive management of modifiable risk factors for cardiovascular disease.

ENDOCRINE DISEASE

Diabetes mellitus

The estimated prevalence of diabetes mellitus is 3% in HIV-infected people who have never received antiretroviral therapy, but glucose intolerance increases to the range of 10% to 25% in those who have started it.⁴⁵ Glucose disorders are associated with traditional risk factors as well as with HIV-associated factors such as lipodystrophy and antiretroviral therapy, specifically long-term use of protease inhibitors.⁴⁶ Although increasing age and obesity clearly play a role in the development of diabetes mellitus in this population, HIV-specific factors may also allow diabetes to develop at a lower level of adiposity than in people without HIV infection.⁴⁷

Strategies for preventing type 2 diabetes mellitus in HIV-infected patients focus on avoiding excessive weight gain, especially after starting antiretroviral therapy; regularly screening for diabetes using hemoglobin A_1c, both before and after starting antiretroviral therapy; and continuing to check hemoglobin A_1c every 6 months. The target hemoglobin A_1c should be less than 7.0%. This threshold should be increased to 8% in frail elderly adults if their anticipated life expectancy is less than 5 years, given their higher risk of hypoglycemia, polypharmacy, and drug interactions.⁴⁸ In addition, as in HIV-negative patients, diabetes screening should be performed if systolic blood pressure exceeds 135/80 mm Hg.

Insulin sensitizers such as metformin and thiazolidinediones should be considered for treating diabetes in HIV-infected patients if no contraindications exist. Consideration may also be given to switching the antiretroviral regimen from a protease inhibitor-based regimen to a nonnucleoside reverse transcriptase inhibitor-based regimen.⁴⁸

Take-home points

• Glucose intolerance has been associated with HIV-specific factors, including lipodystrophy and antiretroviral therapy.
• Avoiding excessive weight gain, use of insulin-sensitizing medications, and alteration in antiretroviral regimens should be considered for the treatment of diabetes mellitus in HIV infection.

Osteoporosis

Osteoporotic bone disease disproportionately affects patients with advanced HIV infection compared with patients of similar age.⁴⁹ Bone mineral density is lower and the fracture rate is higher in HIV-infected individuals.

The pathogenesis of bone disease appears to be multifactorial. Traditional risk factors include hypogonadism, smoking, alcohol use, and low body weight, while HIV-related risk factors include chronic immune activation and antiretroviral therapy.⁵⁰

Several antiretroviral regimens have been linked to clinically significant bone loss, including both tenofovir-based and protease inhibitor-based regimens.⁵¹ Most studies have shown that bone mineral density decreases by 2% to 6% in the first 2 years after starting these regimens⁵²; however, long-term effects on bone loss are unknown.

Questions remain. For example, what are the exact mechanisms that lead to the acute decrease in bone mineral density after starting antiretroviral therapy? And why is vitamin D deficiency is so prevalent in HIV infection, with low vitamin D levels seen in up to 60% to 75% of elderly HIV-infected patients?⁵³

Osteoporosis and vitamin D deficiency appear to be more prevalent with HIV infection

Both the Work Group for the HIV and Aging Consensus Project⁵⁴ and the European AIDS Clinical Society⁴³ recommend screening for and treating causes of secondary low bone mineral density in HIV-infected men over age 50 and postmenopausal HIV-infected women. These causes include vitamin D deficiency. As of 2013, the National Osteoporosis Foundation guidelines include HIV infection and antiretroviral therapy as osteoporosis risk factors that should trigger screening for low bone mineral density with dual-energy x-ray absorptiometry (DXA).⁵⁵

As in the general population, the preferred treatment for low bone mineral density in people with HIV is a bisphosphonate, in addition to ensuring adequate calcium and vitamin D intake. It is important to repeat DXA imaging every 2 years and to reassess the need for continued bisphosphonate therapy after 3 to 5 years because of a possible increased risk of fracture with prolonged use.

Take-home points

• Osteoporosis and vitamin D deficiency both appear to be more prevalent with HIV infection.
• HIV infection and antiretroviral therapy are risk factors that should prompt DXA screening to evaluate for osteoporosis.

NEUROCOGNITIVE DISORDERS

HIV-associated neurocognitive disorders are common, with an estimated 50% of HIV-infected patients experiencing some degree of cognitive loss and some progressing to dementia.⁵⁶ Unfortunately, studies suggest that cognitive disorders can occur despite good HIV control with antiretroviral therapy, with one report demonstrating that 84% of patients with cognitive complaints and 64% without complaints were affected by an HIV-associated neurocognitive disorder.⁵⁷

HIV-associated dementia is often subcortical, with fluctuating symptoms such as psychomotor retardation, difficulty multitasking, and apathy. In contrast to dementia syndromes such as Alzheimer disease, relentless progression is less common in HIV-infected patients who receive antiretroviral therapy.

The Mini-Mental State Examination should not be used to screen for HIV-associated neurocognitive disorders, as it does not assess the domains that are typically impaired. The Montreal Cognitive Assessment has been suggested as the best screening instrument in elderly HIV-infected patients; it is available at no cost at www.mocatest.org.⁵⁸

As HIV-associated neurocognitive disorder is a diagnosis of exclusion, an evaluation for alternative diagnoses such as syphilis, hypothyroidism, and depression is recommended. If an HIV-associated neurocognitive disorder is diagnosed, referral to specialty care should be considered, as interventions such as lumbar puncture to assess cerebrospinal fluid viral escape and changing the antiretroviral regimen to improve central nervous system penetration are possible options under study.

Patients with poorly controlled HIV and a depressed CD4 count are at risk of a number of central nervous system complications in addition to HIV-associated neurocognitive disorders, eg, central nervous system toxoplasmosis, cryptococcal meningitis, progressive multifocal leukoencephalopathy, and primary central nervous system lymphoma. Adherence to an effective antiretroviral regimen is the primary prevention strategy.

Take-home points

• HIV-associated neurocognitive disorders and dementia can occur despite appropriate HIV control and adherence to antiretroviral therapy.
• Adherence to antiretroviral therapy is the primary prevention against most central nervous system complications in HIV infection.

GERIATRIC SYNDROMES

The aging HIV-infected adult may also be at increased risk of geriatric syndromes.

HIV-infected men are 4.5 to 10 times more likely than age-matched controls to be frail

In particular, a frailty-related phenotype of weight loss, exhaustion, slowness, and low physical activity was more common in HIV-infected elderly than in noninfected elderly.⁵⁹ HIV-infected men are 4.5 to 10 times more likely than age-matched controls to be frail, and the likelihood of frailty increases with age, duration of HIV infection, having a CD4 count lower than 350 × 10⁶/L, and having uncontrolled HIV replication.^60,61

Other geriatric syndromes such as falls, urinary incontinence, and functional impairment have been identified in 25% to 56% of older HIV-infected patients.⁶² Indeed, the combination of HIV and older age may adversely affect performance of instrumental activities of daily living.⁶³ Also, as previously mentioned, nondisclosure, fear of HIV-related social stigmatization, and a desire to be self-reliant are all factors that perpetuate the social isolation that is common among the HIV-infected elderly.

For these reasons, a comprehensive approach involving a geriatrician, an infectious disease specialist, and community social workers is needed to manage the care of this aging population.

Take-home point

• Geriatric syndromes have an important impact on health in aging HIV patients.

CANCER SCREENING IN HIV PATIENTS

People with HIV have an elevated risk of cancer. Specifically, compared with the general population, their risk is:

• 3,640 times higher for Kaposi sarcoma
• 77 times higher for non-Hodgkin lymphomas
• 6 times higher for cervical cancer.^64,65

These cancers are considered “AIDS-defining,” and fortunately, the development of effective antiretroviral therapy in the 1990s has led to a marked reduction in their incidence. However, the aging HIV population is now experiencing a rise in the incidence of non–AIDS-defining cancers, such as cancers of the lung, liver, kidney, anus, head and neck, and skin, as well as Hodgkin lymphoma.⁶⁶ Table 2 shows the standardized incidence ratio of selected non–AIDS-defining cancers in HIV-infected patients as reported in several large international studies.^65,67,68 The etiology for the increased risk of non–AIDS-defining cancers in the HIV-infected population is not clear, but possible explanations include the virus itself, antiretroviral therapy, and co-infection with other viruses such as hepatitis B, hepatitis C, and Epstein-Barr virus.

Guidelines for cancer screening vary by organization, and the American Cancer Society, the National Cancer Institute, and the US Preventive Services Task Force do not have formal screening guidelines for the most common non–AIDS-defining cancers. The European AIDS Clinical Society, however, has proposed some screening recommendations for selected malignancies.⁴³

In general, screening recommendations are similar to those for HIV-negative patients. A specific difference for HIV-infected patients is in cervical cancer screening. HIV-infected women should undergo a Papanicolaou smear at 6-month intervals during the first year after diagnosis of HIV infection and, if the results are normal, annually thereafter. There is no consensus as to whether human papillomavirus testing should be performed routinely on HIV-infected women.

At the time of this writing, there are no recommendations for routine screening for anal cancer, although some specialists recommend anal cytologic screening for HIV-positive men and women, and an annual digital anal examination may be useful to detect masses that could be anal cancer.⁶⁹

Take-home points

• The incidence of non–AIDS-defining cancers is rising in the aging HIV population.
• There are currently no formal recommendations for routine screening for anal cancer.

FINAL WORD

Because patients with HIV are living longer as a result of newer effective combination antiretroviral therapies, physicians face a new challenge of managing conditions in these patients that are traditionally associated with aging. Providers will need to improve their understanding of drug-drug interactions and polypharmacy issues and be able to address the complex medical and psychosocial issues in this growing population. As patients with HIV on effective antiretroviral therapy grow older, the burden of comorbid medical disease will continue to increase.

In the 1980s, human immunodeficiency virus (HIV) infection was considered untreatable and predictably lethal. Today, with highly effective antiretroviral therapy, it has become a chronic condition in which patients have a life expectancy comparable to that in the general population.

This change has led to new challenges for primary care physicians, many of whom now find themselves either the sole medical provider for or the comanager of aging HIV-infected patients. Given that about one-fifth of new HIV diagnoses are now in people over the age of 50, it is crucial that primary care providers be able to recognize and diagnose the disease in this population. In addition, they need to effectively manage the polypharmacy and subsequent drug interactions prevalent in older HIV-infected patients. Finally, the clinician must address comorbid diseases common in the elderly, specifically neurologic, cardiovascular, metabolic, and endocrine disorders, as well as performing routine cancer screening.

Take-home point

• As the number of people age 50 and older with HIV infection increases, primary care providers must be able to both recognize and manage the condition.

RISING PREVALENCE OF HIV IN THE ELDERLY

Globally, about 2.5 million people received a new diagnosis of HIV infection in 2011, and about 35 million people worldwide are currently living with it.¹ An estimated 1.1 million Americans are living with HIV, and of these, about 16% do not know they are infected.²

HIV patients who adhere to treatment and achieve a CD4 count above 350 and a low viral load have a normal life expectancy

Antiretroviral therapy has greatly improved the life expectancy of HIV-infected patients, and the number of HIV-infected people over age 50 continues to rise. A successfully treated HIV-positive person with a CD4 count higher than 350 × 10⁶/L and a suppressed viral load now has a normal life expectancy.³ In 2011, nearly 20% of newly diagnosed HIV-infected people in the United States were over age 50, as were nearly 25% of those with a new diagnosis of acquired immune deficiency syndrome (AIDS).⁴ This year (2015), we expect that more than half of all HIV-infected people in the United States will be over age 50.⁵

The rising prevalence of HIV infection in this age group has prompted reevaluation of screening guidelines. The US Preventive Services Task Force recommends screening for HIV in all people ages 15 to 65, and also after age 65 in people at ongoing risk of infection.⁶ The American College of Physicians has suggested that the range for routine HIV screening be expanded to age 75.⁷ The cost-effectiveness of expanded and more frequent HIV testing appears to justify it.⁸

Take-home points

• An HIV-infected patient who is compliant with an appropriate antiretroviral regimen and has a CD4 count higher than 350 × 10⁶/L and a suppressed viral load now has a normal life expectancy.
• Today, nearly 20% of newly diagnosed HIV-infected people and more than 50% of all HIV-infected people in the United States are over the age of 50.
• The age range for routine screening for HIV infection should be expanded.

HIGH-RISK GROUPS AMONG THE ELDERLY

Early in the HIV epidemic, older patients acquired HIV from blood transfusions received because of hemophilia and other disorders. However, this rapidly ceased after blood banks began screening blood products. Today, people over age 50 who acquire HIV have many of the same risk factors as younger people.

Men who have sex with men are the largest subgroup of HIV-infected people in the United States, even among those over age 50. In particular, white men who have sex with men now constitute the largest demographic group among the HIV-infected elderly.⁴

Intravenous drug users make up about 15% of older people with HIV.

Women who have sex with infected men or with men at risk of HIV infection make up the largest group of older women with HIV.⁴

Sex and the older person

Many older HIV-infected people remain sexually active and continue to engage in unprotected sexual intercourse far into advanced age. According to one survey, 53% of Americans ages 65 to 74 are engaging in sexual activity regularly; however, they are not using protective measures with up to 91% of casual partners and 70% of new partners.^9,10 Many widowed and divorced people are dating again, and they may be unfamiliar with condom use or may be reluctant to use condoms because condoms can often make it difficult to maintain an erection.

Drugs for erectile dysfunction are making it easier for the elderly to engage in both vaginal and anal intercourse, but often without a condom.⁹ Older women who no longer worry about getting pregnant may be less likely to insist their partners use a condom and to practice safe sex. In addition, age-related thinning and dryness can cause vaginal tears, increasing the risk of HIV transmission.¹¹

Take-home points

• People older than 50 have risk factors for HIV similar to those in younger people.
• Men who have sex with men compose the largest group of HIV-infected individuals in the elderly population.
• Unprotected sexual intercourse is common in the elderly for several reasons: unfamiliarity with condom use, difficulty maintaining an erection, lack of concern about possible pregnancy, and vaginal thinning and dryness in women.

UNDERDIAGNOSIS AND LATE DIAGNOSIS IN THE ELDERLY

The cumulative number of AIDS cases in adults age 50 and older increased nearly ninefold from 1990 to the end of 2009. Even more worrisome, one-half of HIV-positive adults over age 50 are diagnosed with AIDS simultaneously or within 1 year of their HIV diagnosis.⁴ This late diagnosis—and therefore late initiation of treatment—is associated with poorer health outcomes and more rapid disease progression.¹²

HIV infection in older adults often goes undiagnosed, for several reasons.

Providers may underestimate the risk in this population and therefore may not discuss HIV transmission or perform testing. Despite a US Centers for Disease Control and Prevention recommendation that people ages 13 to 64 be tested at least once, and more often if sexually active, only 35% of adults ages 45 to 64 have ever been tested for HIV infection.¹³

Age greater than 50 has been strongly associated with higher rates of non–AIDS-related cancers and cardiovascular disease

Older patients may not perceive themselves to be at risk of HIV infection because of lack of insight and information about its prevention and transmission. They are also less likely than younger adults to discuss their sexual habits or drug use with providers.¹⁴ In addition, compared with the young sexually active population, very little HIV prevention education is targeted to older people.¹⁵ Social stigmatization is also a concern for many HIV-infected elderly, as a perceived negative reputation within their community may prevent them from seeking care and disclosing their HIV status.

Take-home points

Reasons that HIV infection is underdiagnosed in the elderly include lack of:

• Provider recognition
• Insight and information about HIV prevention and transmission
• HIV-prevention education targeting the elderly
• Disclosure because of the social stigma of HIV infection.

HIV ACCELERATES AGING, AGING REDUCES IMMUNITY

Many HIV-positive people can expect to live as long as people in the general population, but those who are diagnosed late and thus are started on antiretroviral therapy later in the course of their infection have a reduced life expectancy. Longevity depends on both restoring the CD4 count to near-normal and suppressing the viral load to undetectable levels.^3,16 This is especially important for older adults, as HIV may accelerate aging, and aging itself may speed the progression of HIV disease, so that therapy may result in delayed or only partial restoration of immunity.

Older age at the time of HIV infection is a strong predictor of accelerated HIV disease progression in the absence of therapy.¹⁷ Left untreated, older patients with HIV lose CD4 cells and progress to AIDS and death faster than younger patients. The deleterious effects of chronic immune activation in the course of HIV infection, combined with the immune senescence of aging, are thought to promote this accelerated course.¹⁸

Recent data indicate that starting antiretroviral therapy early can help prevent the CD4-cell impairment that occurs with aging.¹⁹ However, in adults over age 50, the capacity to restore the CD4 count with antiretroviral therapy apears to be reduced, despite demonstrated viral load suppression and better adherence.²⁰ Although mean adherence rates appear higher in older HIV-infected patients, they are worse in those with neurocognitive impairment, highlighting the importance of evaluating neurocognition in this population.²¹

Decreased immune recovery and the subsequent increased risk of serious AIDS events are factors that now favor starting antiretroviral therapy in all HIV patients over age 50, regardless of CD4 count.

Take-home points

• Without treatment, HIV infection in older patients progresses more rapidly to AIDS and death than in younger patients.
• HIV-positive people over age 50 who have never received antiretroviral therapy should be strongly considered for it, regardless of the CD4 count.

SO MANY DRUGS, SO MANY INTERACTIONS

Since HIV patients are now living longer thanks to antiretroviral therapy, they are now experiencing more disease- and treatment-related problems. This has led to an increased likelihood of polypharmacy, defined here as the use of six or more medications.

In general, polypharmacy in the elderly is associated with adverse drug events, drug interactions, inappropriate medication use, delirium, falls, fractures, and poor medication adherence.^22,23 But it becomes even more of a problem in HIV-infected elderly patients, as various drug interactions can alter the effectiveness of the antiretroviral regimen and can result in drug toxicity.

