About 16% of patients with unexplained chronic obstructive pulmonary disease (COPD) acute exacerbations (AE-COPD) had an accompanying pulmonary embolism (PE), usually in regions that could be targeted with anticoagulants, according to a new systematic review and meta-analysis.

About 70% of the time an AE is a response to infection, but about 30% of the time, an AE has no clear cause, the authors said in a report on their research (CHEST. 2017 March;151[3]:544-54). There is a known biological link between inflammation and coagulation, which suggests that patients experiencing AE-COPD may be at increased risk of PE.

The researchers reviewed and analyzed seven studies, comprising 880 patients. Among the authors’ reasons for conducting this research was to update the pooled prevalence of PE in AE-COPD from a previous systematic review published in CHEST in 2009.

The meta-analysis revealed that 16.1% of patients with AE-COPD were also diagnosed with PE (95% confidence interval 8.3%-25.8%). There was a wide range of variation between individual studies (prevalence 3.3%-29.1%). In six studies that reported on deep vein thrombosis, the pooled prevalence of DVT was 10.5% (95% CI 4.3%-19.0%).

Five of the studies identified the PE location. An analysis of those studies showed that 35.0% were in the main pulmonary artery, and 31.7% were in the lobar and inter-lobar arteries. Such findings “[suggest] that the majority of these embolisms have important clinical consequences,” the authors wrote.

The researchers also looked at clinical markers that accompanied AE-COPD and found a potential signal with respect to pleuritic chest pain. One study found a strong association between pleuritic chest pain and AE-COPD patients with PE (81.0% versus 40.0% in those without PE). A second study showed a similar association (24.0% in PE versus 11.5% in non-PE patients), and a third study found no significant difference.

The presence of PE was also linked to hypotension, syncope, and acute right failure on ultrasonography, suggesting that PE may be associated with heart failure.

Patients with PE were less likely to have symptoms consistent with a respiratory tract infection. They also tended to have higher mortality rates and longer hospitalization rates compared with those without PE.

The meta-analysis had some limitations, including the heterogeneity of findings in the included studies, as well as the potential for publication bias, since reports showing unusually low or high rates may be more likely to be published, the researchers noted. There was also a high proportion of male subjects in the included studies.

Overall, the researchers concluded that PE is more likely in patients with pleuritic chest pain and signs of heart failure, and less likely in patients with signs of a respiratory infection. That information “might add to the clinical decision-making in patients with an AE-COPD, because it would be undesirable to perform [computed tomography pulmonary angiography] in every patient with an AE-COPD,” the researchers wrote.

About 16% of patients with unexplained chronic obstructive pulmonary disease (COPD) acute exacerbations (AE-COPD) had an accompanying pulmonary embolism (PE), usually in regions that could be targeted with anticoagulants, according to a new systematic review and meta-analysis.

About 70% of the time an AE is a response to infection, but about 30% of the time, an AE has no clear cause, the authors said in a report on their research (CHEST. 2017 March;151[3]:544-54). There is a known biological link between inflammation and coagulation, which suggests that patients experiencing AE-COPD may be at increased risk of PE.

The researchers reviewed and analyzed seven studies, comprising 880 patients. Among the authors’ reasons for conducting this research was to update the pooled prevalence of PE in AE-COPD from a previous systematic review published in CHEST in 2009.

The meta-analysis revealed that 16.1% of patients with AE-COPD were also diagnosed with PE (95% confidence interval 8.3%-25.8%). There was a wide range of variation between individual studies (prevalence 3.3%-29.1%). In six studies that reported on deep vein thrombosis, the pooled prevalence of DVT was 10.5% (95% CI 4.3%-19.0%).

Five of the studies identified the PE location. An analysis of those studies showed that 35.0% were in the main pulmonary artery, and 31.7% were in the lobar and inter-lobar arteries. Such findings “[suggest] that the majority of these embolisms have important clinical consequences,” the authors wrote.

The researchers also looked at clinical markers that accompanied AE-COPD and found a potential signal with respect to pleuritic chest pain. One study found a strong association between pleuritic chest pain and AE-COPD patients with PE (81.0% versus 40.0% in those without PE). A second study showed a similar association (24.0% in PE versus 11.5% in non-PE patients), and a third study found no significant difference.

The presence of PE was also linked to hypotension, syncope, and acute right failure on ultrasonography, suggesting that PE may be associated with heart failure.

Patients with PE were less likely to have symptoms consistent with a respiratory tract infection. They also tended to have higher mortality rates and longer hospitalization rates compared with those without PE.

The meta-analysis had some limitations, including the heterogeneity of findings in the included studies, as well as the potential for publication bias, since reports showing unusually low or high rates may be more likely to be published, the researchers noted. There was also a high proportion of male subjects in the included studies.

Overall, the researchers concluded that PE is more likely in patients with pleuritic chest pain and signs of heart failure, and less likely in patients with signs of a respiratory infection. That information “might add to the clinical decision-making in patients with an AE-COPD, because it would be undesirable to perform [computed tomography pulmonary angiography] in every patient with an AE-COPD,” the researchers wrote.

About 16% of patients with unexplained chronic obstructive pulmonary disease (COPD) acute exacerbations (AE-COPD) had an accompanying pulmonary embolism (PE), usually in regions that could be targeted with anticoagulants, according to a new systematic review and meta-analysis.

About 70% of the time an AE is a response to infection, but about 30% of the time, an AE has no clear cause, the authors said in a report on their research (CHEST. 2017 March;151[3]:544-54). There is a known biological link between inflammation and coagulation, which suggests that patients experiencing AE-COPD may be at increased risk of PE.

The researchers reviewed and analyzed seven studies, comprising 880 patients. Among the authors’ reasons for conducting this research was to update the pooled prevalence of PE in AE-COPD from a previous systematic review published in CHEST in 2009.

The meta-analysis revealed that 16.1% of patients with AE-COPD were also diagnosed with PE (95% confidence interval 8.3%-25.8%). There was a wide range of variation between individual studies (prevalence 3.3%-29.1%). In six studies that reported on deep vein thrombosis, the pooled prevalence of DVT was 10.5% (95% CI 4.3%-19.0%).

Five of the studies identified the PE location. An analysis of those studies showed that 35.0% were in the main pulmonary artery, and 31.7% were in the lobar and inter-lobar arteries. Such findings “[suggest] that the majority of these embolisms have important clinical consequences,” the authors wrote.

The researchers also looked at clinical markers that accompanied AE-COPD and found a potential signal with respect to pleuritic chest pain. One study found a strong association between pleuritic chest pain and AE-COPD patients with PE (81.0% versus 40.0% in those without PE). A second study showed a similar association (24.0% in PE versus 11.5% in non-PE patients), and a third study found no significant difference.

The presence of PE was also linked to hypotension, syncope, and acute right failure on ultrasonography, suggesting that PE may be associated with heart failure.

Patients with PE were less likely to have symptoms consistent with a respiratory tract infection. They also tended to have higher mortality rates and longer hospitalization rates compared with those without PE.

The meta-analysis had some limitations, including the heterogeneity of findings in the included studies, as well as the potential for publication bias, since reports showing unusually low or high rates may be more likely to be published, the researchers noted. There was also a high proportion of male subjects in the included studies.

Overall, the researchers concluded that PE is more likely in patients with pleuritic chest pain and signs of heart failure, and less likely in patients with signs of a respiratory infection. That information “might add to the clinical decision-making in patients with an AE-COPD, because it would be undesirable to perform [computed tomography pulmonary angiography] in every patient with an AE-COPD,” the researchers wrote.

OJAI, CA—Spontaneous CSF leaks are treatable, often misdiagnosed, and can cause a neurologic syndrome that may include headache, nausea, and tinnitus. Spinal fluid leaks also can lead to serious complications, including seizures. Patients may have a CSF leak for years or decades before it is diagnosed.

Although CSF leaks may not be readily apparent on imaging, a suspected CSF leak is important to consider because it is fixable, said Dr. Carroll, Assistant Professor of Anesthesiology and Perioperative and Pain Medicine at Stanford University Medical Center in California and a member of the Stanford CSF leak program.

Postdural Puncture Headache Versus Spontaneous CSF Leaks

A spontaneous CSF leak and the clinical syndrome that it causes may be confused with a postdural puncture headache.

With a postdural puncture headache, a patient usually has a single leak site in the dorsal dura. “There is up to a 90% response to a single epidural blood patch. Its natural history is generally well understood and benign. It is rarely mysterious, and it is ultimately fixable,” said Dr. Carroll. In contrast, “a spontaneous CSF leak is often mysterious in terms of the onset, cause, and diagnosis.”

The natural history of CSF leaks is poorly understood. The percentage of patients whose spontaneous leaks seal on their own or whose leaks cause a catastrophe (eg, coma, seizures, or hematomas) is not known. Between 30% and 40% of patients with spontaneous leaks have leaks from multiple sites at diagnosis. “With a spontaneous leak a dural rent is more likely in the ventral dura, anterior to the spinal cord or at the nerve root, making the dura less amenable to patching. A single patch at the correct spinal level will fix the problem only 30% of the time. With multiple patches, the success rate can approach 65% to 75%.” If the first epidural blood patch fails, it should be repeated. Directed epidural blood patches, placement of fibrin sealant, and surgical treatment are other treatment options.

Headaches

Most patients with post-puncture CSF leaks have classic orthostatic headaches. The orthostatic headaches from spontaneous leaks are often atypical, however, in that patients may not feel better immediately when they lie down and worse when they stand, Dr. Carroll said. Headaches may occur late in the day after prolonged upright time or with exertion. In addition, patients may “go from having an orthostatic headache to having a terrible headache all the time, regardless of what position they are in.”

Nausea and Vomiting

Nausea and vomiting can be the main symptom of a CSF leak. Dr. Carroll described a patient with complex regional pain syndrome who underwent a spinal cord stimulation trial. Afterward, she had a postdural puncture headache and received an epidural blood patch. “After that, she developed vomiting up to nine times a day.” A CSF leak was not visible on the first CT myelogram but was apparent on the second. The leak was “so small it was missed by the slice thickness” of the first CT myelogram, said Dr. Carroll. She ultimately required surgery to fix the leak. The patient improved, although she continued vomiting three times per day.

Tinnitus

CSF leaks may cause tinnitus. “You can get ringing in the ears when you have migraine,” Dr. Carroll said. But if patients have tinnitus when they are not having headaches, “you should be thinking that there is something else going on.” Data suggest that CSF fluid is connected to inner ear fluid so a change of pressure in CSF changes inner ear pressure, and patients with high or low CSF pressure may get tinnitus.

Other symptoms may include neck pain and fatigue. “I have had the parents of patients tell me that the most remarkable thing that they see when we patch their sons or daughters is how they are bouncing around the house,” he said. Many patients complain of difficulty with concentrating, task persistence, and other nondescript, nonfocal neurologic symptoms.

Imaging Limitations

Imaging of patients with CSF leaks often initially is read as normal, and MRI is not an adequate evaluation in the high clinical suspicion of a leak, Dr. Carroll said. “It is a good place to start, because if you see a leak on your MRI, maybe you do not have to get a CT myelogram,” he said. “But if you have a clinical suspicion of a leak … you should pursue that in the face of your radiologist telling you that there is nothing.”

Schievink et al in 2007 looked at several years of data from an emergency department to assess how often imaging findings consistent with CSF leaks were missed. They reviewed MRIs of patients with headache to look for evidence of intracranial hypotension, and then compared the number of CSF leaks with the number of subarachnoid hemorrhages seen during the same time. They found that for every subarachnoid hemorrhage, there were approximately 0.5 CSF leaks (23 subarachnoid hemorrhages and 11 CSF leaks). The results suggested that spontaneous intracranial hypotension is more common than previously thought and its diagnosis in emergency departments is problematic. The 11 people with MRI evidence of intracranial hypotension subsequently were diagnosed with CSF leaks and treated.  None were diagnosed at the time of the MRI while in the emergency department.