The most common classes of medications used in the elderly are antihypertensives, lipid-lowering agents, antiplatelet medications, antidepressants, anxiolytics, sedatives, and analgesics, and many of these have notable interactions with current antiretroviral regimens.^24,25 Most medications, including antiretrovirals, are cleared by the liver or kidneys, and the function of these organs often decreases with age, resulting in impaired elimination and in drug accumulation.

Information on drug interactions is readily available from the US Department of Health and Human Services,²⁶ drug interaction databases,^27,28 and drug interaction software. The combination of antiretroviral therapy and preexisting polypharmacy significantly increases the risk of serious interactions, which can lead to drug toxicity, poorer adherence with antiretroviral therapy, loss of efficacy of the coadministered medication, or resurgence of HIV infection due to drug-drug interactions affecting the metabolism and ultimate efficacy of the antiretroviral therapy. An increased awareness of common drug-drug interactions can prevent coadministration of potentially harmful medications in elderly HIV patients.

Important interactions between antiretroviral drugs and other drug classes are summarized in Table 1.^25–28 Most notably:

• Simvastatin and lovastatin are contraindicated with any protease inhibitor.
• Proton pump inhibitors are not recommended for patients taking ritonavir-boosted atazanavir. If a proton pump inhibitor is necessary, the daily dose should not exceed 20 mg of omeprazole or its equivalent in patients who have never taken a protease inhibitor, and it should be taken 12 hours before boosted atazanavir.²⁶
• Corticosteroids, whether systemic, inhaled, or intranasal (eg, fluticasone, budesonide), should be avoided in combination with any protease inhibitor, as they can cause iatrogenic Cushing syndrome and also pose the risk of adrenal crisis during acute illness.²⁷

Take-home points

• In cases of preexisting polypharmacy, antiretroviral therapy can lead to significant drug toxicity, poor adherence to medications, and resurgence of HIV infection.
• Increased provider awareness of common drug-drug interactions can prevent the prescribing of potentially harmful drug combinations to HIV-infected elderly patients.

COMORBIDITIES

In recent years, more than half of the deaths in HIV patients on antiretroviral therapy have been from noninfectious comorbidities such as cardiovascular disease, bone disease, and renal failure, which often coexist and are associated with advanced age.²⁹ In fact, both older age and each additional year of antiretroviral therapy are independent predictors of polypathology (simultaneous occurrence of two or more defined diseases).³⁰ The Antiretroviral Therapy Cohort Collaboration found that age greater than 50 was strongly associated with increasing rates of non–AIDS-related malignancy and cardiovascular disease.³¹

CARDIOVASCULAR DISEASE

With the increasing life expectancy of HIV-infected adults on antiretroviral therapy, cardiovascular disease has become an important concern. HIV-infected adults appear to have a significantly greater risk of myocardial infarction and coronary artery disease than age-matched HIV-negative individuals.³² Strikingly, being older than 50 itself increases the risk of hospitalization for cardiovascular disease fivefold (incidence rate ratio 5.01, 95% confidence interval 3.41–7.38).³³ In addition, HIV infection is associated with a risk of acute myocardial infarction 50% higher than that explained by recognized risk factors.³⁴

This high prevalence of coronary artery disease is likely from a combination of factors, including increasing age and the chronic inflammation and immune activation associated with HIV infection.³⁵ An association between untreated HIV disease and markers of risk for cardiovascular disease has been identified.^36,37

HIV is associated with a 50% higher risk of acute myocardial infarction beyond traditional risk factors

In addition, antiretroviral therapy is associated with dyslipidemia, which is most pronounced with protease inhibitor regimens. Whether specific lipid changes associated with individual antiretroviral drugs affect cardiovascular risk remains uncertain. In the Data Collection on Adverse Events of Anti-HIV Drugs studies,³⁸ only cumulative exposure to indinavir, lopinavir-ritonavir, and didanosine was associated with an increased risk of myocardial infarction.³⁸

Traditional risk factors such as obesity, tobacco use, and genetic predisposition also apply to HIV-infected people.³⁹ In fact, the prevalence of traditional risk factors such as smoking and dyslipidemia is generally higher in HIV-infected people than in the general population, although this situation may be improving.⁴⁰

Science needs to elucidate the relationship between traditional and nontraditional risk factors for cardiovascular disease in older HIV-infected adults. In the meantime, older patients with HIV require aggressive management of modifiable risk factors.

Tools for assessing cardiovascular risk include the Framingham risk score⁴¹ and the Data Collection on Adverse Events of Anti-HIV Drugs 5-year risk calculator.⁴² The European AIDS Clinical Society guidelines recommend considering changing the antiretroviral regimen if the patient’s 10-year risk of cardiovascular disease is more than 20%.⁴³ Recommended strategies for reducing cardiovascular risk in elderly patients with HIV infection include counseling about smoking cessation and weight loss at every clinic visit and optimally controlling dyslipidemia and hypertension using nationally accepted standardized guidelines.⁴⁴

Take-home points

• HIV infection is associated with a 50% higher risk of acute myocardial infarction beyond that explained by traditional risk factors.
• Chronic inflammation, immune activation, and dyslipidemia associated with antiretroviral therapy all contribute to cardiovascular disease in HIV-infected patients.
• HIV-infected elderly patients require aggressive management of modifiable risk factors for cardiovascular disease.

ENDOCRINE DISEASE

Diabetes mellitus

The estimated prevalence of diabetes mellitus is 3% in HIV-infected people who have never received antiretroviral therapy, but glucose intolerance increases to the range of 10% to 25% in those who have started it.⁴⁵ Glucose disorders are associated with traditional risk factors as well as with HIV-associated factors such as lipodystrophy and antiretroviral therapy, specifically long-term use of protease inhibitors.⁴⁶ Although increasing age and obesity clearly play a role in the development of diabetes mellitus in this population, HIV-specific factors may also allow diabetes to develop at a lower level of adiposity than in people without HIV infection.⁴⁷

Strategies for preventing type 2 diabetes mellitus in HIV-infected patients focus on avoiding excessive weight gain, especially after starting antiretroviral therapy; regularly screening for diabetes using hemoglobin A_1c, both before and after starting antiretroviral therapy; and continuing to check hemoglobin A_1c every 6 months. The target hemoglobin A_1c should be less than 7.0%. This threshold should be increased to 8% in frail elderly adults if their anticipated life expectancy is less than 5 years, given their higher risk of hypoglycemia, polypharmacy, and drug interactions.⁴⁸ In addition, as in HIV-negative patients, diabetes screening should be performed if systolic blood pressure exceeds 135/80 mm Hg.

Insulin sensitizers such as metformin and thiazolidinediones should be considered for treating diabetes in HIV-infected patients if no contraindications exist. Consideration may also be given to switching the antiretroviral regimen from a protease inhibitor-based regimen to a nonnucleoside reverse transcriptase inhibitor-based regimen.⁴⁸

Take-home points

• Glucose intolerance has been associated with HIV-specific factors, including lipodystrophy and antiretroviral therapy.
• Avoiding excessive weight gain, use of insulin-sensitizing medications, and alteration in antiretroviral regimens should be considered for the treatment of diabetes mellitus in HIV infection.

Osteoporosis

Osteoporotic bone disease disproportionately affects patients with advanced HIV infection compared with patients of similar age.⁴⁹ Bone mineral density is lower and the fracture rate is higher in HIV-infected individuals.

The pathogenesis of bone disease appears to be multifactorial. Traditional risk factors include hypogonadism, smoking, alcohol use, and low body weight, while HIV-related risk factors include chronic immune activation and antiretroviral therapy.⁵⁰

Several antiretroviral regimens have been linked to clinically significant bone loss, including both tenofovir-based and protease inhibitor-based regimens.⁵¹ Most studies have shown that bone mineral density decreases by 2% to 6% in the first 2 years after starting these regimens⁵²; however, long-term effects on bone loss are unknown.

Questions remain. For example, what are the exact mechanisms that lead to the acute decrease in bone mineral density after starting antiretroviral therapy? And why is vitamin D deficiency is so prevalent in HIV infection, with low vitamin D levels seen in up to 60% to 75% of elderly HIV-infected patients?⁵³

Osteoporosis and vitamin D deficiency appear to be more prevalent with HIV infection

Both the Work Group for the HIV and Aging Consensus Project⁵⁴ and the European AIDS Clinical Society⁴³ recommend screening for and treating causes of secondary low bone mineral density in HIV-infected men over age 50 and postmenopausal HIV-infected women. These causes include vitamin D deficiency. As of 2013, the National Osteoporosis Foundation guidelines include HIV infection and antiretroviral therapy as osteoporosis risk factors that should trigger screening for low bone mineral density with dual-energy x-ray absorptiometry (DXA).⁵⁵

As in the general population, the preferred treatment for low bone mineral density in people with HIV is a bisphosphonate, in addition to ensuring adequate calcium and vitamin D intake. It is important to repeat DXA imaging every 2 years and to reassess the need for continued bisphosphonate therapy after 3 to 5 years because of a possible increased risk of fracture with prolonged use.

Take-home points

• Osteoporosis and vitamin D deficiency both appear to be more prevalent with HIV infection.
• HIV infection and antiretroviral therapy are risk factors that should prompt DXA screening to evaluate for osteoporosis.

NEUROCOGNITIVE DISORDERS

HIV-associated neurocognitive disorders are common, with an estimated 50% of HIV-infected patients experiencing some degree of cognitive loss and some progressing to dementia.⁵⁶ Unfortunately, studies suggest that cognitive disorders can occur despite good HIV control with antiretroviral therapy, with one report demonstrating that 84% of patients with cognitive complaints and 64% without complaints were affected by an HIV-associated neurocognitive disorder.⁵⁷

HIV-associated dementia is often subcortical, with fluctuating symptoms such as psychomotor retardation, difficulty multitasking, and apathy. In contrast to dementia syndromes such as Alzheimer disease, relentless progression is less common in HIV-infected patients who receive antiretroviral therapy.

The Mini-Mental State Examination should not be used to screen for HIV-associated neurocognitive disorders, as it does not assess the domains that are typically impaired. The Montreal Cognitive Assessment has been suggested as the best screening instrument in elderly HIV-infected patients; it is available at no cost at www.mocatest.org.⁵⁸

As HIV-associated neurocognitive disorder is a diagnosis of exclusion, an evaluation for alternative diagnoses such as syphilis, hypothyroidism, and depression is recommended. If an HIV-associated neurocognitive disorder is diagnosed, referral to specialty care should be considered, as interventions such as lumbar puncture to assess cerebrospinal fluid viral escape and changing the antiretroviral regimen to improve central nervous system penetration are possible options under study.

Patients with poorly controlled HIV and a depressed CD4 count are at risk of a number of central nervous system complications in addition to HIV-associated neurocognitive disorders, eg, central nervous system toxoplasmosis, cryptococcal meningitis, progressive multifocal leukoencephalopathy, and primary central nervous system lymphoma. Adherence to an effective antiretroviral regimen is the primary prevention strategy.

Take-home points

• HIV-associated neurocognitive disorders and dementia can occur despite appropriate HIV control and adherence to antiretroviral therapy.
• Adherence to antiretroviral therapy is the primary prevention against most central nervous system complications in HIV infection.

GERIATRIC SYNDROMES

The aging HIV-infected adult may also be at increased risk of geriatric syndromes.

HIV-infected men are 4.5 to 10 times more likely than age-matched controls to be frail

In particular, a frailty-related phenotype of weight loss, exhaustion, slowness, and low physical activity was more common in HIV-infected elderly than in noninfected elderly.⁵⁹ HIV-infected men are 4.5 to 10 times more likely than age-matched controls to be frail, and the likelihood of frailty increases with age, duration of HIV infection, having a CD4 count lower than 350 × 10⁶/L, and having uncontrolled HIV replication.^60,61

Other geriatric syndromes such as falls, urinary incontinence, and functional impairment have been identified in 25% to 56% of older HIV-infected patients.⁶² Indeed, the combination of HIV and older age may adversely affect performance of instrumental activities of daily living.⁶³ Also, as previously mentioned, nondisclosure, fear of HIV-related social stigmatization, and a desire to be self-reliant are all factors that perpetuate the social isolation that is common among the HIV-infected elderly.

For these reasons, a comprehensive approach involving a geriatrician, an infectious disease specialist, and community social workers is needed to manage the care of this aging population.

Take-home point

• Geriatric syndromes have an important impact on health in aging HIV patients.

CANCER SCREENING IN HIV PATIENTS

People with HIV have an elevated risk of cancer. Specifically, compared with the general population, their risk is:

• 3,640 times higher for Kaposi sarcoma
• 77 times higher for non-Hodgkin lymphomas
• 6 times higher for cervical cancer.^64,65

These cancers are considered “AIDS-defining,” and fortunately, the development of effective antiretroviral therapy in the 1990s has led to a marked reduction in their incidence. However, the aging HIV population is now experiencing a rise in the incidence of non–AIDS-defining cancers, such as cancers of the lung, liver, kidney, anus, head and neck, and skin, as well as Hodgkin lymphoma.⁶⁶ Table 2 shows the standardized incidence ratio of selected non–AIDS-defining cancers in HIV-infected patients as reported in several large international studies.^65,67,68 The etiology for the increased risk of non–AIDS-defining cancers in the HIV-infected population is not clear, but possible explanations include the virus itself, antiretroviral therapy, and co-infection with other viruses such as hepatitis B, hepatitis C, and Epstein-Barr virus.

Guidelines for cancer screening vary by organization, and the American Cancer Society, the National Cancer Institute, and the US Preventive Services Task Force do not have formal screening guidelines for the most common non–AIDS-defining cancers. The European AIDS Clinical Society, however, has proposed some screening recommendations for selected malignancies.⁴³

In general, screening recommendations are similar to those for HIV-negative patients. A specific difference for HIV-infected patients is in cervical cancer screening. HIV-infected women should undergo a Papanicolaou smear at 6-month intervals during the first year after diagnosis of HIV infection and, if the results are normal, annually thereafter. There is no consensus as to whether human papillomavirus testing should be performed routinely on HIV-infected women.

At the time of this writing, there are no recommendations for routine screening for anal cancer, although some specialists recommend anal cytologic screening for HIV-positive men and women, and an annual digital anal examination may be useful to detect masses that could be anal cancer.⁶⁹

Take-home points

• The incidence of non–AIDS-defining cancers is rising in the aging HIV population.
• There are currently no formal recommendations for routine screening for anal cancer.

FINAL WORD

Because patients with HIV are living longer as a result of newer effective combination antiretroviral therapies, physicians face a new challenge of managing conditions in these patients that are traditionally associated with aging. Providers will need to improve their understanding of drug-drug interactions and polypharmacy issues and be able to address the complex medical and psychosocial issues in this growing population. As patients with HIV on effective antiretroviral therapy grow older, the burden of comorbid medical disease will continue to increase.

With the growing use of marijuana, reports have appeared of a newly recognized condition in long-term heavy users termed cannabinoid hyperemesis syndrome.¹

This syndrome is interesting for at least two reasons. First, paradoxically, marijuana appears to have an emetic effect with chronic use, whereas it usually has the opposite effect and is used as an antiemetic in patients undergoing chemotherapy. Second, patients develop a compulsion to bathe or shower in extremely hot water to relieve the symptoms.

In this article, we review the pathophysiology, clinical presentation, diagnosis, and management of this emerging condition.

MARIJUANA USE ON THE RISE

Marijuana is the most widely used illicit drug worldwide. Although statistics on its use vary, a report from the Pew Research Center² stated that 49% of Americans say they have tried it. Several states now allow the use of marijuana for medicinal purposes, and Colorado and Washington have legalized it for recreational use. This marks a major turning point and may accelerate the slow-growing acceptance of marijuana use in the United States.

Marijuana has been used to treat HIV-associated anorexia and wasting, convulsions, glaucoma, headache, and chemotherapy-induced nausea and vomiting.^3–5

Cannabinoid hyperemesis syndrome was first described in 2004 in South Australia.¹ Since its recognition, an increasing number of cases have been identified worldwide. However, there are still no population-based studies to estimate its exact prevalence.

THC PREVENTS VOMITING—AND CAUSES IT

Delta-9-tetrahydrocannabinol (THC) is the principal psychoactive component in marijuana.^6,7 There are two types of cannabinoid receptors in humans: CB1 and CB2. Both are found in the central nervous system and autonomic nervous system. Activation of CB1 receptors is responsible for the psychoactive effects of cannabinoids such as altered consciousness, euphoria, relaxation, perceptual disturbances, intensified sensory experiences, cognitive impairment, and increased reaction time. The physiologic role of CB2 is not known.

THC as an antiemetic

The antiemetic property of THC is not well understood but has been linked to activation of CB1 receptors found on the enteric plexus, presynaptic parasympathetic system, and central nervous system, particularly the cerebellum, hypothalamus, and vomiting center in the medulla.^1,8–12 Stimulation and blockade of CB1 receptors can inhibit and induce vomiting in a dose-dependent manner, implicating endogenous cannabinoids in emetic circuits.¹²

THC as a proemetic

The mechanism of the paradoxical hyperemetic effect of THC is unknown, but several concepts have been proposed.

Chronic cannabis use can lead to down-regulation of CB1 receptors.¹³ Simonetto et al¹⁰ suggested that the central effects of long-term cannabis use on the hypothalamic-pituitary-adrenal axis may play a central role in the development of hyperemesis.¹⁰

Cannabinoids have a long half-life and are lipophilic.¹ When used infrequently, they prevent vomiting. But with chronic use, high concentrations of THC can accumulate in the body, including cerebral fat, and can cause severe nausea and vomiting.^8,9 This paradoxic hyperemesis was observed in people using intravenous crude marijuana extract.⁷ The same response was also noted in ferrets injected with 2-arachidonoylglycerol, a potent cannabinoid agonist.¹¹

Patients who experience hyperemesis from chronic cannabis use may also have a genetic variation in their hepatic drug-transforming enzymes that results in excessive levels of cannabis metabolites that promote emesis.^1,14

Delayed gastric emptying has also been linked to the proemetic effect of THC. However, this association became controversial when a large case series study showed that only 30% of patients with cannabinoid hyperemesis syndrome had delayed emptying on gastric scintigraphy.¹⁰

It is also possible that excessive stimulation of cannabinoid receptors in the gut can cause diffuse splanchnic vasodilation and contribute to the abdominal pain.¹³

DIAGNOSING CANNABINOID HYPEREMESIS SYNDROME

Cannabinoid hyperemesis syndrome is a clinical diagnosis typically seen in young patients (under age 50) with a long history of marijuana use. They present with severe, cyclic nausea and vomiting and admit to compulsively taking extremely hot showers or baths. Most patients report using marijuana for more than a year before developing episodes of severe vomiting. However, one study found that as many as 32% of patients had used it less than 1 year before experiencing symptoms.¹⁰

Other associated nonspecific symptoms are diaphoresis, bloating, abdominal discomfort, flushing, and weight loss. Symptoms are relieved with long, hot showers or baths and cessation of marijuana use. Taking a complete history is key to making the diagnosis.