Causes of Leaks

The four main causes of CSF leaks are medical procedures; whiplash; bony, sharp calcifications penetrating the dura; and genetic disorders of connective tissue.

Webb et al conducted a study to evaluate headaches in patients who had a known wet tap (ie, unintentional dural puncture) after a labor epidural. The researchers reviewed quality assurance data in an obstetrics anesthesia division and identified 40 patients who had known wet taps and 40 controls who had received an epidural without a wet tap during the same week and were matched for age and weight. Investigators contacted patients between 12 and 24 months later (mean, 18 months) and asked them about the incidence of chronic headache. The incidence of chronic headache in controls was 5% versus nearly 30% in patients who had had a wet tap. The investigators then compared patients who were managed conservatively (ie, they did not receive an epidural blood patch) versus patients who were managed with a blood patch. “If you got a blood patch, your risk of having a chronic headache 18 months later was only half as much as if you did not get a blood patch,” he said.

Connective Tissue Disorders and Calcifications

Because connective tissue disorders are associated with CSF leaks, headache physicians should determine patients’ Beighton Hypermobility Scores, Dr. Carroll said. The score is derived from a simple test that assesses joint hypermobility. For instance, patients receive a point if they can touch their thumb to their wrist or straighten their elbow more than 10° beyond 180°. A score between 3 and 5 raises suspicion that the patient might have a hereditary disorder of connective tissue. Cataracts at an early age, being unusually tall or short, degenerative disc disease, and history of aneurysm also are associated with an increased risk of CSF leaks.

With regard to calcifications, Dr. Carroll described a patient whose main complaint was confusion upon standing too long. The patient also had neck pain. They determined that he had a calcified bone spur that was puncturing the spinal cord, causing a leak.

Whiplash

Trauma and whiplash can cause leaks. Researchers in Japan studied 66 patients with chronic whiplash-associated disorders (ie, they had a whiplash accident and complained of neck and head pain, as well as difficulty with fatigue or memory). The patients were given a radionuclide cisternogram. Thirty-seven of the 66 patients had imaging that was positive for a CSF leak. “After being patched, roughly half the people who were found to have a leak went back to work, whereas they had not been working before,” he said. Another study found that 10% of people with brachial plexus injuries have spinal fluid leaks.

Overlap With POTS

The fact that Ehlers-Danlos also is associated with postural orthostatic tachycardia syndrome (POTS) raises the possibility that patients with CSF leaks may be misdiagnosed as having POTS.

“Why should a hereditary disorder of connective tissue be associated with the only two known conditions that are associated with feeling worse when you are up?” Dr. Carroll asked. Among patients with POTS, 60% have headaches, and many have dizziness and nausea. Dr. Carroll asked the POTS clinics at Stanford to refer patients with POTS, headache, and Ehlers-Danlos syndrome to him. The first referred patient’s history was consistent with a CSF leak. She had been passing out and had severe headaches for more than 10 years. Although her initial imaging was read as negative for CSF leaks, and an MRI showed no signs of intracranial hypotension, “when we patched her, in fact, she got better.” Subsequently, more patients diagnosed with POTS have been referred to the CSF leak program.

Patients initially may be diagnosed as having chronic fatigue syndrome, fibromyalgia, or irritable bowel syndrome when a CSF leak is causing their symptoms. It is a tragedy when patients “have a fixable leak and … nothing is done to treat that underlying problem,” Dr. Carroll said.

—Jake Remaly

Suggested Reading

Ishikawa S, Yokoyama M, Mizobuchi S, et al. Epidural blood patch therapy for chronic whiplash-associated disorder. Anesth Analg. 2007;105(3):809-814.

Schievink WI. Spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension. JAMA. 2006;295(19):2286-2296.

Schievink WI, Maya MM, Moser F, et al. Frequency of spontaneous intracranial hypotension in the emergency department. J Headache Pain. 2007;8(6):325-328.

Webb CA, Weyker PD, Zhang L, et al. Unintentional dural puncture with a Tuohy needle increases risk of chronic headache. Anesth Analg. 2012;115(1):124-132.

OJAI, CA—Spontaneous CSF leaks are treatable, often misdiagnosed, and can cause a neurologic syndrome that may include headache, nausea, and tinnitus. Spinal fluid leaks also can lead to serious complications, including seizures. Patients may have a CSF leak for years or decades before it is diagnosed.

Although CSF leaks may not be readily apparent on imaging, a suspected CSF leak is important to consider because it is fixable, said Dr. Carroll, Assistant Professor of Anesthesiology and Perioperative and Pain Medicine at Stanford University Medical Center in California and a member of the Stanford CSF leak program.

Postdural Puncture Headache Versus Spontaneous CSF Leaks

A spontaneous CSF leak and the clinical syndrome that it causes may be confused with a postdural puncture headache.

With a postdural puncture headache, a patient usually has a single leak site in the dorsal dura. “There is up to a 90% response to a single epidural blood patch. Its natural history is generally well understood and benign. It is rarely mysterious, and it is ultimately fixable,” said Dr. Carroll. In contrast, “a spontaneous CSF leak is often mysterious in terms of the onset, cause, and diagnosis.”

The natural history of CSF leaks is poorly understood. The percentage of patients whose spontaneous leaks seal on their own or whose leaks cause a catastrophe (eg, coma, seizures, or hematomas) is not known. Between 30% and 40% of patients with spontaneous leaks have leaks from multiple sites at diagnosis. “With a spontaneous leak a dural rent is more likely in the ventral dura, anterior to the spinal cord or at the nerve root, making the dura less amenable to patching. A single patch at the correct spinal level will fix the problem only 30% of the time. With multiple patches, the success rate can approach 65% to 75%.” If the first epidural blood patch fails, it should be repeated. Directed epidural blood patches, placement of fibrin sealant, and surgical treatment are other treatment options.

Headaches

Most patients with post-puncture CSF leaks have classic orthostatic headaches. The orthostatic headaches from spontaneous leaks are often atypical, however, in that patients may not feel better immediately when they lie down and worse when they stand, Dr. Carroll said. Headaches may occur late in the day after prolonged upright time or with exertion. In addition, patients may “go from having an orthostatic headache to having a terrible headache all the time, regardless of what position they are in.”

Nausea and Vomiting

Nausea and vomiting can be the main symptom of a CSF leak. Dr. Carroll described a patient with complex regional pain syndrome who underwent a spinal cord stimulation trial. Afterward, she had a postdural puncture headache and received an epidural blood patch. “After that, she developed vomiting up to nine times a day.” A CSF leak was not visible on the first CT myelogram but was apparent on the second. The leak was “so small it was missed by the slice thickness” of the first CT myelogram, said Dr. Carroll. She ultimately required surgery to fix the leak. The patient improved, although she continued vomiting three times per day.

Tinnitus

CSF leaks may cause tinnitus. “You can get ringing in the ears when you have migraine,” Dr. Carroll said. But if patients have tinnitus when they are not having headaches, “you should be thinking that there is something else going on.” Data suggest that CSF fluid is connected to inner ear fluid so a change of pressure in CSF changes inner ear pressure, and patients with high or low CSF pressure may get tinnitus.

Other symptoms may include neck pain and fatigue. “I have had the parents of patients tell me that the most remarkable thing that they see when we patch their sons or daughters is how they are bouncing around the house,” he said. Many patients complain of difficulty with concentrating, task persistence, and other nondescript, nonfocal neurologic symptoms.

Imaging Limitations

Imaging of patients with CSF leaks often initially is read as normal, and MRI is not an adequate evaluation in the high clinical suspicion of a leak, Dr. Carroll said. “It is a good place to start, because if you see a leak on your MRI, maybe you do not have to get a CT myelogram,” he said. “But if you have a clinical suspicion of a leak … you should pursue that in the face of your radiologist telling you that there is nothing.”

Schievink et al in 2007 looked at several years of data from an emergency department to assess how often imaging findings consistent with CSF leaks were missed. They reviewed MRIs of patients with headache to look for evidence of intracranial hypotension, and then compared the number of CSF leaks with the number of subarachnoid hemorrhages seen during the same time. They found that for every subarachnoid hemorrhage, there were approximately 0.5 CSF leaks (23 subarachnoid hemorrhages and 11 CSF leaks). The results suggested that spontaneous intracranial hypotension is more common than previously thought and its diagnosis in emergency departments is problematic. The 11 people with MRI evidence of intracranial hypotension subsequently were diagnosed with CSF leaks and treated.  None were diagnosed at the time of the MRI while in the emergency department.

Causes of Leaks

The four main causes of CSF leaks are medical procedures; whiplash; bony, sharp calcifications penetrating the dura; and genetic disorders of connective tissue.

Webb et al conducted a study to evaluate headaches in patients who had a known wet tap (ie, unintentional dural puncture) after a labor epidural. The researchers reviewed quality assurance data in an obstetrics anesthesia division and identified 40 patients who had known wet taps and 40 controls who had received an epidural without a wet tap during the same week and were matched for age and weight. Investigators contacted patients between 12 and 24 months later (mean, 18 months) and asked them about the incidence of chronic headache. The incidence of chronic headache in controls was 5% versus nearly 30% in patients who had had a wet tap. The investigators then compared patients who were managed conservatively (ie, they did not receive an epidural blood patch) versus patients who were managed with a blood patch. “If you got a blood patch, your risk of having a chronic headache 18 months later was only half as much as if you did not get a blood patch,” he said.

Connective Tissue Disorders and Calcifications

Because connective tissue disorders are associated with CSF leaks, headache physicians should determine patients’ Beighton Hypermobility Scores, Dr. Carroll said. The score is derived from a simple test that assesses joint hypermobility. For instance, patients receive a point if they can touch their thumb to their wrist or straighten their elbow more than 10° beyond 180°. A score between 3 and 5 raises suspicion that the patient might have a hereditary disorder of connective tissue. Cataracts at an early age, being unusually tall or short, degenerative disc disease, and history of aneurysm also are associated with an increased risk of CSF leaks.

With regard to calcifications, Dr. Carroll described a patient whose main complaint was confusion upon standing too long. The patient also had neck pain. They determined that he had a calcified bone spur that was puncturing the spinal cord, causing a leak.

Whiplash

Trauma and whiplash can cause leaks. Researchers in Japan studied 66 patients with chronic whiplash-associated disorders (ie, they had a whiplash accident and complained of neck and head pain, as well as difficulty with fatigue or memory). The patients were given a radionuclide cisternogram. Thirty-seven of the 66 patients had imaging that was positive for a CSF leak. “After being patched, roughly half the people who were found to have a leak went back to work, whereas they had not been working before,” he said. Another study found that 10% of people with brachial plexus injuries have spinal fluid leaks.

Overlap With POTS

The fact that Ehlers-Danlos also is associated with postural orthostatic tachycardia syndrome (POTS) raises the possibility that patients with CSF leaks may be misdiagnosed as having POTS.

“Why should a hereditary disorder of connective tissue be associated with the only two known conditions that are associated with feeling worse when you are up?” Dr. Carroll asked. Among patients with POTS, 60% have headaches, and many have dizziness and nausea. Dr. Carroll asked the POTS clinics at Stanford to refer patients with POTS, headache, and Ehlers-Danlos syndrome to him. The first referred patient’s history was consistent with a CSF leak. She had been passing out and had severe headaches for more than 10 years. Although her initial imaging was read as negative for CSF leaks, and an MRI showed no signs of intracranial hypotension, “when we patched her, in fact, she got better.” Subsequently, more patients diagnosed with POTS have been referred to the CSF leak program.

Patients initially may be diagnosed as having chronic fatigue syndrome, fibromyalgia, or irritable bowel syndrome when a CSF leak is causing their symptoms. It is a tragedy when patients “have a fixable leak and … nothing is done to treat that underlying problem,” Dr. Carroll said.