In 2004, Allen et al¹ first defined cannabinoid hyperemesis as excessive marijuana use associated with cyclical vomiting and abdominal pain.¹ In 2012, Simonetto et al¹⁰ proposed diagnostic criteria (Table 1). Although not yet validated, these criteria are based on the largest series of cases of cannabinoid hyperemesis syndrome to date (98 patients).¹⁰

THE THREE PHASES OF CANNABINOID HYPEREMESIS

The clinical presentation of cannabinoid hyperemesis syndrome can be divided into three phases: prodromal, vomiting, and resolution.

Prodromal phase

During this phase, patients often appear anxious and agitated and display a spectrum of autonomic symptoms such as sweating, flushing, and constantly sipping water due to thirst. They may sometimes have abdominal pain that is usually epigastric but may also be diffuse. Their symptoms are associated with severe nausea, usually early in the morning or when they see or smell food. Appetite and eating patterns remain normal. Compulsive hot bathing or showering is minimal at this phase.

Vomiting phase

In this next phase, patients experience incapacitating nausea and vomiting that may occur without warning and are resistant to conventional antiemetics such as ondansetron and promethazine.¹⁴ However, patients eventually learn that hot baths or showers relieve the symptoms, and this behavior eventually becomes a compulsion. The higher the temperature of the water, the better the effect on symptoms.¹ Low-grade pyrexia, excessive thirst, orthostasis, abdominal tenderness, weight loss, and sometimes even superficial skin burns have been reported.^1,9,15–18

Recovery phase

During the final phase of cannabinoid hyperemesis syndrome, most patients experience marked resolution of symptoms after 24 to 48 hours of conservative management (bowel rest until symptoms resolve, slowly advancing diet as tolerated, intravenous fluids, and electrolyte monitoring and repletion as necessary), and most importantly, cessation of cannabis use. However, the time from cessation of marijuana use to resolution of symptoms may be as long as 1 week to 1 month.^1,10,14 Patients begin to resume their normal diet and daily activities. The bathing-showering compulsion subsides, and patients regain lost weight after 3 to 6 months.¹

In all case series and reports, resumption of cannabis use causes the symptoms to recur. This recurrence is compelling evidence that cannabis is the cause of the hyperemesis and should be part of the essential criteria for the diagnosis of cannabinoid hyperemesis syndrome.

WHY COMPULSIVE HOT BATHING?

The mechanism behind this unique characteristic of cannabinoid hyperemesis syndrome is not known. Several theories have been suggested, but no study has identified the exact explanation for this phenomenon.^{1,9,10,13–15,17–31}

One suggested mechanism is a response by the thermoregulatory center of the brain to the dose-dependent hypothermic effects of THC, or even a direct effect of CB1 receptor activation in the hypothalamus.⁹ Cannabis toxicity could disrupt the equilibrium of satiety, thirst, digestive, and thermoregulatory systems of the hypothalamus, and this interference could resolve with hot bathing.¹

The so-called “cutaneous steal” syndrome has also been proposed, in which cutaneous vasodilation caused by hot water decreases the blood volume available for the splanchnic circulation thought to be responsible for the abdominal pain and vomiting.¹³ The compulsive hot bathing may also be a response by the brain to the anxiety or psychological stress induced by severe nausea and vomiting.¹⁴

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of cannabinoid hyperemesis syndrome includes mainly cyclic vomiting syndrome and psychogenic vomiting. A careful history is useful, as is ruling out medication-induced reactions, toxins, pregnancy, and gastrointestinal, neurologic, metabolic, and endocrine causes. All three of these vomiting syndromes can present with a cyclic pattern of nausea and vomiting. Cannabis use is common in all three and so is not helpful in differentiating them. But the characteristic compulsive hot bathing and showering is unique and pathognomonic of cannabinoid hyperemesis syndrome.³²

Endoscopic examination may reveal esophagitis and gastritis from severe bouts of retching.²⁶

Cyclic vomiting syndrome

The Rome III criteria for the diagnosis of cyclic vomiting syndrome include three or more stereotypic episodes of acute-onset nausea and vomiting lasting less than 1 week, alternating with intervals of completely normal health. The criteria should be fulfilled for the previous 3 months with symptom onset at least 6 months before diagnosis.³³

In a series of 17 patients with adult-onset cyclic vomiting syndrome,¹⁸ the average age at onset was 30, and 13 (76%) of the patients were women. Fifteen (88%) of the patients experienced a prodrome or aura of abdominal pain or headache, and in this group, a trigger such as emotional stress and infection could also be identified in 9 (60%).

Unlike in cannabinoid hyperemesis syndrome, most patients with cyclic vomiting syndrome have a family history of migraine headache, and the prevalence of psychological stressors is high.³¹ Also, patients with cannabinoid hyperemesis syndrome do not respond to medications that usually abort migraine episodes,¹⁵ whereas patients with cyclic vomiting syndrome, especially those who have a family history of migraines, may respond to antimigraine medications such as triptans. There is evidence of clinical psychological overlap between cyclic vomiting syndrome, abdominal migraine, and migraine headaches. Some authors recommend antimigraine therapy even in the absence of a family or personal history of migraine if, after a careful history and physical examination, the diagnosis of cyclic vomiting syndrome seems likely. Moreover, nonmedical management such as sleep, dark rooms, and quiet environment are not as effective in cannabinoid hyperemesis syndrome as they are in cyclic vomiting syndrome.¹⁸

Psychogenic vomiting

Psychogenic vomiting is classically defined as vomiting caused by psychological mechanisms without any obvious organic cause.¹³ It occurs most commonly in patients with major depressive disorder or conversion disorder.³⁴ The mechanism appears to be a combination of past organic or gastrointestinal functional abnormalities and emotional problems, and multiple patterns of vomiting can occur. Most of these patients can be treated with behavioral therapy, antidepressant drug therapy, and supportive psychotherapy.^34,35

ASKING A SERIES OF QUESTIONS

Most patients with cannabinoid hyperemesis syndrome have a history of frequent visits to emergency departments or clinics for persistent nausea and vomiting, and they may have undergone extensive diagnostic workups to exclude structural, inflammatory, infectious, and functional diseases of the bowel.^23,24

To prevent unnecessary testing and use of healthcare resources, Wallace et al³² proposed an algorithm to help guide clinicians in diagnosing and treating patients with suspected cannabinoid hyperemesis syndrome. A patient presenting with severe nausea and vomiting should prompt a series of questions:

Do the signs and symptoms suggest a severe underlying medical cause? If so, this should be pursued.

Do symptoms improve while taking a hot shower or bath? If not, pursue an appropriate diagnostic evaluation and treatment for conditions other than cannabinoid hyperemesis syndrome.

Is the bathing compulsive? If not, consider other diagnoses, but remain suspicious about cannabinoid hyperemesis syndrome.

Does the patient currently use cannabis daily or almost daily, and has the patient done so for at least the past year? If the patient denies using cannabis, a urine drug screen for THC may be useful. If the patient admits to use, a presumptive diagnosis of cannabinoid hyperemesis syndrome can be made.

Does the patient have signs or symptoms of volume depletion, or is the patient unable to tolerate oral hydration? Encourage oral hydration or provide intravenous hydration, and provide cannabis cessation counseling.

Do the symptoms improve? If yes, great! Provide cessation counseling, resources, and follow-up. If not:

Is the patient still using cannabis? If not, it is time to rethink the diagnosis.

Treatment in the acute setting is supportive and includes intravenous hydration and correction of electrolytes. Conventional antiemetics such as ondansetron, metoclopramide, prochlorperazine, and promethazine have not been effective in relieving hyperemesis.^9,12,14 This implies that the mechanism of emesis likely does not involve dopaminergic and serotonin pathways in the central and autonomic nervous systems.

Cessation of cannabis use is key for long-term resolution of symptoms. Efforts should be made to provide counseling and encourage patients to stop using the drug entirely (Figure 1).

SOMETHING TO THINK ABOUT

With the high prevalence of chronic cannabis abuse and the recent legalization of recreational marijuana use, we will all likely encounter a patient with cannabinoid hyperemesis. With adequate knowledge of this phenomenon, we can avoid unnecessary workups and inappropriate medical and surgical treatment in patients presenting with recurrent vomiting of unknown cause. The diagnosis can easily be made by simply asking for a history of chronic marijuana use and symptoms related to cannabinoid hyperemesis syndrome, such as relief of symptoms with hot baths or showers and with marijuana cessation.

Conservative management and fluid resuscitation is important in the acute setting, but cessation of marijuana use and follow-up counseling are the key components for treating patients with cannabinoid hyperemesis syndrome and for preventing recurrence.

With the growing use of marijuana, reports have appeared of a newly recognized condition in long-term heavy users termed cannabinoid hyperemesis syndrome.¹

This syndrome is interesting for at least two reasons. First, paradoxically, marijuana appears to have an emetic effect with chronic use, whereas it usually has the opposite effect and is used as an antiemetic in patients undergoing chemotherapy. Second, patients develop a compulsion to bathe or shower in extremely hot water to relieve the symptoms.

In this article, we review the pathophysiology, clinical presentation, diagnosis, and management of this emerging condition.

MARIJUANA USE ON THE RISE

Marijuana is the most widely used illicit drug worldwide. Although statistics on its use vary, a report from the Pew Research Center² stated that 49% of Americans say they have tried it. Several states now allow the use of marijuana for medicinal purposes, and Colorado and Washington have legalized it for recreational use. This marks a major turning point and may accelerate the slow-growing acceptance of marijuana use in the United States.

Marijuana has been used to treat HIV-associated anorexia and wasting, convulsions, glaucoma, headache, and chemotherapy-induced nausea and vomiting.^3–5

Cannabinoid hyperemesis syndrome was first described in 2004 in South Australia.¹ Since its recognition, an increasing number of cases have been identified worldwide. However, there are still no population-based studies to estimate its exact prevalence.

THC PREVENTS VOMITING—AND CAUSES IT

Delta-9-tetrahydrocannabinol (THC) is the principal psychoactive component in marijuana.^6,7 There are two types of cannabinoid receptors in humans: CB1 and CB2. Both are found in the central nervous system and autonomic nervous system. Activation of CB1 receptors is responsible for the psychoactive effects of cannabinoids such as altered consciousness, euphoria, relaxation, perceptual disturbances, intensified sensory experiences, cognitive impairment, and increased reaction time. The physiologic role of CB2 is not known.

THC as an antiemetic

The antiemetic property of THC is not well understood but has been linked to activation of CB1 receptors found on the enteric plexus, presynaptic parasympathetic system, and central nervous system, particularly the cerebellum, hypothalamus, and vomiting center in the medulla.^1,8–12 Stimulation and blockade of CB1 receptors can inhibit and induce vomiting in a dose-dependent manner, implicating endogenous cannabinoids in emetic circuits.¹²

THC as a proemetic

The mechanism of the paradoxical hyperemetic effect of THC is unknown, but several concepts have been proposed.

Chronic cannabis use can lead to down-regulation of CB1 receptors.¹³ Simonetto et al¹⁰ suggested that the central effects of long-term cannabis use on the hypothalamic-pituitary-adrenal axis may play a central role in the development of hyperemesis.¹⁰

Cannabinoids have a long half-life and are lipophilic.¹ When used infrequently, they prevent vomiting. But with chronic use, high concentrations of THC can accumulate in the body, including cerebral fat, and can cause severe nausea and vomiting.^8,9 This paradoxic hyperemesis was observed in people using intravenous crude marijuana extract.⁷ The same response was also noted in ferrets injected with 2-arachidonoylglycerol, a potent cannabinoid agonist.¹¹

Patients who experience hyperemesis from chronic cannabis use may also have a genetic variation in their hepatic drug-transforming enzymes that results in excessive levels of cannabis metabolites that promote emesis.^1,14

Delayed gastric emptying has also been linked to the proemetic effect of THC. However, this association became controversial when a large case series study showed that only 30% of patients with cannabinoid hyperemesis syndrome had delayed emptying on gastric scintigraphy.¹⁰

It is also possible that excessive stimulation of cannabinoid receptors in the gut can cause diffuse splanchnic vasodilation and contribute to the abdominal pain.¹³

DIAGNOSING CANNABINOID HYPEREMESIS SYNDROME

Cannabinoid hyperemesis syndrome is a clinical diagnosis typically seen in young patients (under age 50) with a long history of marijuana use. They present with severe, cyclic nausea and vomiting and admit to compulsively taking extremely hot showers or baths. Most patients report using marijuana for more than a year before developing episodes of severe vomiting. However, one study found that as many as 32% of patients had used it less than 1 year before experiencing symptoms.¹⁰

Other associated nonspecific symptoms are diaphoresis, bloating, abdominal discomfort, flushing, and weight loss. Symptoms are relieved with long, hot showers or baths and cessation of marijuana use. Taking a complete history is key to making the diagnosis.

In 2004, Allen et al¹ first defined cannabinoid hyperemesis as excessive marijuana use associated with cyclical vomiting and abdominal pain.¹ In 2012, Simonetto et al¹⁰ proposed diagnostic criteria (Table 1). Although not yet validated, these criteria are based on the largest series of cases of cannabinoid hyperemesis syndrome to date (98 patients).¹⁰

THE THREE PHASES OF CANNABINOID HYPEREMESIS

The clinical presentation of cannabinoid hyperemesis syndrome can be divided into three phases: prodromal, vomiting, and resolution.

Prodromal phase

During this phase, patients often appear anxious and agitated and display a spectrum of autonomic symptoms such as sweating, flushing, and constantly sipping water due to thirst. They may sometimes have abdominal pain that is usually epigastric but may also be diffuse. Their symptoms are associated with severe nausea, usually early in the morning or when they see or smell food. Appetite and eating patterns remain normal. Compulsive hot bathing or showering is minimal at this phase.

Vomiting phase

In this next phase, patients experience incapacitating nausea and vomiting that may occur without warning and are resistant to conventional antiemetics such as ondansetron and promethazine.¹⁴ However, patients eventually learn that hot baths or showers relieve the symptoms, and this behavior eventually becomes a compulsion. The higher the temperature of the water, the better the effect on symptoms.¹ Low-grade pyrexia, excessive thirst, orthostasis, abdominal tenderness, weight loss, and sometimes even superficial skin burns have been reported.^1,9,15–18

Recovery phase

During the final phase of cannabinoid hyperemesis syndrome, most patients experience marked resolution of symptoms after 24 to 48 hours of conservative management (bowel rest until symptoms resolve, slowly advancing diet as tolerated, intravenous fluids, and electrolyte monitoring and repletion as necessary), and most importantly, cessation of cannabis use. However, the time from cessation of marijuana use to resolution of symptoms may be as long as 1 week to 1 month.^1,10,14 Patients begin to resume their normal diet and daily activities. The bathing-showering compulsion subsides, and patients regain lost weight after 3 to 6 months.¹

In all case series and reports, resumption of cannabis use causes the symptoms to recur. This recurrence is compelling evidence that cannabis is the cause of the hyperemesis and should be part of the essential criteria for the diagnosis of cannabinoid hyperemesis syndrome.

WHY COMPULSIVE HOT BATHING?

The mechanism behind this unique characteristic of cannabinoid hyperemesis syndrome is not known. Several theories have been suggested, but no study has identified the exact explanation for this phenomenon.^{1,9,10,13–15,17–31}

One suggested mechanism is a response by the thermoregulatory center of the brain to the dose-dependent hypothermic effects of THC, or even a direct effect of CB1 receptor activation in the hypothalamus.⁹ Cannabis toxicity could disrupt the equilibrium of satiety, thirst, digestive, and thermoregulatory systems of the hypothalamus, and this interference could resolve with hot bathing.¹

The so-called “cutaneous steal” syndrome has also been proposed, in which cutaneous vasodilation caused by hot water decreases the blood volume available for the splanchnic circulation thought to be responsible for the abdominal pain and vomiting.¹³ The compulsive hot bathing may also be a response by the brain to the anxiety or psychological stress induced by severe nausea and vomiting.¹⁴

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of cannabinoid hyperemesis syndrome includes mainly cyclic vomiting syndrome and psychogenic vomiting. A careful history is useful, as is ruling out medication-induced reactions, toxins, pregnancy, and gastrointestinal, neurologic, metabolic, and endocrine causes. All three of these vomiting syndromes can present with a cyclic pattern of nausea and vomiting. Cannabis use is common in all three and so is not helpful in differentiating them. But the characteristic compulsive hot bathing and showering is unique and pathognomonic of cannabinoid hyperemesis syndrome.³²

Endoscopic examination may reveal esophagitis and gastritis from severe bouts of retching.²⁶

Cyclic vomiting syndrome

The Rome III criteria for the diagnosis of cyclic vomiting syndrome include three or more stereotypic episodes of acute-onset nausea and vomiting lasting less than 1 week, alternating with intervals of completely normal health. The criteria should be fulfilled for the previous 3 months with symptom onset at least 6 months before diagnosis.³³

In a series of 17 patients with adult-onset cyclic vomiting syndrome,¹⁸ the average age at onset was 30, and 13 (76%) of the patients were women. Fifteen (88%) of the patients experienced a prodrome or aura of abdominal pain or headache, and in this group, a trigger such as emotional stress and infection could also be identified in 9 (60%).