—Jake Remaly

Suggested Reading

Ishikawa S, Yokoyama M, Mizobuchi S, et al. Epidural blood patch therapy for chronic whiplash-associated disorder. Anesth Analg. 2007;105(3):809-814.

Schievink WI. Spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension. JAMA. 2006;295(19):2286-2296.

Schievink WI, Maya MM, Moser F, et al. Frequency of spontaneous intracranial hypotension in the emergency department. J Headache Pain. 2007;8(6):325-328.

Webb CA, Weyker PD, Zhang L, et al. Unintentional dural puncture with a Tuohy needle increases risk of chronic headache. Anesth Analg. 2012;115(1):124-132.

OJAI, CA—Spontaneous CSF leaks are treatable, often misdiagnosed, and can cause a neurologic syndrome that may include headache, nausea, and tinnitus. Spinal fluid leaks also can lead to serious complications, including seizures. Patients may have a CSF leak for years or decades before it is diagnosed.

Although CSF leaks may not be readily apparent on imaging, a suspected CSF leak is important to consider because it is fixable, said Dr. Carroll, Assistant Professor of Anesthesiology and Perioperative and Pain Medicine at Stanford University Medical Center in California and a member of the Stanford CSF leak program.

Postdural Puncture Headache Versus Spontaneous CSF Leaks

A spontaneous CSF leak and the clinical syndrome that it causes may be confused with a postdural puncture headache.

With a postdural puncture headache, a patient usually has a single leak site in the dorsal dura. “There is up to a 90% response to a single epidural blood patch. Its natural history is generally well understood and benign. It is rarely mysterious, and it is ultimately fixable,” said Dr. Carroll. In contrast, “a spontaneous CSF leak is often mysterious in terms of the onset, cause, and diagnosis.”

The natural history of CSF leaks is poorly understood. The percentage of patients whose spontaneous leaks seal on their own or whose leaks cause a catastrophe (eg, coma, seizures, or hematomas) is not known. Between 30% and 40% of patients with spontaneous leaks have leaks from multiple sites at diagnosis. “With a spontaneous leak a dural rent is more likely in the ventral dura, anterior to the spinal cord or at the nerve root, making the dura less amenable to patching. A single patch at the correct spinal level will fix the problem only 30% of the time. With multiple patches, the success rate can approach 65% to 75%.” If the first epidural blood patch fails, it should be repeated. Directed epidural blood patches, placement of fibrin sealant, and surgical treatment are other treatment options.

Headaches

Most patients with post-puncture CSF leaks have classic orthostatic headaches. The orthostatic headaches from spontaneous leaks are often atypical, however, in that patients may not feel better immediately when they lie down and worse when they stand, Dr. Carroll said. Headaches may occur late in the day after prolonged upright time or with exertion. In addition, patients may “go from having an orthostatic headache to having a terrible headache all the time, regardless of what position they are in.”

Nausea and Vomiting

Nausea and vomiting can be the main symptom of a CSF leak. Dr. Carroll described a patient with complex regional pain syndrome who underwent a spinal cord stimulation trial. Afterward, she had a postdural puncture headache and received an epidural blood patch. “After that, she developed vomiting up to nine times a day.” A CSF leak was not visible on the first CT myelogram but was apparent on the second. The leak was “so small it was missed by the slice thickness” of the first CT myelogram, said Dr. Carroll. She ultimately required surgery to fix the leak. The patient improved, although she continued vomiting three times per day.

Tinnitus

CSF leaks may cause tinnitus. “You can get ringing in the ears when you have migraine,” Dr. Carroll said. But if patients have tinnitus when they are not having headaches, “you should be thinking that there is something else going on.” Data suggest that CSF fluid is connected to inner ear fluid so a change of pressure in CSF changes inner ear pressure, and patients with high or low CSF pressure may get tinnitus.

Other symptoms may include neck pain and fatigue. “I have had the parents of patients tell me that the most remarkable thing that they see when we patch their sons or daughters is how they are bouncing around the house,” he said. Many patients complain of difficulty with concentrating, task persistence, and other nondescript, nonfocal neurologic symptoms.

Imaging Limitations

Imaging of patients with CSF leaks often initially is read as normal, and MRI is not an adequate evaluation in the high clinical suspicion of a leak, Dr. Carroll said. “It is a good place to start, because if you see a leak on your MRI, maybe you do not have to get a CT myelogram,” he said. “But if you have a clinical suspicion of a leak … you should pursue that in the face of your radiologist telling you that there is nothing.”

Schievink et al in 2007 looked at several years of data from an emergency department to assess how often imaging findings consistent with CSF leaks were missed. They reviewed MRIs of patients with headache to look for evidence of intracranial hypotension, and then compared the number of CSF leaks with the number of subarachnoid hemorrhages seen during the same time. They found that for every subarachnoid hemorrhage, there were approximately 0.5 CSF leaks (23 subarachnoid hemorrhages and 11 CSF leaks). The results suggested that spontaneous intracranial hypotension is more common than previously thought and its diagnosis in emergency departments is problematic. The 11 people with MRI evidence of intracranial hypotension subsequently were diagnosed with CSF leaks and treated.  None were diagnosed at the time of the MRI while in the emergency department.

Causes of Leaks

The four main causes of CSF leaks are medical procedures; whiplash; bony, sharp calcifications penetrating the dura; and genetic disorders of connective tissue.

Webb et al conducted a study to evaluate headaches in patients who had a known wet tap (ie, unintentional dural puncture) after a labor epidural. The researchers reviewed quality assurance data in an obstetrics anesthesia division and identified 40 patients who had known wet taps and 40 controls who had received an epidural without a wet tap during the same week and were matched for age and weight. Investigators contacted patients between 12 and 24 months later (mean, 18 months) and asked them about the incidence of chronic headache. The incidence of chronic headache in controls was 5% versus nearly 30% in patients who had had a wet tap. The investigators then compared patients who were managed conservatively (ie, they did not receive an epidural blood patch) versus patients who were managed with a blood patch. “If you got a blood patch, your risk of having a chronic headache 18 months later was only half as much as if you did not get a blood patch,” he said.

Connective Tissue Disorders and Calcifications

Because connective tissue disorders are associated with CSF leaks, headache physicians should determine patients’ Beighton Hypermobility Scores, Dr. Carroll said. The score is derived from a simple test that assesses joint hypermobility. For instance, patients receive a point if they can touch their thumb to their wrist or straighten their elbow more than 10° beyond 180°. A score between 3 and 5 raises suspicion that the patient might have a hereditary disorder of connective tissue. Cataracts at an early age, being unusually tall or short, degenerative disc disease, and history of aneurysm also are associated with an increased risk of CSF leaks.

With regard to calcifications, Dr. Carroll described a patient whose main complaint was confusion upon standing too long. The patient also had neck pain. They determined that he had a calcified bone spur that was puncturing the spinal cord, causing a leak.

Whiplash

Trauma and whiplash can cause leaks. Researchers in Japan studied 66 patients with chronic whiplash-associated disorders (ie, they had a whiplash accident and complained of neck and head pain, as well as difficulty with fatigue or memory). The patients were given a radionuclide cisternogram. Thirty-seven of the 66 patients had imaging that was positive for a CSF leak. “After being patched, roughly half the people who were found to have a leak went back to work, whereas they had not been working before,” he said. Another study found that 10% of people with brachial plexus injuries have spinal fluid leaks.

Overlap With POTS

The fact that Ehlers-Danlos also is associated with postural orthostatic tachycardia syndrome (POTS) raises the possibility that patients with CSF leaks may be misdiagnosed as having POTS.

“Why should a hereditary disorder of connective tissue be associated with the only two known conditions that are associated with feeling worse when you are up?” Dr. Carroll asked. Among patients with POTS, 60% have headaches, and many have dizziness and nausea. Dr. Carroll asked the POTS clinics at Stanford to refer patients with POTS, headache, and Ehlers-Danlos syndrome to him. The first referred patient’s history was consistent with a CSF leak. She had been passing out and had severe headaches for more than 10 years. Although her initial imaging was read as negative for CSF leaks, and an MRI showed no signs of intracranial hypotension, “when we patched her, in fact, she got better.” Subsequently, more patients diagnosed with POTS have been referred to the CSF leak program.

Patients initially may be diagnosed as having chronic fatigue syndrome, fibromyalgia, or irritable bowel syndrome when a CSF leak is causing their symptoms. It is a tragedy when patients “have a fixable leak and … nothing is done to treat that underlying problem,” Dr. Carroll said.

—Jake Remaly

Suggested Reading

Ishikawa S, Yokoyama M, Mizobuchi S, et al. Epidural blood patch therapy for chronic whiplash-associated disorder. Anesth Analg. 2007;105(3):809-814.

Schievink WI. Spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension. JAMA. 2006;295(19):2286-2296.

Schievink WI, Maya MM, Moser F, et al. Frequency of spontaneous intracranial hypotension in the emergency department. J Headache Pain. 2007;8(6):325-328.

Webb CA, Weyker PD, Zhang L, et al. Unintentional dural puncture with a Tuohy needle increases risk of chronic headache. Anesth Analg. 2012;115(1):124-132.

The Diagnosis: Verrucous Hemangioma

Verrucous hemangioma (VH) is a rare vascular anomaly that has not been definitively delineated as a malformation or a tumor, as it has features of both. Verrucous hemangioma presents at birth as a compressible soft mass with a red violaceous hue favoring the legs.^1,2 Over time VH will develop a warty, friable, and keratotic surface that can begin to evolve as early as 6 months or as late as 34 years of age.³ Verrucous hemangioma does not involute and tends to grow proportionally with the patient. Thus, VH classically has been considered a vascular malformation.

On histopathology VH shows collections of uniform, thin-walled vessels with a multilamellated basement membrane throughout the dermis, similar to an infantile hemangioma (IH). These lesions extend deep into the subcutaneous tissue and often involve the underlying fascia. The papillary dermis has large ectatic vessels, while the epidermis displays verrucous hyperkeratosis, papillomatosis, and irregular acanthosis without viral change (Figure).^4,5 The superficial component can resemble an angiokeratoma; however, VH is differentiated by a deeper component that is often larger in size and has a more protracted clinical course.

Similar to IH, immunohistochemical studies have shown that VH expresses Wilms tumor 1 and glucose transporter 1 but is negative for D2-40.⁴ These findings suggest that VH is a vascular tumor rather than a vascular malformation, as was previously reported.⁶ Additional research has shown that the immunohistochemical staining profile of VH is nearly identical to IH, which has led to postulation that VH may be of placental mesodermal origin, as has been hypothesized for IH.⁵

Due to its deep infiltration and tendency for recurrence, VH is most effectively treated with wide local excision.^3,6-8 Preoperative planning with magnetic resonance imaging may be indicated. Although laser monotherapy and other local destructive therapies have been largely unsuccessful, postsurgical laser therapy with CO2 lasers as well as dual pulsed dye laser and Nd:YAG laser have shown promise in preventing recurrence.³

The Diagnosis: Verrucous Hemangioma

Verrucous hemangioma (VH) is a rare vascular anomaly that has not been definitively delineated as a malformation or a tumor, as it has features of both. Verrucous hemangioma presents at birth as a compressible soft mass with a red violaceous hue favoring the legs.^1,2 Over time VH will develop a warty, friable, and keratotic surface that can begin to evolve as early as 6 months or as late as 34 years of age.³ Verrucous hemangioma does not involute and tends to grow proportionally with the patient. Thus, VH classically has been considered a vascular malformation.

On histopathology VH shows collections of uniform, thin-walled vessels with a multilamellated basement membrane throughout the dermis, similar to an infantile hemangioma (IH). These lesions extend deep into the subcutaneous tissue and often involve the underlying fascia. The papillary dermis has large ectatic vessels, while the epidermis displays verrucous hyperkeratosis, papillomatosis, and irregular acanthosis without viral change (Figure).^4,5 The superficial component can resemble an angiokeratoma; however, VH is differentiated by a deeper component that is often larger in size and has a more protracted clinical course.