Unlike in cannabinoid hyperemesis syndrome, most patients with cyclic vomiting syndrome have a family history of migraine headache, and the prevalence of psychological stressors is high.³¹ Also, patients with cannabinoid hyperemesis syndrome do not respond to medications that usually abort migraine episodes,¹⁵ whereas patients with cyclic vomiting syndrome, especially those who have a family history of migraines, may respond to antimigraine medications such as triptans. There is evidence of clinical psychological overlap between cyclic vomiting syndrome, abdominal migraine, and migraine headaches. Some authors recommend antimigraine therapy even in the absence of a family or personal history of migraine if, after a careful history and physical examination, the diagnosis of cyclic vomiting syndrome seems likely. Moreover, nonmedical management such as sleep, dark rooms, and quiet environment are not as effective in cannabinoid hyperemesis syndrome as they are in cyclic vomiting syndrome.¹⁸

Psychogenic vomiting

Psychogenic vomiting is classically defined as vomiting caused by psychological mechanisms without any obvious organic cause.¹³ It occurs most commonly in patients with major depressive disorder or conversion disorder.³⁴ The mechanism appears to be a combination of past organic or gastrointestinal functional abnormalities and emotional problems, and multiple patterns of vomiting can occur. Most of these patients can be treated with behavioral therapy, antidepressant drug therapy, and supportive psychotherapy.^34,35

ASKING A SERIES OF QUESTIONS

Most patients with cannabinoid hyperemesis syndrome have a history of frequent visits to emergency departments or clinics for persistent nausea and vomiting, and they may have undergone extensive diagnostic workups to exclude structural, inflammatory, infectious, and functional diseases of the bowel.^23,24

To prevent unnecessary testing and use of healthcare resources, Wallace et al³² proposed an algorithm to help guide clinicians in diagnosing and treating patients with suspected cannabinoid hyperemesis syndrome. A patient presenting with severe nausea and vomiting should prompt a series of questions:

Do the signs and symptoms suggest a severe underlying medical cause? If so, this should be pursued.

Do symptoms improve while taking a hot shower or bath? If not, pursue an appropriate diagnostic evaluation and treatment for conditions other than cannabinoid hyperemesis syndrome.

Is the bathing compulsive? If not, consider other diagnoses, but remain suspicious about cannabinoid hyperemesis syndrome.

Does the patient currently use cannabis daily or almost daily, and has the patient done so for at least the past year? If the patient denies using cannabis, a urine drug screen for THC may be useful. If the patient admits to use, a presumptive diagnosis of cannabinoid hyperemesis syndrome can be made.

Does the patient have signs or symptoms of volume depletion, or is the patient unable to tolerate oral hydration? Encourage oral hydration or provide intravenous hydration, and provide cannabis cessation counseling.

Do the symptoms improve? If yes, great! Provide cessation counseling, resources, and follow-up. If not:

Is the patient still using cannabis? If not, it is time to rethink the diagnosis.

Treatment in the acute setting is supportive and includes intravenous hydration and correction of electrolytes. Conventional antiemetics such as ondansetron, metoclopramide, prochlorperazine, and promethazine have not been effective in relieving hyperemesis.^9,12,14 This implies that the mechanism of emesis likely does not involve dopaminergic and serotonin pathways in the central and autonomic nervous systems.

Cessation of cannabis use is key for long-term resolution of symptoms. Efforts should be made to provide counseling and encourage patients to stop using the drug entirely (Figure 1).

SOMETHING TO THINK ABOUT

With the high prevalence of chronic cannabis abuse and the recent legalization of recreational marijuana use, we will all likely encounter a patient with cannabinoid hyperemesis. With adequate knowledge of this phenomenon, we can avoid unnecessary workups and inappropriate medical and surgical treatment in patients presenting with recurrent vomiting of unknown cause. The diagnosis can easily be made by simply asking for a history of chronic marijuana use and symptoms related to cannabinoid hyperemesis syndrome, such as relief of symptoms with hot baths or showers and with marijuana cessation.

Conservative management and fluid resuscitation is important in the acute setting, but cessation of marijuana use and follow-up counseling are the key components for treating patients with cannabinoid hyperemesis syndrome and for preventing recurrence.

With the growing use of marijuana, reports have appeared of a newly recognized condition in long-term heavy users termed cannabinoid hyperemesis syndrome.¹

This syndrome is interesting for at least two reasons. First, paradoxically, marijuana appears to have an emetic effect with chronic use, whereas it usually has the opposite effect and is used as an antiemetic in patients undergoing chemotherapy. Second, patients develop a compulsion to bathe or shower in extremely hot water to relieve the symptoms.

In this article, we review the pathophysiology, clinical presentation, diagnosis, and management of this emerging condition.

MARIJUANA USE ON THE RISE

Marijuana is the most widely used illicit drug worldwide. Although statistics on its use vary, a report from the Pew Research Center² stated that 49% of Americans say they have tried it. Several states now allow the use of marijuana for medicinal purposes, and Colorado and Washington have legalized it for recreational use. This marks a major turning point and may accelerate the slow-growing acceptance of marijuana use in the United States.

Marijuana has been used to treat HIV-associated anorexia and wasting, convulsions, glaucoma, headache, and chemotherapy-induced nausea and vomiting.^3–5

Cannabinoid hyperemesis syndrome was first described in 2004 in South Australia.¹ Since its recognition, an increasing number of cases have been identified worldwide. However, there are still no population-based studies to estimate its exact prevalence.

THC PREVENTS VOMITING—AND CAUSES IT

Delta-9-tetrahydrocannabinol (THC) is the principal psychoactive component in marijuana.^6,7 There are two types of cannabinoid receptors in humans: CB1 and CB2. Both are found in the central nervous system and autonomic nervous system. Activation of CB1 receptors is responsible for the psychoactive effects of cannabinoids such as altered consciousness, euphoria, relaxation, perceptual disturbances, intensified sensory experiences, cognitive impairment, and increased reaction time. The physiologic role of CB2 is not known.

THC as an antiemetic

The antiemetic property of THC is not well understood but has been linked to activation of CB1 receptors found on the enteric plexus, presynaptic parasympathetic system, and central nervous system, particularly the cerebellum, hypothalamus, and vomiting center in the medulla.^1,8–12 Stimulation and blockade of CB1 receptors can inhibit and induce vomiting in a dose-dependent manner, implicating endogenous cannabinoids in emetic circuits.¹²

THC as a proemetic

The mechanism of the paradoxical hyperemetic effect of THC is unknown, but several concepts have been proposed.

Chronic cannabis use can lead to down-regulation of CB1 receptors.¹³ Simonetto et al¹⁰ suggested that the central effects of long-term cannabis use on the hypothalamic-pituitary-adrenal axis may play a central role in the development of hyperemesis.¹⁰

Cannabinoids have a long half-life and are lipophilic.¹ When used infrequently, they prevent vomiting. But with chronic use, high concentrations of THC can accumulate in the body, including cerebral fat, and can cause severe nausea and vomiting.^8,9 This paradoxic hyperemesis was observed in people using intravenous crude marijuana extract.⁷ The same response was also noted in ferrets injected with 2-arachidonoylglycerol, a potent cannabinoid agonist.¹¹

Patients who experience hyperemesis from chronic cannabis use may also have a genetic variation in their hepatic drug-transforming enzymes that results in excessive levels of cannabis metabolites that promote emesis.^1,14

Delayed gastric emptying has also been linked to the proemetic effect of THC. However, this association became controversial when a large case series study showed that only 30% of patients with cannabinoid hyperemesis syndrome had delayed emptying on gastric scintigraphy.¹⁰

It is also possible that excessive stimulation of cannabinoid receptors in the gut can cause diffuse splanchnic vasodilation and contribute to the abdominal pain.¹³

DIAGNOSING CANNABINOID HYPEREMESIS SYNDROME

Cannabinoid hyperemesis syndrome is a clinical diagnosis typically seen in young patients (under age 50) with a long history of marijuana use. They present with severe, cyclic nausea and vomiting and admit to compulsively taking extremely hot showers or baths. Most patients report using marijuana for more than a year before developing episodes of severe vomiting. However, one study found that as many as 32% of patients had used it less than 1 year before experiencing symptoms.¹⁰

Other associated nonspecific symptoms are diaphoresis, bloating, abdominal discomfort, flushing, and weight loss. Symptoms are relieved with long, hot showers or baths and cessation of marijuana use. Taking a complete history is key to making the diagnosis.

In 2004, Allen et al¹ first defined cannabinoid hyperemesis as excessive marijuana use associated with cyclical vomiting and abdominal pain.¹ In 2012, Simonetto et al¹⁰ proposed diagnostic criteria (Table 1). Although not yet validated, these criteria are based on the largest series of cases of cannabinoid hyperemesis syndrome to date (98 patients).¹⁰

THE THREE PHASES OF CANNABINOID HYPEREMESIS

The clinical presentation of cannabinoid hyperemesis syndrome can be divided into three phases: prodromal, vomiting, and resolution.

Prodromal phase

During this phase, patients often appear anxious and agitated and display a spectrum of autonomic symptoms such as sweating, flushing, and constantly sipping water due to thirst. They may sometimes have abdominal pain that is usually epigastric but may also be diffuse. Their symptoms are associated with severe nausea, usually early in the morning or when they see or smell food. Appetite and eating patterns remain normal. Compulsive hot bathing or showering is minimal at this phase.

Vomiting phase

In this next phase, patients experience incapacitating nausea and vomiting that may occur without warning and are resistant to conventional antiemetics such as ondansetron and promethazine.¹⁴ However, patients eventually learn that hot baths or showers relieve the symptoms, and this behavior eventually becomes a compulsion. The higher the temperature of the water, the better the effect on symptoms.¹ Low-grade pyrexia, excessive thirst, orthostasis, abdominal tenderness, weight loss, and sometimes even superficial skin burns have been reported.^1,9,15–18

Recovery phase

During the final phase of cannabinoid hyperemesis syndrome, most patients experience marked resolution of symptoms after 24 to 48 hours of conservative management (bowel rest until symptoms resolve, slowly advancing diet as tolerated, intravenous fluids, and electrolyte monitoring and repletion as necessary), and most importantly, cessation of cannabis use. However, the time from cessation of marijuana use to resolution of symptoms may be as long as 1 week to 1 month.^1,10,14 Patients begin to resume their normal diet and daily activities. The bathing-showering compulsion subsides, and patients regain lost weight after 3 to 6 months.¹

In all case series and reports, resumption of cannabis use causes the symptoms to recur. This recurrence is compelling evidence that cannabis is the cause of the hyperemesis and should be part of the essential criteria for the diagnosis of cannabinoid hyperemesis syndrome.

WHY COMPULSIVE HOT BATHING?

The mechanism behind this unique characteristic of cannabinoid hyperemesis syndrome is not known. Several theories have been suggested, but no study has identified the exact explanation for this phenomenon.^{1,9,10,13–15,17–31}

One suggested mechanism is a response by the thermoregulatory center of the brain to the dose-dependent hypothermic effects of THC, or even a direct effect of CB1 receptor activation in the hypothalamus.⁹ Cannabis toxicity could disrupt the equilibrium of satiety, thirst, digestive, and thermoregulatory systems of the hypothalamus, and this interference could resolve with hot bathing.¹

The so-called “cutaneous steal” syndrome has also been proposed, in which cutaneous vasodilation caused by hot water decreases the blood volume available for the splanchnic circulation thought to be responsible for the abdominal pain and vomiting.¹³ The compulsive hot bathing may also be a response by the brain to the anxiety or psychological stress induced by severe nausea and vomiting.¹⁴

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of cannabinoid hyperemesis syndrome includes mainly cyclic vomiting syndrome and psychogenic vomiting. A careful history is useful, as is ruling out medication-induced reactions, toxins, pregnancy, and gastrointestinal, neurologic, metabolic, and endocrine causes. All three of these vomiting syndromes can present with a cyclic pattern of nausea and vomiting. Cannabis use is common in all three and so is not helpful in differentiating them. But the characteristic compulsive hot bathing and showering is unique and pathognomonic of cannabinoid hyperemesis syndrome.³²

Endoscopic examination may reveal esophagitis and gastritis from severe bouts of retching.²⁶

Cyclic vomiting syndrome

The Rome III criteria for the diagnosis of cyclic vomiting syndrome include three or more stereotypic episodes of acute-onset nausea and vomiting lasting less than 1 week, alternating with intervals of completely normal health. The criteria should be fulfilled for the previous 3 months with symptom onset at least 6 months before diagnosis.³³

In a series of 17 patients with adult-onset cyclic vomiting syndrome,¹⁸ the average age at onset was 30, and 13 (76%) of the patients were women. Fifteen (88%) of the patients experienced a prodrome or aura of abdominal pain or headache, and in this group, a trigger such as emotional stress and infection could also be identified in 9 (60%).

Unlike in cannabinoid hyperemesis syndrome, most patients with cyclic vomiting syndrome have a family history of migraine headache, and the prevalence of psychological stressors is high.³¹ Also, patients with cannabinoid hyperemesis syndrome do not respond to medications that usually abort migraine episodes,¹⁵ whereas patients with cyclic vomiting syndrome, especially those who have a family history of migraines, may respond to antimigraine medications such as triptans. There is evidence of clinical psychological overlap between cyclic vomiting syndrome, abdominal migraine, and migraine headaches. Some authors recommend antimigraine therapy even in the absence of a family or personal history of migraine if, after a careful history and physical examination, the diagnosis of cyclic vomiting syndrome seems likely. Moreover, nonmedical management such as sleep, dark rooms, and quiet environment are not as effective in cannabinoid hyperemesis syndrome as they are in cyclic vomiting syndrome.¹⁸

Psychogenic vomiting

Psychogenic vomiting is classically defined as vomiting caused by psychological mechanisms without any obvious organic cause.¹³ It occurs most commonly in patients with major depressive disorder or conversion disorder.³⁴ The mechanism appears to be a combination of past organic or gastrointestinal functional abnormalities and emotional problems, and multiple patterns of vomiting can occur. Most of these patients can be treated with behavioral therapy, antidepressant drug therapy, and supportive psychotherapy.^34,35

ASKING A SERIES OF QUESTIONS

Most patients with cannabinoid hyperemesis syndrome have a history of frequent visits to emergency departments or clinics for persistent nausea and vomiting, and they may have undergone extensive diagnostic workups to exclude structural, inflammatory, infectious, and functional diseases of the bowel.^23,24

To prevent unnecessary testing and use of healthcare resources, Wallace et al³² proposed an algorithm to help guide clinicians in diagnosing and treating patients with suspected cannabinoid hyperemesis syndrome. A patient presenting with severe nausea and vomiting should prompt a series of questions:

Do the signs and symptoms suggest a severe underlying medical cause? If so, this should be pursued.

Do symptoms improve while taking a hot shower or bath? If not, pursue an appropriate diagnostic evaluation and treatment for conditions other than cannabinoid hyperemesis syndrome.

Is the bathing compulsive? If not, consider other diagnoses, but remain suspicious about cannabinoid hyperemesis syndrome.

Does the patient currently use cannabis daily or almost daily, and has the patient done so for at least the past year? If the patient denies using cannabis, a urine drug screen for THC may be useful. If the patient admits to use, a presumptive diagnosis of cannabinoid hyperemesis syndrome can be made.

Does the patient have signs or symptoms of volume depletion, or is the patient unable to tolerate oral hydration? Encourage oral hydration or provide intravenous hydration, and provide cannabis cessation counseling.

Do the symptoms improve? If yes, great! Provide cessation counseling, resources, and follow-up. If not:

Is the patient still using cannabis? If not, it is time to rethink the diagnosis.

Treatment in the acute setting is supportive and includes intravenous hydration and correction of electrolytes. Conventional antiemetics such as ondansetron, metoclopramide, prochlorperazine, and promethazine have not been effective in relieving hyperemesis.^9,12,14 This implies that the mechanism of emesis likely does not involve dopaminergic and serotonin pathways in the central and autonomic nervous systems.

Cessation of cannabis use is key for long-term resolution of symptoms. Efforts should be made to provide counseling and encourage patients to stop using the drug entirely (Figure 1).

SOMETHING TO THINK ABOUT

With the high prevalence of chronic cannabis abuse and the recent legalization of recreational marijuana use, we will all likely encounter a patient with cannabinoid hyperemesis. With adequate knowledge of this phenomenon, we can avoid unnecessary workups and inappropriate medical and surgical treatment in patients presenting with recurrent vomiting of unknown cause. The diagnosis can easily be made by simply asking for a history of chronic marijuana use and symptoms related to cannabinoid hyperemesis syndrome, such as relief of symptoms with hot baths or showers and with marijuana cessation.

Conservative management and fluid resuscitation is important in the acute setting, but cessation of marijuana use and follow-up counseling are the key components for treating patients with cannabinoid hyperemesis syndrome and for preventing recurrence.

Bell palsy is an idiopathic peripheral nerve disorder involving the facial nerve (ie, cranial nerve VII) and manifesting as acute, ipsilateral facial muscle weakness. It is named after Sir Charles Bell, who in 1821 first described the anatomy of the facial nerve.¹ Although the disorder is clinically benign, patients can be devastated by its disfigurement.

The annual incidence of Bell palsy is 20 per 100,000, with no predilection for sex or ethnicity. It can affect people at any age, but the incidence is slightly higher after age 40.^2,3 Risk factors include diabetes, pregnancy, severe preeclampsia, obesity, and hypertension.^4–7

THE FACIAL NERVE IS VULNERABLE TO TRAUMA AND COMPRESSION

A basic understanding of the neuroanatomy of the facial nerve provides clues for distinguishing a central lesion from a peripheral lesion. This differentiation is important because the causes and management differ.