Similar to IH, immunohistochemical studies have shown that VH expresses Wilms tumor 1 and glucose transporter 1 but is negative for D2-40.⁴ These findings suggest that VH is a vascular tumor rather than a vascular malformation, as was previously reported.⁶ Additional research has shown that the immunohistochemical staining profile of VH is nearly identical to IH, which has led to postulation that VH may be of placental mesodermal origin, as has been hypothesized for IH.⁵

Due to its deep infiltration and tendency for recurrence, VH is most effectively treated with wide local excision.^3,6-8 Preoperative planning with magnetic resonance imaging may be indicated. Although laser monotherapy and other local destructive therapies have been largely unsuccessful, postsurgical laser therapy with CO2 lasers as well as dual pulsed dye laser and Nd:YAG laser have shown promise in preventing recurrence.³

The Diagnosis: Verrucous Hemangioma

Verrucous hemangioma (VH) is a rare vascular anomaly that has not been definitively delineated as a malformation or a tumor, as it has features of both. Verrucous hemangioma presents at birth as a compressible soft mass with a red violaceous hue favoring the legs.^1,2 Over time VH will develop a warty, friable, and keratotic surface that can begin to evolve as early as 6 months or as late as 34 years of age.³ Verrucous hemangioma does not involute and tends to grow proportionally with the patient. Thus, VH classically has been considered a vascular malformation.

On histopathology VH shows collections of uniform, thin-walled vessels with a multilamellated basement membrane throughout the dermis, similar to an infantile hemangioma (IH). These lesions extend deep into the subcutaneous tissue and often involve the underlying fascia. The papillary dermis has large ectatic vessels, while the epidermis displays verrucous hyperkeratosis, papillomatosis, and irregular acanthosis without viral change (Figure).^4,5 The superficial component can resemble an angiokeratoma; however, VH is differentiated by a deeper component that is often larger in size and has a more protracted clinical course.

Similar to IH, immunohistochemical studies have shown that VH expresses Wilms tumor 1 and glucose transporter 1 but is negative for D2-40.⁴ These findings suggest that VH is a vascular tumor rather than a vascular malformation, as was previously reported.⁶ Additional research has shown that the immunohistochemical staining profile of VH is nearly identical to IH, which has led to postulation that VH may be of placental mesodermal origin, as has been hypothesized for IH.⁵

Due to its deep infiltration and tendency for recurrence, VH is most effectively treated with wide local excision.^3,6-8 Preoperative planning with magnetic resonance imaging may be indicated. Although laser monotherapy and other local destructive therapies have been largely unsuccessful, postsurgical laser therapy with CO2 lasers as well as dual pulsed dye laser and Nd:YAG laser have shown promise in preventing recurrence.³

From Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.

Abstracts

• Objective: To identify patient factors associated with willingness to take daily weight loss medication and weight loss expectations using these medications.
• Methods: A random sample of 331 primary care patients aged 18–65 years with a BMI ≥ 35 kg/m² were recruited from 4 diverse primary care practices in Boston, MA. We conducted telephone interviews and chart reviews to assess patients’ willingness to take a weight loss medication and their expectations for weight loss. We used sequential logistic regression models to identify demographic, clinical, and quality of life (QOL) factors associated with this willingness.
• Results: Of 331 subjects, 69% were women, 35% were white, 35% were black, and 25% were Hispanic; 249 (75%) of patients were willing to take a daily weight loss medication if recommended by their doctor but required a median weight loss of 15% to 24%; only 17% of patients were willing to take a medication for ≤ 10% weight loss. Men were significantly more willing than women (1.2 [95% CI 1.0–1.4]). Diabetes was the only comorbidity associated with willingness to consider pharmacotherapy (1.2 [1.0–1.3]) but only modestly improved model performance (C-statistic increased from 0.59 to 0.60). In contrast, lower QOL, especially low self-esteem and sex life, were stronger correlates (C-statistic 0.72).
• Conclusion: A majority of obese primary care patients were willing to take a daily weight loss pill; however, most required more than 10% weight loss to consider pharmacotherapy worthwhile. Poor QOL, especially low self-esteem and poor sex life, were stronger correlates than having diabetes.

Key words: obesity; primary care; weight loss medication.

In the United States, obesity continues to be unrelentingly prevalent, affecting more than one-third of adults (34.9%) [1]. This statistic has ominous implications when considering that obesity is a risk factor for numerous chronic diseases, such as coronary heart disease, diabetes, sleep apnea, osteoarthritis, and some types of cancers [2]. Moreover, it is associated with increased risk of all-cause and cardiovascular disease mortality. Promisingly, an initial 5% to 10% weight loss over 6 months has been associated with improvement in LDL, HDL, triglycerides, glucose, hemoglobin A1C, diabetes risk, blood pressure, and medication use [2]. Therefore, although patients may not be able to achieve their ideal body weight or normal BMI, modest weight loss can still have beneficial health effects.

Weight loss medications are effective adjunctive therapies in helping patients lose up to 10% of their body weight on average when combined with diet and exercise [3–5]. There are currently 5 medications approved by the Food and Drug Administration for long-term use for weight loss: orlistat, lorcaserin, phentermine-topiramate, bupropion-naltrexone, and liraglutide. Despite their proven efficacy, there are barriers to initiating a long-term weight loss medication. Insurance reimbursement is limited for these medications, thus resulting in high out-of-pocket cost for patients that they may be unable or unwilling to pay [6]. There may also be safety concerns given that several weight loss medications, including fenfluramine, sibutramine, and rimonabant, have been withdrawn from the market because of adverse effects [7]. Thus, in deciding whether to initiate a pharmacologic weight loss regimen, patients must believe that the weight loss benefits will exceed the potential risks.