The facial nerve is a mixed sensory and motor nerve, carrying fibers involved in facial expression, taste, lacrimation, salivation, and sensation of the ear. It originates in the lower pons and exits the brainstem ventrally at the pontomedullary junction. After entering the internal acoustic meatus, it travels 20 to 30 mm in the facial canal, the longest bony course of any cranial nerve, making it highly susceptible to trauma and compression by edema.⁸

In the facial canal, it makes a posterior and inferior turn, forming a bend (ie, the genu of the facial nerve). The genu is proximal to the geniculate ganglion, which contains the facial nerve’s primary sensory neurons for taste and sensation. The motor branch of the facial nerve then exits the cranium via the stylomastoid foramen and passes through the parotid gland, where it divides into temporofacial and cervicofacial trunks.⁹

The facial nerve has five terminal branches that innervate the muscles of facial expression:

• The temporal branch (muscles of the forehead and superior part of the orbicularis oculi)
• The zygomatic branch (muscles of the nasolabial fold and cheek, eg, nasalis and zygomaticus).
• The buccal branch (the buccinators and inferior part of the orbicularis oculi)
• The marginal mandibular branch (the depressors of the mouth, eg, depressor anguli and mentalis)
• The cervical branch (the platysma muscle).

INFLAMMATION IS BELIEVED TO BE RESPONSIBLE

Although the precise cause of Bell palsy is not known, one theory is that inflammation of the nerve causes focal edema, demyelination, and ischemia. Several studies have suggested that herpes virus simplex type 1 infection may be involved.¹⁰

FACIAL DROOPING, EYELID WEAKNESS, OTHER SYMPTOMS

Symptoms of Bell palsy include ipsilateral sagging of the eyebrow, drooping of the face, flattening of the nasolabial fold, and inability to fully close the eye, pucker the lips, or raise the corner of the mouth (Figure 1). Symptoms develop within hours and are maximal by 3 days.

About 70% of patients have associated ipsilateral pain around the ear. If facial pain is present with sensory and hearing loss, a tumor of the parotid gland or viral otitis must be considered.¹¹ Other complaints may include hyperacusis due to disruption of nerve fibers to the stapedius muscle, changes in taste, and dry eye from parasympathetic dysfunction. Some patients report paresthesias over the face, which most often represent motor symptoms misconstrued as sensory changes.

PHYSICAL EXAMINATION

The clinical examination should include a complete neurologic and general examination, including otoscopy and attention to the skin and parotid gland. Vesicles or scabbing around the ear should prompt testing for herpes zoster. Careful observation during the interview while the patient is talking may reveal subtle signs of weakness and provide additional clues.

A systematic approach to the assessment of a patient with suspected Bell palsy is recommended (Table 1) and outlined below:

Does the patient have peripheral facial palsy?

In Bell palsy, wrinkling of the forehead on the affected side when raising the eyebrows is either asymmetrical or absent.

If the forehead muscles are spared and the lower face is weak, this signifies a central lesion such as a stroke or other structural abnormality and not a peripheral lesion of the facial nerve (eg, Bell palsy).

Can the patient close the eyes tightly?

Normally, the patient should be able to close both eyes tightly, and the eyelashes should be buried between the eyelids. In Bell palsy, when the patient attempts to close the eyes, the affected side shows incomplete closure and the eye may remain partly open.

Assess the strength of the orbicularis oculi by trying to open the eyes. The patient who is attempting to close the eyelids tightly but cannot will demonstrate the Bell phenomenon, ie, the examiner is able to force open the eyelids, and the eyes are deviated upward and laterally.

Closely observe the blink pattern, as the involved side in Bell palsy may slightly lag behind the normal eye, and the patient may be unable to close the eye completely.

Is the smile symmetric?

Note flattening of the nasolabial fold on one side, which indicates facial weakness.

Can the patient puff out the cheeks?

Ask the patient to hold air in the mouth against resistance. This assesses the strength of the buccinator muscle.

Can the patient purse the lips?

Ask the patient to pucker or purse the lips and observe for asymmetry or weakness on the affected side.

Test the orbicularis oris muscle by trying to spread the lips apart while the patient resists, and observe for weakness on one side.

Is there a symmetric grimace?

This will test the muscles involved in depressing the angles of the mouth and platysma.

Are taste, sensation, and hearing intact?

Other testable functions of the facial nerve, including taste, sensation, and hearing, do not always need to be assessed but can be in patients with specific sensory deficits.

Facial palsy that does not improve after 3 weeks should prompt a referral to a neurologist

Abnormalities in taste can support localization of the problem either proximal or distal to the branch point of fibers mediating taste. The facial nerve supplies taste fibers to the anterior two-thirds of the tongue. Sweet and salty taste can be screened with sugar and salt. Tell the patient to close the eyes, and using a tongue blade, apply a small amount of sugar or salt on the side of the tongue. Ask the patient to identify the taste and repeat with the other sample after he or she has rinsed the mouth.

Somatic sensory fibers supplied by the facial nerve innervate the inner ear and a small area behind the ear, but these may be difficult to assess objectively. Formal audiologic testing may be needed if hearing is impaired.

Facial nerve reflexes

A number of facial reflexes can be tested, including the orbicularis oculi, palpebral-oculogyric, and corneal reflexes.¹²

The orbicularis oculi reflex is tested by gentle finger percussion of the glabella while observing for involuntary blinking with each stimulus. The afferent branch of this reflex is carried by the trigeminal nerve, while the efferent response is carried by the facial nerve. In peripheral facial nerve palsy, this reflex is weakened or absent on the affected side.

The palpebral-oculogyric reflex, or Bell phenomenon, produces upward and lateral deviation of the eyes when attempting forceful eyelid closure. In this reflex, the afferent fibers are carried by the facial nerve and the efferent fibers travel in the oculomotor nerve to the superior rectus muscle. In Bell palsy, this reflex is visible because of failure of adequate eyelid closure.

The corneal reflex is elicited by stimulating the cornea with a wisp of cotton, causing reflexive closure of the both eyes. The affected side may show slowed or absent lid closure when tested on either side. The sensory afferent fibers are carried by the trigeminal nerve, and the motor efferent fibers are carried by the facial nerve.

Grading of facial paralysis

The House-Brackmann scale is the most widely used tool for grading the degree of facial paralysis and for predicting recovery. Grades are I to VI, with grade I indicating normal function, and grade VI, complete paralysis.

Patients with some preserved motor function generally have good recovery, but those with complete paralysis may have long-term residual deficits.¹³

A DIAGNOSIS OF EXCLUSION

The diagnosis of Bell palsy is made by excluding other causes of unilateral facial paralysis, and 30% to 60% of cases of facial palsy are caused by an underlying disorder that mimics Bell palsy, including central nervous system lesion (eg, stroke, demyelinating disease), parotid gland tumor, Lyme disease, Ramsay Hunt syndrome, granulomatous disease, otitis media, cholesteatoma, diabetes, trauma, and Guillain-Barré syndrome (Table 2).^14,15 Many of these conditions have associated features that help distinguish them from Bell palsy. Facial palsy that does not improve after 3 weeks should prompt referral to a neurologist.

Brain lesions

It is uncommon to have isolated facial palsy with a cortical or subcortical brain lesion, since the corticobulbar and corticospinal tracts travel in close proximity. Cortical signs such as hemiparesis, hemisensory loss, neglect, and dysarthria suggest a lesion of the cerebral cortex. Additionally, forehead muscle sparing is expected in supranuclear lesions.

Brainstem lesions can manifest with multiple ipsilateral cranial nerve palsies and contralateral limb weakness. Sarcoidosis and leptomeningeal carcinomatosis tend to involve the skull base and present with multiple cranial neuropathies.

Tumors of the brain or parotid gland have an insidious onset and may cause systemic signs such as fevers, chills, and weight loss. Headache, seizures, and hearing loss indicate an intracranial lesion. A palpable mass near the ear, neck, or parotid gland requires imaging of the face to look for a parotid gland tumor.

Infection

A number of infections can cause acute facial paralysis. The most common is herpes simplex virus, and the next most common is varicella zoster.¹⁴ Herpes simplex virus, Ramsay Hunt syndrome, and Lyme disease may have associated pain and skin changes. Erythema of the tympanic membrane suggests otitis media, especially in the setting of ear pain and hearing loss.

Ramsay Hunt syndrome is caused by reactivation of the herpes zoster virus from the geniculate ganglion, affecting the facial nerve. Careful examination of the ear canal and the oropharynx may show vesicles.

In Lyme disease, facial palsy is the most common cranial neuropathy, seen in 50% to 63% of patients with Borrelia burgdorferi meningitis.^16,17 In people with a history of rash, arthralgia, tick bite, or travel to an endemic region, Lyme titers should be checked before starting the patient on corticosteroids.

Bilateral facial palsy is rare and occurs in fewer than 1% of patients. It has been reported in patients with Lyme disease, Guillain-Barré syndrome, sarcoidosis, diabetes mellitus, viral infection, and pontine glioma.¹⁸

DIAGNOSTIC EVALUATION

Serologic testing, electrodiagnostic studies, and imaging are not routinely necessary to diagnose Bell palsy

Serologic testing, electrodiagnostic studies, and imaging are not routinely necessary to diagnose Bell palsy. However, referral to the appropriate specialist (neurologist, otolaryngologist, optometrist, ophthalmologist) is advised if the patient has sparing of the forehead muscle, multiple cranial neuropathies, signs of infection, or persistent weakness without significant improvement at 3 weeks.

Laboratory testing

A complete blood cell count with differential may point to infection or a lymphoproliferative disorder. When indicated, screening for diabetes mellitus with fasting blood glucose or hemoglobin A_1c may be helpful. In Lyme-endemic regions, patients should undergo an enzyme-linked immunosorbent assay or an indirect fluorescent antibody test to screen for the disease. If positive, the diagnosis of Lyme disease should be confirmed by Western blot. If vesicles are present on examination, check serum antibodies for herpes zoster. In the appropriate clinical setting, angiotensin-converting enzyme, human immunodeficiency virus, and inflammatory markers can be tested.

Cerebrospinal fluid analysis is generally not helpful in diagnosing Bell palsy but can differentiate it from Guillain-Barré syndrome, leptomeningeal carcinomatosis, and infection involving the central nervous system.

Imaging

Imaging is not recommended in the initial evaluation of Bell palsy unless symptoms and the examination are atypical. From 5% to 7% of cases of facial palsy are caused by a tumor (eg, facial neuroma, cholesteatoma, hemangioma, meningioma), whether benign or malignant.^14,15 Therefore, in patients with insidious onset of symptoms that do not improve in about 3 weeks, contrast-enhanced computed tomography or gadolinium-enhanced magnetic resonance imaging of the internal auditory canal and face is warranted.

Electrodiagnostic studies

Electrodiagnostic testing is typically not part of the evaluation of acute Bell palsy, but in patients with complete paralysis, it may help assess the degree of nerve injury and the chances of recovery, especially since patients with complete paralysis have a higher risk of incomplete recovery.¹⁹ Electrodiagnostic studies should be performed at least 1 week after symptom onset to avoid false-negative results.

TREATMENT

The treatment of Bell palsy focuses on maximizing recovery and minimizing associated complications.

Protect the eyes

Patients who cannot completely close their eyes should be given instructions on ocular protective care to prevent exposure keratopathy. Frequent application of lubricant eyedrops with artificial tears during the day or ophthalmic ointment at bedtime is recommended. The physician should also recommend protective eyewear such as sunglasses during the day. Eye patching or taping at night may be useful but could be harmful if applied too loosely or too tightly. Patients with vision loss or eye irritation should be referred to an ophthalmologist.¹⁹

Corticosteroids are recommended in the first 72 hours

In two randomized clinical trials (conducted by Sullivan et al²⁰ in 511 patients and Engström et al²¹ in 829 patients), prednisolone was found to be beneficial if started within 72 hours of symptom onset.

In a double-blind, randomized, placebo-controlled study of prednisone in 58 patients, those who received the drug recovered faster, although long-term outcomes in these patients were not significantly different than those in the control group.²² The American Academy of Neurology²³ rated this study as class II, ie, not meeting all of its criteria for the highest level of evidence, class I. Nevertheless, although prednisone lacks class I evidence, its use is recommended because it is a precursor to its active metabolite, prednisolone, which has been studied extensively.

The current guidelines of the American Academy of Neurology, updated in 2012, state, “For patients with new-onset Bell palsy, steroids are highly likely to be effective and should be offered to increase the probability of recovery of facial nerve function”²³ (level A evidence, ie, established as effective). They also concluded that adverse effects of corticosteroids were generally minor and temporary.

Similarly, the guidelines of the American Academy of Otolaryngology–Head and Neck Surgery, published in 2013, recommend oral corticosteroids within 72 hours of onset of symptoms of Bell palsy for patients age 16 and older.¹⁹ The recommendation is for a 10-day course of corticosteroids with at least 5 days at a high dose (prednisolone 50 mg orally daily for 10 days, or prednisone 60 mg orally daily for 5 days, followed by a 5-day taper). The benefit of corticosteroids after 72 hours is unclear (Table 3).¹⁹

Even though the guidelines recommend corticosteroids, the decision to use them in diabetic patients and pregnant women should be individualized. Discretion is advised, as not all patients with Bell palsy need to be treated. Most recover spontaneously, especially those with mild symptoms.

Antiviral therapy may offer modest benefit

Antiviral therapy has not been shown to be beneficial in Bell palsy, and current guidelines do not recommend oral antiviral therapy alone.¹⁹ However, an antiviral combined with a corticosteroid may offer modest benefit if started within 72 hours of symptom onset (level C evidence, ie, possibly effective).²³ Patients starting antiviral therapy should understand that its benefit has not been established.

Surgical decompression remains controversial

A Cochrane systematic review in 2011 found insufficient evidence regarding the safety and efficacy of surgical intervention in Bell palsy.²⁴ Surgery should be considered only for patients with complete paralysis with a greater than 90% reduction in motor amplitude on a nerve conduction study compared with the unaffected side, and absent volitional activity on needle examination.^19,25

Acupuncture: No recommendation

Currently, there is no recommendation for acupuncture in the treatment of Bell palsy.¹⁹ A recent randomized clinical trial suggests benefit from acupuncture combined with corticosteroids,²⁶ but high-quality studies to support its use are lacking.²⁶

Physical therapy: Insufficient evidence

There is insufficient evidence to show that physical therapy has benefit—or harm—in Bell palsy. However, some low-quality studies indicated that facial exercises and mime therapy may improve function in patients with moderate paralysis.²⁷

Follow-up

Instruct patients to call at 2 weeks to report progress of symptoms

Patients should be instructed to call at 2 weeks to report progress of symptoms and to be reevaluated within or at 1 month, with close attention to facial weakness and eye irritation. Further evaluation is needed if there has been no improvement, if symptoms have worsened, or if new symptoms have appeared.

The psychosocial impact of Bell palsy cannot be discounted, as the disfigurement can have negative implications for self-esteem and social relationships. Appropriate referral to an ophthalmologist, neurologist, otolaryngologist, social worker, or a plastic surgeon may be necessary.

COMPLICATIONS AND PROGNOSIS

Most patients with Bell palsy recover completely, but up to 30% have residual symptoms at 6 months.^14,20 Furthermore, although Bell palsy usually has a monophasic course, 7% to 12% of patients have a recurrence.^3,15

Long-term complications can include residual facial weakness, facial synkinesis, facial contracture, and facial spasm.^14,28 Incomplete eye closure may benefit from surgery (tarsorrhaphy or gold-weight implantation) to prevent corneal ulceration. Facial synkinesis is due to aberrant nerve regeneration and occurs in 15% to 20% of patients after recovery from Bell palsy.²⁹ Patients may describe tearing while chewing (“crocodile tears”), involuntary movement of the corners of the mouth with blinking, or ipsilateral eye-closing when the jaw opens (“jaw-winking”). Facial contracture, facial synkinesis, and facial spasm can be treated with botulinum toxin injection.³⁰

Bell palsy is an idiopathic peripheral nerve disorder involving the facial nerve (ie, cranial nerve VII) and manifesting as acute, ipsilateral facial muscle weakness. It is named after Sir Charles Bell, who in 1821 first described the anatomy of the facial nerve.¹ Although the disorder is clinically benign, patients can be devastated by its disfigurement.

The annual incidence of Bell palsy is 20 per 100,000, with no predilection for sex or ethnicity. It can affect people at any age, but the incidence is slightly higher after age 40.^2,3 Risk factors include diabetes, pregnancy, severe preeclampsia, obesity, and hypertension.^4–7

THE FACIAL NERVE IS VULNERABLE TO TRAUMA AND COMPRESSION

A basic understanding of the neuroanatomy of the facial nerve provides clues for distinguishing a central lesion from a peripheral lesion. This differentiation is important because the causes and management differ.

The facial nerve is a mixed sensory and motor nerve, carrying fibers involved in facial expression, taste, lacrimation, salivation, and sensation of the ear. It originates in the lower pons and exits the brainstem ventrally at the pontomedullary junction. After entering the internal acoustic meatus, it travels 20 to 30 mm in the facial canal, the longest bony course of any cranial nerve, making it highly susceptible to trauma and compression by edema.⁸

In the facial canal, it makes a posterior and inferior turn, forming a bend (ie, the genu of the facial nerve). The genu is proximal to the geniculate ganglion, which contains the facial nerve’s primary sensory neurons for taste and sensation. The motor branch of the facial nerve then exits the cranium via the stylomastoid foramen and passes through the parotid gland, where it divides into temporofacial and cervicofacial trunks.⁹

The facial nerve has five terminal branches that innervate the muscles of facial expression:

• The temporal branch (muscles of the forehead and superior part of the orbicularis oculi)
• The zygomatic branch (muscles of the nasolabial fold and cheek, eg, nasalis and zygomaticus).
• The buccal branch (the buccinators and inferior part of the orbicularis oculi)
• The marginal mandibular branch (the depressors of the mouth, eg, depressor anguli and mentalis)
• The cervical branch (the platysma muscle).

INFLAMMATION IS BELIEVED TO BE RESPONSIBLE

Although the precise cause of Bell palsy is not known, one theory is that inflammation of the nerve causes focal edema, demyelination, and ischemia. Several studies have suggested that herpes virus simplex type 1 infection may be involved.¹⁰

FACIAL DROOPING, EYELID WEAKNESS, OTHER SYMPTOMS

Symptoms of Bell palsy include ipsilateral sagging of the eyebrow, drooping of the face, flattening of the nasolabial fold, and inability to fully close the eye, pucker the lips, or raise the corner of the mouth (Figure 1). Symptoms develop within hours and are maximal by 3 days.

About 70% of patients have associated ipsilateral pain around the ear. If facial pain is present with sensory and hearing loss, a tumor of the parotid gland or viral otitis must be considered.¹¹ Other complaints may include hyperacusis due to disruption of nerve fibers to the stapedius muscle, changes in taste, and dry eye from parasympathetic dysfunction. Some patients report paresthesias over the face, which most often represent motor symptoms misconstrued as sensory changes.

PHYSICAL EXAMINATION

The clinical examination should include a complete neurologic and general examination, including otoscopy and attention to the skin and parotid gland. Vesicles or scabbing around the ear should prompt testing for herpes zoster. Careful observation during the interview while the patient is talking may reveal subtle signs of weakness and provide additional clues.

A systematic approach to the assessment of a patient with suspected Bell palsy is recommended (Table 1) and outlined below:

Does the patient have peripheral facial palsy?

In Bell palsy, wrinkling of the forehead on the affected side when raising the eyebrows is either asymmetrical or absent.

If the forehead muscles are spared and the lower face is weak, this signifies a central lesion such as a stroke or other structural abnormality and not a peripheral lesion of the facial nerve (eg, Bell palsy).

Can the patient close the eyes tightly?

Normally, the patient should be able to close both eyes tightly, and the eyelashes should be buried between the eyelids. In Bell palsy, when the patient attempts to close the eyes, the affected side shows incomplete closure and the eye may remain partly open.

Assess the strength of the orbicularis oculi by trying to open the eyes. The patient who is attempting to close the eyelids tightly but cannot will demonstrate the Bell phenomenon, ie, the examiner is able to force open the eyelids, and the eyes are deviated upward and laterally.

Closely observe the blink pattern, as the involved side in Bell palsy may slightly lag behind the normal eye, and the patient may be unable to close the eye completely.

Is the smile symmetric?

Note flattening of the nasolabial fold on one side, which indicates facial weakness.

Can the patient puff out the cheeks?

Ask the patient to hold air in the mouth against resistance. This assesses the strength of the buccinator muscle.

Can the patient purse the lips?

Ask the patient to pucker or purse the lips and observe for asymmetry or weakness on the affected side.

Test the orbicularis oris muscle by trying to spread the lips apart while the patient resists, and observe for weakness on one side.

Is there a symmetric grimace?

This will test the muscles involved in depressing the angles of the mouth and platysma.

Are taste, sensation, and hearing intact?

Other testable functions of the facial nerve, including taste, sensation, and hearing, do not always need to be assessed but can be in patients with specific sensory deficits.

Facial palsy that does not improve after 3 weeks should prompt a referral to a neurologist

Abnormalities in taste can support localization of the problem either proximal or distal to the branch point of fibers mediating taste. The facial nerve supplies taste fibers to the anterior two-thirds of the tongue. Sweet and salty taste can be screened with sugar and salt. Tell the patient to close the eyes, and using a tongue blade, apply a small amount of sugar or salt on the side of the tongue. Ask the patient to identify the taste and repeat with the other sample after he or she has rinsed the mouth.

Somatic sensory fibers supplied by the facial nerve innervate the inner ear and a small area behind the ear, but these may be difficult to assess objectively. Formal audiologic testing may be needed if hearing is impaired.

Facial nerve reflexes

A number of facial reflexes can be tested, including the orbicularis oculi, palpebral-oculogyric, and corneal reflexes.¹²

The orbicularis oculi reflex is tested by gentle finger percussion of the glabella while observing for involuntary blinking with each stimulus. The afferent branch of this reflex is carried by the trigeminal nerve, while the efferent response is carried by the facial nerve. In peripheral facial nerve palsy, this reflex is weakened or absent on the affected side.

The palpebral-oculogyric reflex, or Bell phenomenon, produces upward and lateral deviation of the eyes when attempting forceful eyelid closure. In this reflex, the afferent fibers are carried by the facial nerve and the efferent fibers travel in the oculomotor nerve to the superior rectus muscle. In Bell palsy, this reflex is visible because of failure of adequate eyelid closure.

The corneal reflex is elicited by stimulating the cornea with a wisp of cotton, causing reflexive closure of the both eyes. The affected side may show slowed or absent lid closure when tested on either side. The sensory afferent fibers are carried by the trigeminal nerve, and the motor efferent fibers are carried by the facial nerve.

Grading of facial paralysis

The House-Brackmann scale is the most widely used tool for grading the degree of facial paralysis and for predicting recovery. Grades are I to VI, with grade I indicating normal function, and grade VI, complete paralysis.

Patients with some preserved motor function generally have good recovery, but those with complete paralysis may have long-term residual deficits.¹³

A DIAGNOSIS OF EXCLUSION

The diagnosis of Bell palsy is made by excluding other causes of unilateral facial paralysis, and 30% to 60% of cases of facial palsy are caused by an underlying disorder that mimics Bell palsy, including central nervous system lesion (eg, stroke, demyelinating disease), parotid gland tumor, Lyme disease, Ramsay Hunt syndrome, granulomatous disease, otitis media, cholesteatoma, diabetes, trauma, and Guillain-Barré syndrome (Table 2).^14,15 Many of these conditions have associated features that help distinguish them from Bell palsy. Facial palsy that does not improve after 3 weeks should prompt referral to a neurologist.

Brain lesions

It is uncommon to have isolated facial palsy with a cortical or subcortical brain lesion, since the corticobulbar and corticospinal tracts travel in close proximity. Cortical signs such as hemiparesis, hemisensory loss, neglect, and dysarthria suggest a lesion of the cerebral cortex. Additionally, forehead muscle sparing is expected in supranuclear lesions.

Brainstem lesions can manifest with multiple ipsilateral cranial nerve palsies and contralateral limb weakness. Sarcoidosis and leptomeningeal carcinomatosis tend to involve the skull base and present with multiple cranial neuropathies.

Tumors of the brain or parotid gland have an insidious onset and may cause systemic signs such as fevers, chills, and weight loss. Headache, seizures, and hearing loss indicate an intracranial lesion. A palpable mass near the ear, neck, or parotid gland requires imaging of the face to look for a parotid gland tumor.

Infection

A number of infections can cause acute facial paralysis. The most common is herpes simplex virus, and the next most common is varicella zoster.¹⁴ Herpes simplex virus, Ramsay Hunt syndrome, and Lyme disease may have associated pain and skin changes. Erythema of the tympanic membrane suggests otitis media, especially in the setting of ear pain and hearing loss.

Ramsay Hunt syndrome is caused by reactivation of the herpes zoster virus from the geniculate ganglion, affecting the facial nerve. Careful examination of the ear canal and the oropharynx may show vesicles.

In Lyme disease, facial palsy is the most common cranial neuropathy, seen in 50% to 63% of patients with Borrelia burgdorferi meningitis.^16,17 In people with a history of rash, arthralgia, tick bite, or travel to an endemic region, Lyme titers should be checked before starting the patient on corticosteroids.

Bilateral facial palsy is rare and occurs in fewer than 1% of patients. It has been reported in patients with Lyme disease, Guillain-Barré syndrome, sarcoidosis, diabetes mellitus, viral infection, and pontine glioma.¹⁸

DIAGNOSTIC EVALUATION

Serologic testing, electrodiagnostic studies, and imaging are not routinely necessary to diagnose Bell palsy

Serologic testing, electrodiagnostic studies, and imaging are not routinely necessary to diagnose Bell palsy. However, referral to the appropriate specialist (neurologist, otolaryngologist, optometrist, ophthalmologist) is advised if the patient has sparing of the forehead muscle, multiple cranial neuropathies, signs of infection, or persistent weakness without significant improvement at 3 weeks.

Laboratory testing

A complete blood cell count with differential may point to infection or a lymphoproliferative disorder. When indicated, screening for diabetes mellitus with fasting blood glucose or hemoglobin A_1c may be helpful. In Lyme-endemic regions, patients should undergo an enzyme-linked immunosorbent assay or an indirect fluorescent antibody test to screen for the disease. If positive, the diagnosis of Lyme disease should be confirmed by Western blot. If vesicles are present on examination, check serum antibodies for herpes zoster. In the appropriate clinical setting, angiotensin-converting enzyme, human immunodeficiency virus, and inflammatory markers can be tested.

Cerebrospinal fluid analysis is generally not helpful in diagnosing Bell palsy but can differentiate it from Guillain-Barré syndrome, leptomeningeal carcinomatosis, and infection involving the central nervous system.

Imaging

Imaging is not recommended in the initial evaluation of Bell palsy unless symptoms and the examination are atypical. From 5% to 7% of cases of facial palsy are caused by a tumor (eg, facial neuroma, cholesteatoma, hemangioma, meningioma), whether benign or malignant.^14,15 Therefore, in patients with insidious onset of symptoms that do not improve in about 3 weeks, contrast-enhanced computed tomography or gadolinium-enhanced magnetic resonance imaging of the internal auditory canal and face is warranted.

Electrodiagnostic studies

Electrodiagnostic testing is typically not part of the evaluation of acute Bell palsy, but in patients with complete paralysis, it may help assess the degree of nerve injury and the chances of recovery, especially since patients with complete paralysis have a higher risk of incomplete recovery.¹⁹ Electrodiagnostic studies should be performed at least 1 week after symptom onset to avoid false-negative results.

TREATMENT

The treatment of Bell palsy focuses on maximizing recovery and minimizing associated complications.

Protect the eyes

Patients who cannot completely close their eyes should be given instructions on ocular protective care to prevent exposure keratopathy. Frequent application of lubricant eyedrops with artificial tears during the day or ophthalmic ointment at bedtime is recommended. The physician should also recommend protective eyewear such as sunglasses during the day. Eye patching or taping at night may be useful but could be harmful if applied too loosely or too tightly. Patients with vision loss or eye irritation should be referred to an ophthalmologist.¹⁹

Corticosteroids are recommended in the first 72 hours

In two randomized clinical trials (conducted by Sullivan et al²⁰ in 511 patients and Engström et al²¹ in 829 patients), prednisolone was found to be beneficial if started within 72 hours of symptom onset.

In a double-blind, randomized, placebo-controlled study of prednisone in 58 patients, those who received the drug recovered faster, although long-term outcomes in these patients were not significantly different than those in the control group.²² The American Academy of Neurology²³ rated this study as class II, ie, not meeting all of its criteria for the highest level of evidence, class I. Nevertheless, although prednisone lacks class I evidence, its use is recommended because it is a precursor to its active metabolite, prednisolone, which has been studied extensively.

The current guidelines of the American Academy of Neurology, updated in 2012, state, “For patients with new-onset Bell palsy, steroids are highly likely to be effective and should be offered to increase the probability of recovery of facial nerve function”²³ (level A evidence, ie, established as effective). They also concluded that adverse effects of corticosteroids were generally minor and temporary.

Similarly, the guidelines of the American Academy of Otolaryngology–Head and Neck Surgery, published in 2013, recommend oral corticosteroids within 72 hours of onset of symptoms of Bell palsy for patients age 16 and older.¹⁹ The recommendation is for a 10-day course of corticosteroids with at least 5 days at a high dose (prednisolone 50 mg orally daily for 10 days, or prednisone 60 mg orally daily for 5 days, followed by a 5-day taper). The benefit of corticosteroids after 72 hours is unclear (Table 3).¹⁹

Even though the guidelines recommend corticosteroids, the decision to use them in diabetic patients and pregnant women should be individualized. Discretion is advised, as not all patients with Bell palsy need to be treated. Most recover spontaneously, especially those with mild symptoms.

Antiviral therapy may offer modest benefit

Antiviral therapy has not been shown to be beneficial in Bell palsy, and current guidelines do not recommend oral antiviral therapy alone.¹⁹ However, an antiviral combined with a corticosteroid may offer modest benefit if started within 72 hours of symptom onset (level C evidence, ie, possibly effective).²³ Patients starting antiviral therapy should understand that its benefit has not been established.

Surgical decompression remains controversial

A Cochrane systematic review in 2011 found insufficient evidence regarding the safety and efficacy of surgical intervention in Bell palsy.²⁴ Surgery should be considered only for patients with complete paralysis with a greater than 90% reduction in motor amplitude on a nerve conduction study compared with the unaffected side, and absent volitional activity on needle examination.^19,25

Acupuncture: No recommendation

Currently, there is no recommendation for acupuncture in the treatment of Bell palsy.¹⁹ A recent randomized clinical trial suggests benefit from acupuncture combined with corticosteroids,²⁶ but high-quality studies to support its use are lacking.²⁶

Physical therapy: Insufficient evidence

There is insufficient evidence to show that physical therapy has benefit—or harm—in Bell palsy. However, some low-quality studies indicated that facial exercises and mime therapy may improve function in patients with moderate paralysis.²⁷

Follow-up

Instruct patients to call at 2 weeks to report progress of symptoms

Patients should be instructed to call at 2 weeks to report progress of symptoms and to be reevaluated within or at 1 month, with close attention to facial weakness and eye irritation. Further evaluation is needed if there has been no improvement, if symptoms have worsened, or if new symptoms have appeared.

The psychosocial impact of Bell palsy cannot be discounted, as the disfigurement can have negative implications for self-esteem and social relationships. Appropriate referral to an ophthalmologist, neurologist, otolaryngologist, social worker, or a plastic surgeon may be necessary.

COMPLICATIONS AND PROGNOSIS

Most patients with Bell palsy recover completely, but up to 30% have residual symptoms at 6 months.^14,20 Furthermore, although Bell palsy usually has a monophasic course, 7% to 12% of patients have a recurrence.^3,15

Long-term complications can include residual facial weakness, facial synkinesis, facial contracture, and facial spasm.^14,28 Incomplete eye closure may benefit from surgery (tarsorrhaphy or gold-weight implantation) to prevent corneal ulceration. Facial synkinesis is due to aberrant nerve regeneration and occurs in 15% to 20% of patients after recovery from Bell palsy.²⁹ Patients may describe tearing while chewing (“crocodile tears”), involuntary movement of the corners of the mouth with blinking, or ipsilateral eye-closing when the jaw opens (“jaw-winking”). Facial contracture, facial synkinesis, and facial spasm can be treated with botulinum toxin injection.³⁰

Bell palsy is an idiopathic peripheral nerve disorder involving the facial nerve (ie, cranial nerve VII) and manifesting as acute, ipsilateral facial muscle weakness. It is named after Sir Charles Bell, who in 1821 first described the anatomy of the facial nerve.¹ Although the disorder is clinically benign, patients can be devastated by its disfigurement.

The annual incidence of Bell palsy is 20 per 100,000, with no predilection for sex or ethnicity. It can affect people at any age, but the incidence is slightly higher after age 40.^2,3 Risk factors include diabetes, pregnancy, severe preeclampsia, obesity, and hypertension.^4–7

THE FACIAL NERVE IS VULNERABLE TO TRAUMA AND COMPRESSION

A basic understanding of the neuroanatomy of the facial nerve provides clues for distinguishing a central lesion from a peripheral lesion. This differentiation is important because the causes and management differ.

The facial nerve is a mixed sensory and motor nerve, carrying fibers involved in facial expression, taste, lacrimation, salivation, and sensation of the ear. It originates in the lower pons and exits the brainstem ventrally at the pontomedullary junction. After entering the internal acoustic meatus, it travels 20 to 30 mm in the facial canal, the longest bony course of any cranial nerve, making it highly susceptible to trauma and compression by edema.⁸

In the facial canal, it makes a posterior and inferior turn, forming a bend (ie, the genu of the facial nerve). The genu is proximal to the geniculate ganglion, which contains the facial nerve’s primary sensory neurons for taste and sensation. The motor branch of the facial nerve then exits the cranium via the stylomastoid foramen and passes through the parotid gland, where it divides into temporofacial and cervicofacial trunks.⁹

The facial nerve has five terminal branches that innervate the muscles of facial expression:

• The temporal branch (muscles of the forehead and superior part of the orbicularis oculi)
• The zygomatic branch (muscles of the nasolabial fold and cheek, eg, nasalis and zygomaticus).
• The buccal branch (the buccinators and inferior part of the orbicularis oculi)
• The marginal mandibular branch (the depressors of the mouth, eg, depressor anguli and mentalis)
• The cervical branch (the platysma muscle).

INFLAMMATION IS BELIEVED TO BE RESPONSIBLE

Although the precise cause of Bell palsy is not known, one theory is that inflammation of the nerve causes focal edema, demyelination, and ischemia. Several studies have suggested that herpes virus simplex type 1 infection may be involved.¹⁰

FACIAL DROOPING, EYELID WEAKNESS, OTHER SYMPTOMS

Symptoms of Bell palsy include ipsilateral sagging of the eyebrow, drooping of the face, flattening of the nasolabial fold, and inability to fully close the eye, pucker the lips, or raise the corner of the mouth (Figure 1). Symptoms develop within hours and are maximal by 3 days.

About 70% of patients have associated ipsilateral pain around the ear. If facial pain is present with sensory and hearing loss, a tumor of the parotid gland or viral otitis must be considered.¹¹ Other complaints may include hyperacusis due to disruption of nerve fibers to the stapedius muscle, changes in taste, and dry eye from parasympathetic dysfunction. Some patients report paresthesias over the face, which most often represent motor symptoms misconstrued as sensory changes.

PHYSICAL EXAMINATION

The clinical examination should include a complete neurologic and general examination, including otoscopy and attention to the skin and parotid gland. Vesicles or scabbing around the ear should prompt testing for herpes zoster. Careful observation during the interview while the patient is talking may reveal subtle signs of weakness and provide additional clues.

A systematic approach to the assessment of a patient with suspected Bell palsy is recommended (Table 1) and outlined below:

Does the patient have peripheral facial palsy?

In Bell palsy, wrinkling of the forehead on the affected side when raising the eyebrows is either asymmetrical or absent.

If the forehead muscles are spared and the lower face is weak, this signifies a central lesion such as a stroke or other structural abnormality and not a peripheral lesion of the facial nerve (eg, Bell palsy).

Can the patient close the eyes tightly?

Normally, the patient should be able to close both eyes tightly, and the eyelashes should be buried between the eyelids. In Bell palsy, when the patient attempts to close the eyes, the affected side shows incomplete closure and the eye may remain partly open.

Assess the strength of the orbicularis oculi by trying to open the eyes. The patient who is attempting to close the eyelids tightly but cannot will demonstrate the Bell phenomenon, ie, the examiner is able to force open the eyelids, and the eyes are deviated upward and laterally.

Closely observe the blink pattern, as the involved side in Bell palsy may slightly lag behind the normal eye, and the patient may be unable to close the eye completely.

Is the smile symmetric?

Note flattening of the nasolabial fold on one side, which indicates facial weakness.

Can the patient puff out the cheeks?

Ask the patient to hold air in the mouth against resistance. This assesses the strength of the buccinator muscle.

Can the patient purse the lips?

Ask the patient to pucker or purse the lips and observe for asymmetry or weakness on the affected side.

Test the orbicularis oris muscle by trying to spread the lips apart while the patient resists, and observe for weakness on one side.

Is there a symmetric grimace?

This will test the muscles involved in depressing the angles of the mouth and platysma.

Are taste, sensation, and hearing intact?

Other testable functions of the facial nerve, including taste, sensation, and hearing, do not always need to be assessed but can be in patients with specific sensory deficits.

Facial palsy that does not improve after 3 weeks should prompt a referral to a neurologist

Abnormalities in taste can support localization of the problem either proximal or distal to the branch point of fibers mediating taste. The facial nerve supplies taste fibers to the anterior two-thirds of the tongue. Sweet and salty taste can be screened with sugar and salt. Tell the patient to close the eyes, and using a tongue blade, apply a small amount of sugar or salt on the side of the tongue. Ask the patient to identify the taste and repeat with the other sample after he or she has rinsed the mouth.

Somatic sensory fibers supplied by the facial nerve innervate the inner ear and a small area behind the ear, but these may be difficult to assess objectively. Formal audiologic testing may be needed if hearing is impaired.

Facial nerve reflexes

A number of facial reflexes can be tested, including the orbicularis oculi, palpebral-oculogyric, and corneal reflexes.¹²

The orbicularis oculi reflex is tested by gentle finger percussion of the glabella while observing for involuntary blinking with each stimulus. The afferent branch of this reflex is carried by the trigeminal nerve, while the efferent response is carried by the facial nerve. In peripheral facial nerve palsy, this reflex is weakened or absent on the affected side.

The palpebral-oculogyric reflex, or Bell phenomenon, produces upward and lateral deviation of the eyes when attempting forceful eyelid closure. In this reflex, the afferent fibers are carried by the facial nerve and the efferent fibers travel in the oculomotor nerve to the superior rectus muscle. In Bell palsy, this reflex is visible because of failure of adequate eyelid closure.

The corneal reflex is elicited by stimulating the cornea with a wisp of cotton, causing reflexive closure of the both eyes. The affected side may show slowed or absent lid closure when tested on either side. The sensory afferent fibers are carried by the trigeminal nerve, and the motor efferent fibers are carried by the facial nerve.

Grading of facial paralysis

The House-Brackmann scale is the most widely used tool for grading the degree of facial paralysis and for predicting recovery. Grades are I to VI, with grade I indicating normal function, and grade VI, complete paralysis.

Patients with some preserved motor function generally have good recovery, but those with complete paralysis may have long-term residual deficits.¹³

A DIAGNOSIS OF EXCLUSION

The diagnosis of Bell palsy is made by excluding other causes of unilateral facial paralysis, and 30% to 60% of cases of facial palsy are caused by an underlying disorder that mimics Bell palsy, including central nervous system lesion (eg, stroke, demyelinating disease), parotid gland tumor, Lyme disease, Ramsay Hunt syndrome, granulomatous disease, otitis media, cholesteatoma, diabetes, trauma, and Guillain-Barré syndrome (Table 2).^14,15 Many of these conditions have associated features that help distinguish them from Bell palsy. Facial palsy that does not improve after 3 weeks should prompt referral to a neurologist.

Brain lesions

It is uncommon to have isolated facial palsy with a cortical or subcortical brain lesion, since the corticobulbar and corticospinal tracts travel in close proximity. Cortical signs such as hemiparesis, hemisensory loss, neglect, and dysarthria suggest a lesion of the cerebral cortex. Additionally, forehead muscle sparing is expected in supranuclear lesions.

Brainstem lesions can manifest with multiple ipsilateral cranial nerve palsies and contralateral limb weakness. Sarcoidosis and leptomeningeal carcinomatosis tend to involve the skull base and present with multiple cranial neuropathies.

Tumors of the brain or parotid gland have an insidious onset and may cause systemic signs such as fevers, chills, and weight loss. Headache, seizures, and hearing loss indicate an intracranial lesion. A palpable mass near the ear, neck, or parotid gland requires imaging of the face to look for a parotid gland tumor.

Infection

A number of infections can cause acute facial paralysis. The most common is herpes simplex virus, and the next most common is varicella zoster.¹⁴ Herpes simplex virus, Ramsay Hunt syndrome, and Lyme disease may have associated pain and skin changes. Erythema of the tympanic membrane suggests otitis media, especially in the setting of ear pain and hearing loss.

Ramsay Hunt syndrome is caused by reactivation of the herpes zoster virus from the geniculate ganglion, affecting the facial nerve. Careful examination of the ear canal and the oropharynx may show vesicles.

In Lyme disease, facial palsy is the most common cranial neuropathy, seen in 50% to 63% of patients with Borrelia burgdorferi meningitis.^16,17 In people with a history of rash, arthralgia, tick bite, or travel to an endemic region, Lyme titers should be checked before starting the patient on corticosteroids.

Bilateral facial palsy is rare and occurs in fewer than 1% of patients. It has been reported in patients with Lyme disease, Guillain-Barré syndrome, sarcoidosis, diabetes mellitus, viral infection, and pontine glioma.¹⁸

DIAGNOSTIC EVALUATION

Serologic testing, electrodiagnostic studies, and imaging are not routinely necessary to diagnose Bell palsy

Serologic testing, electrodiagnostic studies, and imaging are not routinely necessary to diagnose Bell palsy. However, referral to the appropriate specialist (neurologist, otolaryngologist, optometrist, ophthalmologist) is advised if the patient has sparing of the forehead muscle, multiple cranial neuropathies, signs of infection, or persistent weakness without significant improvement at 3 weeks.

Laboratory testing

A complete blood cell count with differential may point to infection or a lymphoproliferative disorder. When indicated, screening for diabetes mellitus with fasting blood glucose or hemoglobin A_1c may be helpful. In Lyme-endemic regions, patients should undergo an enzyme-linked immunosorbent assay or an indirect fluorescent antibody test to screen for the disease. If positive, the diagnosis of Lyme disease should be confirmed by Western blot. If vesicles are present on examination, check serum antibodies for herpes zoster. In the appropriate clinical setting, angiotensin-converting enzyme, human immunodeficiency virus, and inflammatory markers can be tested.

Cerebrospinal fluid analysis is generally not helpful in diagnosing Bell palsy but can differentiate it from Guillain-Barré syndrome, leptomeningeal carcinomatosis, and infection involving the central nervous system.

Imaging

Imaging is not recommended in the initial evaluation of Bell palsy unless symptoms and the examination are atypical. From 5% to 7% of cases of facial palsy are caused by a tumor (eg, facial neuroma, cholesteatoma, hemangioma, meningioma), whether benign or malignant.^14,15 Therefore, in patients with insidious onset of symptoms that do not improve in about 3 weeks, contrast-enhanced computed tomography or gadolinium-enhanced magnetic resonance imaging of the internal auditory canal and face is warranted.

Electrodiagnostic studies

Electrodiagnostic testing is typically not part of the evaluation of acute Bell palsy, but in patients with complete paralysis, it may help assess the degree of nerve injury and the chances of recovery, especially since patients with complete paralysis have a higher risk of incomplete recovery.¹⁹ Electrodiagnostic studies should be performed at least 1 week after symptom onset to avoid false-negative results.

TREATMENT

The treatment of Bell palsy focuses on maximizing recovery and minimizing associated complications.

Protect the eyes

Patients who cannot completely close their eyes should be given instructions on ocular protective care to prevent exposure keratopathy. Frequent application of lubricant eyedrops with artificial tears during the day or ophthalmic ointment at bedtime is recommended. The physician should also recommend protective eyewear such as sunglasses during the day. Eye patching or taping at night may be useful but could be harmful if applied too loosely or too tightly. Patients with vision loss or eye irritation should be referred to an ophthalmologist.¹⁹

Corticosteroids are recommended in the first 72 hours

In two randomized clinical trials (conducted by Sullivan et al²⁰ in 511 patients and Engström et al²¹ in 829 patients), prednisolone was found to be beneficial if started within 72 hours of symptom onset.

In a double-blind, randomized, placebo-controlled study of prednisone in 58 patients, those who received the drug recovered faster, although long-term outcomes in these patients were not significantly different than those in the control group.²² The American Academy of Neurology²³ rated this study as class II, ie, not meeting all of its criteria for the highest level of evidence, class I. Nevertheless, although prednisone lacks class I evidence, its use is recommended because it is a precursor to its active metabolite, prednisolone, which has been studied extensively.

The current guidelines of the American Academy of Neurology, updated in 2012, state, “For patients with new-onset Bell palsy, steroids are highly likely to be effective and should be offered to increase the probability of recovery of facial nerve function”²³ (level A evidence, ie, established as effective). They also concluded that adverse effects of corticosteroids were generally minor and temporary.

Similarly, the guidelines of the American Academy of Otolaryngology–Head and Neck Surgery, published in 2013, recommend oral corticosteroids within 72 hours of onset of symptoms of Bell palsy for patients age 16 and older.¹⁹ The recommendation is for a 10-day course of corticosteroids with at least 5 days at a high dose (prednisolone 50 mg orally daily for 10 days, or prednisone 60 mg orally daily for 5 days, followed by a 5-day taper). The benefit of corticosteroids after 72 hours is unclear (Table 3).¹⁹

Even though the guidelines recommend corticosteroids, the decision to use them in diabetic patients and pregnant women should be individualized. Discretion is advised, as not all patients with Bell palsy need to be treated. Most recover spontaneously, especially those with mild symptoms.

Antiviral therapy may offer modest benefit

Antiviral therapy has not been shown to be beneficial in Bell palsy, and current guidelines do not recommend oral antiviral therapy alone.¹⁹ However, an antiviral combined with a corticosteroid may offer modest benefit if started within 72 hours of symptom onset (level C evidence, ie, possibly effective).²³ Patients starting antiviral therapy should understand that its benefit has not been established.

Surgical decompression remains controversial

A Cochrane systematic review in 2011 found insufficient evidence regarding the safety and efficacy of surgical intervention in Bell palsy.²⁴ Surgery should be considered only for patients with complete paralysis with a greater than 90% reduction in motor amplitude on a nerve conduction study compared with the unaffected side, and absent volitional activity on needle examination.^19,25

Acupuncture: No recommendation

Currently, there is no recommendation for acupuncture in the treatment of Bell palsy.¹⁹ A recent randomized clinical trial suggests benefit from acupuncture combined with corticosteroids,²⁶ but high-quality studies to support its use are lacking.²⁶

Physical therapy: Insufficient evidence

There is insufficient evidence to show that physical therapy has benefit—or harm—in Bell palsy. However, some low-quality studies indicated that facial exercises and mime therapy may improve function in patients with moderate paralysis.²⁷

Follow-up

Instruct patients to call at 2 weeks to report progress of symptoms

Patients should be instructed to call at 2 weeks to report progress of symptoms and to be reevaluated within or at 1 month, with close attention to facial weakness and eye irritation. Further evaluation is needed if there has been no improvement, if symptoms have worsened, or if new symptoms have appeared.

The psychosocial impact of Bell palsy cannot be discounted, as the disfigurement can have negative implications for self-esteem and social relationships. Appropriate referral to an ophthalmologist, neurologist, otolaryngologist, social worker, or a plastic surgeon may be necessary.

COMPLICATIONS AND PROGNOSIS

Most patients with Bell palsy recover completely, but up to 30% have residual symptoms at 6 months.^14,20 Furthermore, although Bell palsy usually has a monophasic course, 7% to 12% of patients have a recurrence.^3,15

Long-term complications can include residual facial weakness, facial synkinesis, facial contracture, and facial spasm.^14,28 Incomplete eye closure may benefit from surgery (tarsorrhaphy or gold-weight implantation) to prevent corneal ulceration. Facial synkinesis is due to aberrant nerve regeneration and occurs in 15% to 20% of patients after recovery from Bell palsy.²⁹ Patients may describe tearing while chewing (“crocodile tears”), involuntary movement of the corners of the mouth with blinking, or ipsilateral eye-closing when the jaw opens (“jaw-winking”). Facial contracture, facial synkinesis, and facial spasm can be treated with botulinum toxin injection.³⁰

A 45-year-old woman presents with shortness of breath that has been progressively worsening for 3 weeks. She has no history of medical conditions and is taking no medications. Her blood pressure is 132/68 mm Hg, pulse 90 beats per minute, respirations 14 per minute, and oxygen saturation 95% on room air by pulse oximetry.

Physical examination reveals clear lung fields and no jugular venous distention or peripheral edema. However, she has a grade 3 of 6 continuous murmur audible over the entire precordium that does not change in intensity with respiration.

1. Which of the following is the likely cause of this patient’s cardiac murmur?

• Ventricular septal defect
• Atrial septal defect
• Ruptured sinus of Valsalva aneurysm
• Aortic regurgitation
• Patent ductus arteriosus
• Pulmonic stenosis

Table 1 summarizes the characteristics of the murmurs caused by these various cardiac defects.

Ventricular septal defect causes murmurs that are characteristically holosystolic and heard best at the lower left sternal border with radiation to the right lower sternal border, which overlies the defect.

The murmur of restrictive ventricular septal defect is most often holosystolic because the pressure difference between the ventricles is generated almost instantly at the onset of systole with a left-to-right shunt continuing throughout ventricular contraction. In contrast, nonrestrictive ventricular septal defects generally do not generate a murmur, since pressure is equalized across the defect. This left-to-right shunting may lead to right ventricular volume overload, resulting in delayed closure of the pulmonary valve and a widely split S2. Irreversible pulmonary hypertension with shunt reversal may occur if the defect remains untreated.¹

Atrial septal defect. The most characteristic feature of atrial septal defect is a fixed split S2 resulting from right ventricular volume overload due to left-to-right atrial shunting of blood flow. As flow is shunted from the left to the right atrium and subsequently into the right ventricle, ejection of excess blood through the pulmonary valve produces a midsystolic flow murmur, heard best over the left upper sternal border, that may radiate to the back.

Ruptured sinus of Valsalva aneurysm. The pressure is higher in the aorta than in the right atrium throughout the cardiac cycle, and if a shunt is created between the two structures by a ruptured sinus of Valsalva aneurysm, the blood flow across this shunt throughout the cardiac cycle produces a continuous murmur. In contrast, if a sinus of Valsalva aneurysm ruptures into the right ventricle, the murmur is accentuated in diastole and attenuated in systole, and is often associated with pounding pulses and a thrill along either the left or right sternal border.¹

Aortic regurgitation causes a diastolic murmur as blood flows retrograde into the left ventricle through the incompetent aortic valve. This murmur is usually described as a blowing, decrescendo murmur heard best at the third left intercostal space.

Patent ductus arteriosus is a communication between the descending thoracic aorta and the pulmonary artery that fails to close at birth. The hallmark murmur associated with this defect is a continuous “machine-like” murmur located at the upper left sternal border, often radiating down the left side of the sternum into the back. Of note, increasing the systemic pressure by the Valsalva maneuver or handgrip exercise will increase the diastolic component of the continuous murmur associated with ruptured sinus of Valsalva aneurysm, helping to differentiate it from patent ductus arteriosus.²

Pulmonic stenosis causes a systolic murmur heard best at the second intercostal space along the left sternal border and having a crescendo-decrescendo intensity and harsh quality. As the right ventricle takes longer to eject its blood volume through the stenotic pulmonary valve, the delay in closure between the aortic and pulmonary valve is widened, resulting in a significant splitting of the S2. In addition, any maneuver that increases preload will also increase the intensity of the murmur.³

Our patient has a murmur that is continuous, is heard across the entire precordium, and has no respiratory variation. These features are most consistent with a sinus of Valsalva aneurysm that has ruptured into the right atrium.

The 2008 update of the joint American College of Cardiology and American Heart Association guidelines⁴ recommends further evaluation of diastolic or continuous murmurs with echocardiography, as these murmurs are most often signs of a pathologic condition. In addition, echocardiography is warranted to evaluate grade 3 or higher systolic murmurs and those that are holosystolic.⁴

SINUS OF VALSALVA ANEURYSM

Sinus of Valsalva aneurysm is rare, with an incidence of 0.09% to 0.15%. From 65% to 85% are in the right coronary cusp, 10% to 30% are in the noncoronary cusp, and fewer than 5% are in the left coronary cusp.⁵

This condition is most often congenital, accounting for up to 3.5% of congenital cardiac anomalies, though it can be acquired. Formation of the aneurysm is generally related to weakening of elastic fibers and muscular tissues that progresses over time.

Many cases of sinus of Valsalva aneurysm are associated with additional cardiac defects.¹ Ventricular septal defect is the most common coexisting congenital anomaly, occurring in up to 53% of patients and frequently associated with aneurysms involving the right coronary cusp and with sinus of Valsalva aneurysm.⁶ Other congenital anomalies often accompanying sinus of Valsalva aneurysm include pulmonary stenosis, atrial septal defect, bicuspid aortic valve, tetralogy of Fallot, patent ductus arteriosus, coarctation of the aorta, and subaortic stenosis. Another associated condition is aortic regurgitation, for which more than half of affected patients eventually require aortic valve replacement.²

Acquired sinus of Valsalva aneurysm can be the result of endocarditis, trauma, surgery, cardiac catheterization, or inflammatory or degenerative processes including, rarely, tertiary syphilis.³

Sinus of Valsalva aneurysm often remains asymptomatic, but symptoms may arise if the aneurysm ruptures, resulting in intracardiac shunting or aneurysm-associated compression of adjacent cardiac structures such as coronary arteries. Rupture may be spontaneous, secondary to chest trauma or excess exertion, or iatrogenic.

Imaging studies such as echocardiography, cardiac computed tomography, and cardiac magnetic resonance imaging are essential in diagnosing and managing sinus of Valsalva aneurysm and identifying coexisting cardiac anomalies.

Rupture occurs most commonly into the right ventricle, followed in frequency by the right atrium or left atrium. Once rupture occurs, median survival is 1 to 2 years if left untreated, with death often secondary to congestive heart failure or infective endocarditis.⁷

Surgery remains the preferred approach to the treatment of ruptured sinus of Valsalva aneurysm. Operative risk is reasonably low and long-term outcomes are good. The appropriate therapy for unruptured and asymptomatic sinus of Valsalva aneurysm remains less clear.

Successful transcatheter closure of ruptured sinus of Valsalva aneurysm has been described using Amplatzer devices, a procedure that avoids sternotomy and cardiopulmonary bypass. Despite advances in percutaneous techniques, open surgery with or without aortic valve replacement remains the current standard of care.⁸

BACK TO OUR PATIENT

In the case described above, the initial diagnostic study done to evaluate the patient’s dyspnea and murmur was transthoracic echocardiography, which demonstrated a relatively preserved ejection fraction with mild aortic regurgitation and an aneurysmal structure extending from the aortic root toward the right atrium.

Transesophageal echocardiography confirmed this finding (Figure 1). Cross-sectional imaging of the aortic valve (Figure 2) showed the aneurysm arising from the noncoronary cusp and communicating with the right atrium. Color flow Doppler (Figure 3) confirmed continuous flow between the aneurysmal sinus and right atrium throughout the cardiac cycle, consistent with the continuous murmur noted on physical examination.

The aneurysm was also noted on aortography (Figure 4) obtained before the patient underwent surgery to correct it. The surgery was successful, no complications occurred, and the murmur and associated dyspnea had completely resolved at subsequent follow-up.

This case highlights the importance of imaging studies such as echocardiography in diagnosing and managing sinus of Valsalva aneurysm, and also the importance of physical examination in guiding the diagnostic evaluation and differentiating this condition from other cardiac disorders.

A 45-year-old woman presents with shortness of breath that has been progressively worsening for 3 weeks. She has no history of medical conditions and is taking no medications. Her blood pressure is 132/68 mm Hg, pulse 90 beats per minute, respirations 14 per minute, and oxygen saturation 95% on room air by pulse oximetry.

Physical examination reveals clear lung fields and no jugular venous distention or peripheral edema. However, she has a grade 3 of 6 continuous murmur audible over the entire precordium that does not change in intensity with respiration.

1. Which of the following is the likely cause of this patient’s cardiac murmur?

• Ventricular septal defect
• Atrial septal defect
• Ruptured sinus of Valsalva aneurysm
• Aortic regurgitation
• Patent ductus arteriosus
• Pulmonic stenosis

Table 1 summarizes the characteristics of the murmurs caused by these various cardiac defects.

Ventricular septal defect causes murmurs that are characteristically holosystolic and heard best at the lower left sternal border with radiation to the right lower sternal border, which overlies the defect.

The murmur of restrictive ventricular septal defect is most often holosystolic because the pressure difference between the ventricles is generated almost instantly at the onset of systole with a left-to-right shunt continuing throughout ventricular contraction. In contrast, nonrestrictive ventricular septal defects generally do not generate a murmur, since pressure is equalized across the defect. This left-to-right shunting may lead to right ventricular volume overload, resulting in delayed closure of the pulmonary valve and a widely split S2. Irreversible pulmonary hypertension with shunt reversal may occur if the defect remains untreated.¹

Atrial septal defect. The most characteristic feature of atrial septal defect is a fixed split S2 resulting from right ventricular volume overload due to left-to-right atrial shunting of blood flow. As flow is shunted from the left to the right atrium and subsequently into the right ventricle, ejection of excess blood through the pulmonary valve produces a midsystolic flow murmur, heard best over the left upper sternal border, that may radiate to the back.

Ruptured sinus of Valsalva aneurysm. The pressure is higher in the aorta than in the right atrium throughout the cardiac cycle, and if a shunt is created between the two structures by a ruptured sinus of Valsalva aneurysm, the blood flow across this shunt throughout the cardiac cycle produces a continuous murmur. In contrast, if a sinus of Valsalva aneurysm ruptures into the right ventricle, the murmur is accentuated in diastole and attenuated in systole, and is often associated with pounding pulses and a thrill along either the left or right sternal border.¹

Aortic regurgitation causes a diastolic murmur as blood flows retrograde into the left ventricle through the incompetent aortic valve. This murmur is usually described as a blowing, decrescendo murmur heard best at the third left intercostal space.

Patent ductus arteriosus is a communication between the descending thoracic aorta and the pulmonary artery that fails to close at birth. The hallmark murmur associated with this defect is a continuous “machine-like” murmur located at the upper left sternal border, often radiating down the left side of the sternum into the back. Of note, increasing the systemic pressure by the Valsalva maneuver or handgrip exercise will increase the diastolic component of the continuous murmur associated with ruptured sinus of Valsalva aneurysm, helping to differentiate it from patent ductus arteriosus.²

Pulmonic stenosis causes a systolic murmur heard best at the second intercostal space along the left sternal border and having a crescendo-decrescendo intensity and harsh quality. As the right ventricle takes longer to eject its blood volume through the stenotic pulmonary valve, the delay in closure between the aortic and pulmonary valve is widened, resulting in a significant splitting of the S2. In addition, any maneuver that increases preload will also increase the intensity of the murmur.³

Our patient has a murmur that is continuous, is heard across the entire precordium, and has no respiratory variation. These features are most consistent with a sinus of Valsalva aneurysm that has ruptured into the right atrium.

The 2008 update of the joint American College of Cardiology and American Heart Association guidelines⁴ recommends further evaluation of diastolic or continuous murmurs with echocardiography, as these murmurs are most often signs of a pathologic condition. In addition, echocardiography is warranted to evaluate grade 3 or higher systolic murmurs and those that are holosystolic.⁴

SINUS OF VALSALVA ANEURYSM

Sinus of Valsalva aneurysm is rare, with an incidence of 0.09% to 0.15%. From 65% to 85% are in the right coronary cusp, 10% to 30% are in the noncoronary cusp, and fewer than 5% are in the left coronary cusp.⁵

This condition is most often congenital, accounting for up to 3.5% of congenital cardiac anomalies, though it can be acquired. Formation of the aneurysm is generally related to weakening of elastic fibers and muscular tissues that progresses over time.

Many cases of sinus of Valsalva aneurysm are associated with additional cardiac defects.¹ Ventricular septal defect is the most common coexisting congenital anomaly, occurring in up to 53% of patients and frequently associated with aneurysms involving the right coronary cusp and with sinus of Valsalva aneurysm.⁶ Other congenital anomalies often accompanying sinus of Valsalva aneurysm include pulmonary stenosis, atrial septal defect, bicuspid aortic valve, tetralogy of Fallot, patent ductus arteriosus, coarctation of the aorta, and subaortic stenosis. Another associated condition is aortic regurgitation, for which more than half of affected patients eventually require aortic valve replacement.²

Acquired sinus of Valsalva aneurysm can be the result of endocarditis, trauma, surgery, cardiac catheterization, or inflammatory or degenerative processes including, rarely, tertiary syphilis.³

Sinus of Valsalva aneurysm often remains asymptomatic, but symptoms may arise if the aneurysm ruptures, resulting in intracardiac shunting or aneurysm-associated compression of adjacent cardiac structures such as coronary arteries. Rupture may be spontaneous, secondary to chest trauma or excess exertion, or iatrogenic.

Imaging studies such as echocardiography, cardiac computed tomography, and cardiac magnetic resonance imaging are essential in diagnosing and managing sinus of Valsalva aneurysm and identifying coexisting cardiac anomalies.

Rupture occurs most commonly into the right ventricle, followed in frequency by the right atrium or left atrium. Once rupture occurs, median survival is 1 to 2 years if left untreated, with death often secondary to congestive heart failure or infective endocarditis.⁷

Surgery remains the preferred approach to the treatment of ruptured sinus of Valsalva aneurysm. Operative risk is reasonably low and long-term outcomes are good. The appropriate therapy for unruptured and asymptomatic sinus of Valsalva aneurysm remains less clear.

Successful transcatheter closure of ruptured sinus of Valsalva aneurysm has been described using Amplatzer devices, a procedure that avoids sternotomy and cardiopulmonary bypass. Despite advances in percutaneous techniques, open surgery with or without aortic valve replacement remains the current standard of care.⁸

BACK TO OUR PATIENT

In the case described above, the initial diagnostic study done to evaluate the patient’s dyspnea and murmur was transthoracic echocardiography, which demonstrated a relatively preserved ejection fraction with mild aortic regurgitation and an aneurysmal structure extending from the aortic root toward the right atrium.

Transesophageal echocardiography confirmed this finding (Figure 1). Cross-sectional imaging of the aortic valve (Figure 2) showed the aneurysm arising from the noncoronary cusp and communicating with the right atrium. Color flow Doppler (Figure 3) confirmed continuous flow between the aneurysmal sinus and right atrium throughout the cardiac cycle, consistent with the continuous murmur noted on physical examination.

The aneurysm was also noted on aortography (Figure 4) obtained before the patient underwent surgery to correct it. The surgery was successful, no complications occurred, and the murmur and associated dyspnea had completely resolved at subsequent follow-up.

This case highlights the importance of imaging studies such as echocardiography in diagnosing and managing sinus of Valsalva aneurysm, and also the importance of physical examination in guiding the diagnostic evaluation and differentiating this condition from other cardiac disorders.

A 45-year-old woman presents with shortness of breath that has been progressively worsening for 3 weeks. She has no history of medical conditions and is taking no medications. Her blood pressure is 132/68 mm Hg, pulse 90 beats per minute, respirations 14 per minute, and oxygen saturation 95% on room air by pulse oximetry.

Physical examination reveals clear lung fields and no jugular venous distention or peripheral edema. However, she has a grade 3 of 6 continuous murmur audible over the entire precordium that does not change in intensity with respiration.

1. Which of the following is the likely cause of this patient’s cardiac murmur?

• Ventricular septal defect
• Atrial septal defect
• Ruptured sinus of Valsalva aneurysm
• Aortic regurgitation
• Patent ductus arteriosus
• Pulmonic stenosis

Table 1 summarizes the characteristics of the murmurs caused by these various cardiac defects.

Ventricular septal defect causes murmurs that are characteristically holosystolic and heard best at the lower left sternal border with radiation to the right lower sternal border, which overlies the defect.

The murmur of restrictive ventricular septal defect is most often holosystolic because the pressure difference between the ventricles is generated almost instantly at the onset of systole with a left-to-right shunt continuing throughout ventricular contraction. In contrast, nonrestrictive ventricular septal defects generally do not generate a murmur, since pressure is equalized across the defect. This left-to-right shunting may lead to right ventricular volume overload, resulting in delayed closure of the pulmonary valve and a widely split S2. Irreversible pulmonary hypertension with shunt reversal may occur if the defect remains untreated.¹

Atrial septal defect. The most characteristic feature of atrial septal defect is a fixed split S2 resulting from right ventricular volume overload due to left-to-right atrial shunting of blood flow. As flow is shunted from the left to the right atrium and subsequently into the right ventricle, ejection of excess blood through the pulmonary valve produces a midsystolic flow murmur, heard best over the left upper sternal border, that may radiate to the back.

Ruptured sinus of Valsalva aneurysm. The pressure is higher in the aorta than in the right atrium throughout the cardiac cycle, and if a shunt is created between the two structures by a ruptured sinus of Valsalva aneurysm, the blood flow across this shunt throughout the cardiac cycle produces a continuous murmur. In contrast, if a sinus of Valsalva aneurysm ruptures into the right ventricle, the murmur is accentuated in diastole and attenuated in systole, and is often associated with pounding pulses and a thrill along either the left or right sternal border.¹

Aortic regurgitation causes a diastolic murmur as blood flows retrograde into the left ventricle through the incompetent aortic valve. This murmur is usually described as a blowing, decrescendo murmur heard best at the third left intercostal space.

Patent ductus arteriosus is a communication between the descending thoracic aorta and the pulmonary artery that fails to close at birth. The hallmark murmur associated with this defect is a continuous “machine-like” murmur located at the upper left sternal border, often radiating down the left side of the sternum into the back. Of note, increasing the systemic pressure by the Valsalva maneuver or handgrip exercise will increase the diastolic component of the continuous murmur associated with ruptured sinus of Valsalva aneurysm, helping to differentiate it from patent ductus arteriosus.²

Pulmonic stenosis causes a systolic murmur heard best at the second intercostal space along the left sternal border and having a crescendo-decrescendo intensity and harsh quality. As the right ventricle takes longer to eject its blood volume through the stenotic pulmonary valve, the delay in closure between the aortic and pulmonary valve is widened, resulting in a significant splitting of the S2. In addition, any maneuver that increases preload will also increase the intensity of the murmur.³

Our patient has a murmur that is continuous, is heard across the entire precordium, and has no respiratory variation. These features are most consistent with a sinus of Valsalva aneurysm that has ruptured into the right atrium.

The 2008 update of the joint American College of Cardiology and American Heart Association guidelines⁴ recommends further evaluation of diastolic or continuous murmurs with echocardiography, as these murmurs are most often signs of a pathologic condition. In addition, echocardiography is warranted to evaluate grade 3 or higher systolic murmurs and those that are holosystolic.⁴

SINUS OF VALSALVA ANEURYSM

Sinus of Valsalva aneurysm is rare, with an incidence of 0.09% to 0.15%. From 65% to 85% are in the right coronary cusp, 10% to 30% are in the noncoronary cusp, and fewer than 5% are in the left coronary cusp.⁵

This condition is most often congenital, accounting for up to 3.5% of congenital cardiac anomalies, though it can be acquired. Formation of the aneurysm is generally related to weakening of elastic fibers and muscular tissues that progresses over time.

Many cases of sinus of Valsalva aneurysm are associated with additional cardiac defects.¹ Ventricular septal defect is the most common coexisting congenital anomaly, occurring in up to 53% of patients and frequently associated with aneurysms involving the right coronary cusp and with sinus of Valsalva aneurysm.⁶ Other congenital anomalies often accompanying sinus of Valsalva aneurysm include pulmonary stenosis, atrial septal defect, bicuspid aortic valve, tetralogy of Fallot, patent ductus arteriosus, coarctation of the aorta, and subaortic stenosis. Another associated condition is aortic regurgitation, for which more than half of affected patients eventually require aortic valve replacement.²

Acquired sinus of Valsalva aneurysm can be the result of endocarditis, trauma, surgery, cardiac catheterization, or inflammatory or degenerative processes including, rarely, tertiary syphilis.³

Sinus of Valsalva aneurysm often remains asymptomatic, but symptoms may arise if the aneurysm ruptures, resulting in intracardiac shunting or aneurysm-associated compression of adjacent cardiac structures such as coronary arteries. Rupture may be spontaneous, secondary to chest trauma or excess exertion, or iatrogenic.

Imaging studies such as echocardiography, cardiac computed tomography, and cardiac magnetic resonance imaging are essential in diagnosing and managing sinus of Valsalva aneurysm and identifying coexisting cardiac anomalies.

Rupture occurs most commonly into the right ventricle, followed in frequency by the right atrium or left atrium. Once rupture occurs, median survival is 1 to 2 years if left untreated, with death often secondary to congestive heart failure or infective endocarditis.⁷

Surgery remains the preferred approach to the treatment of ruptured sinus of Valsalva aneurysm. Operative risk is reasonably low and long-term outcomes are good. The appropriate therapy for unruptured and asymptomatic sinus of Valsalva aneurysm remains less clear.

Successful transcatheter closure of ruptured sinus of Valsalva aneurysm has been described using Amplatzer devices, a procedure that avoids sternotomy and cardiopulmonary bypass. Despite advances in percutaneous techniques, open surgery with or without aortic valve replacement remains the current standard of care.⁸

BACK TO OUR PATIENT

In the case described above, the initial diagnostic study done to evaluate the patient’s dyspnea and murmur was transthoracic echocardiography, which demonstrated a relatively preserved ejection fraction with mild aortic regurgitation and an aneurysmal structure extending from the aortic root toward the right atrium.

Transesophageal echocardiography confirmed this finding (Figure 1). Cross-sectional imaging of the aortic valve (Figure 2) showed the aneurysm arising from the noncoronary cusp and communicating with the right atrium. Color flow Doppler (Figure 3) confirmed continuous flow between the aneurysmal sinus and right atrium throughout the cardiac cycle, consistent with the continuous murmur noted on physical examination.

The aneurysm was also noted on aortography (Figure 4) obtained before the patient underwent surgery to correct it. The surgery was successful, no complications occurred, and the murmur and associated dyspnea had completely resolved at subsequent follow-up.

This case highlights the importance of imaging studies such as echocardiography in diagnosing and managing sinus of Valsalva aneurysm, and also the importance of physical examination in guiding the diagnostic evaluation and differentiating this condition from other cardiac disorders.