Little is known, however, about patients’ willingness to take weight loss medications or the minimum weight loss they expect to lose to make pharmacotherapy worthwhile. Only a few studies have investigated patient willingness to adopt pharmacotherapy as part of a weight loss regimen, and only one investigated obese patients in the United States [8]. In this context, we surveyed a sociodemographically diverse group of primary care patients with moderate to severe obesity to examine patient characteristics associated with willingness to pursue weight loss pharmacotherapy. We also aimed to evaluate how much weight patients expected to lose in order to make taking a daily medication worth the effort. Characterizing patients seen in primary care who are willing to adopt pharmacotherapy to lose weight may guide weight loss counseling in the primary care setting. Furthermore, determining whether patients have realistic weight loss expectations can help clinicians better counsel their patients on weight loss goals.

Methods

Study Sample

We recruited 337 subjects from 4 diverse primary care practices in Boston, Massachusetts: a large hospital-based academic practice, a community practice in a working-class suburb, a community practice in an affluent suburb, and a health center serving a predominantly socially disadvantaged population. The primary goal of the parent study was to understand the preferences of patients for weight loss treatment, especially bariatric surgery. Therefore, to be included, patients needed to have a BMI ≥ 35 kg/m² at the time of recruitment, been seen in clinic within the past year, be aged 18–65 years, and be English or Spanish speaking. By design, African-American and Hispanic patients were oversampled from an electronic list of potentially eligible patient groups so that we could examine for racial differences in treatment preferences. Study details have been previously described [9].

Data Collection and Measures

Trained interviewers conducted a 45- to 60-minute telephone interview with each participant in either English or Spanish. To assess willingness to use a daily weight loss medication, subjects were asked, “If your doctor recommended it, would you be willing to take a pill or medication every day in order to lose weight?” Those who answered affirmatively were then asked the minimum amount of weight they would have to lose to make taking a pill everyday worthwhile.

Subjects were also asked about demographic information (age, race, education, marital status) and comorbid health conditions commonly associated with obesity (diabetes mellitus, hypertension, asthma, obstructive sleep apnea, GERD, depression, anxiety, back pain, and cardiovascular problems). We assessed quality of life (QOL) using the Impact of Weight on Quality of Life-Lite (IWQOL-Lite), a 31-item instrument designed specifically to assess the impact of obesity on QOL capturing 5 domains (physical function, self-esteem, sexual life, public distress, and work). Subjects were asked to rate a series of statements beginning with “Because of my weight…” as “always true,” “usually true,” “sometimes true,” “rarely true,” or “never true.” Global and domain scores ranged from 0 to 100; higher scores reflected better QOL [10].

Data Analysis

We used descriptive statistics to characterize the proportion of subjects willing to use a daily weight loss medication and the weight loss required for patients to be willing to consider pharmacotherapy. We used a stepwise logistic model to examine demographic, QOL, and clinical factors associated with the willingness to take a weight loss medication as the outcome, with an entry criteria of P value of 0.1 and an exit criteria of 0.05. Log-Poisson distribution using the sandwich estimator was used to obtain relative risks for each significant variable. Adjusted models included age, BMI, sex, and race and any significant comorbidities. We added overall QOL score and individual QOL scores in subsequent models to examine the relative influence of overall vs. domain-specific QOL. Statistical analyses were conducted with SAS (SAS Institute, Cary, NC). We considered the change in model C-statistic when specific variables were added to the model to determine the importance of these factors in contributing to patients’ willingness to consider pharmacotherapy; larger changes in model C-statistic signifies a greater contribution.

Results

Table 2 displays sequentially adjusted models examining various demographic, clinical, and QOL factors associated with willingness to take a weight loss medication. 

Discussion

In our study, we found that a large proportion (75%) of primary care patients with at least moderate obesity were willing to take a daily weight loss medication if their doctor recommended it. After full adjustment, men, those with lower quality of life (QOL), and patients with diabetes were more likely to pursue weight loss pharmacotherapy than their counterparts. Moreover, QOL appeared more important than comorbid diagnoses in contributing to whether patients would consider taking a weight loss medication. Most patients expected to lose more than 10% of their weight to make taking a daily medication worthwhile.

Few studies have examined patients’ willingness to take a medication to lose weight. Tan et al [11] found that only about half of their surveyed outpatients were likely to take a medication to lose weight; however, approximately a quarter of the patients in that study were of normal BMI. In contrast, our study interviewed patients with at least a BMI of 35 kg/m² and the majority of these patients reported a willingness to take a weight loss medication. Nevertheless, patients appear to have unrealistic expectations of the weight loss potential of pharmacotherapy. Only a minority of patients in our study would be willing to take a weight loss medication if the weight loss was no more than 10%, a level that is more consistent with the outcomes achievable in most clinical trials of weight loss medications [12]. Prior studies have also shown that patients often have unrealistic weight loss expectations and are unable to achieve their ideal body weight using diet, exercise, or pharmacotherapy [13,14]. Doyle et al found that percentage of weight loss was the most important treatment attribute when considering weight loss pharmacotherapy when compared to cost, health improvements, side effects, diet and exercise requirements, and method of medication administration [8]. Thus it is important to educate patients on realistic goal setting and the benefits of modest weight loss when considering pharmacotherapy. The weight loss preferences expressed in our study may also influence the weight loss outcomes targets pursued in pharmaceutical development. Interestingly, after full adjustment, BMI did not correlate with willingness to take a weight loss medication. Given that all patients in our study had a BMI of ≥ 35 kg/m², this may imply that variations beyond this BMI threshold did not significantly affect a patient’s willingness to use pharmacotherapy. In contrast, weight-related QOL was an important correlate.

Men were slightly more likely than women to be willing to take a weight loss medication, which is interesting since men have been shown to be less likely to participate in behavioral weight loss programs and diets [15]. One reason may be that many weight loss programs are delivered in group settings which may deter men from participating. Whether this hypothetical willingness to undergo pharmacotherapy would translate to actual use is unclear, especially since there are barriers to pharmacotherapy including out-of-pocket costs. In a prior study in the United Kingdom, women were more likely to have reported prior weight loss medication use than men [16].

Our study did not find differences in willingness to pursue weight loss medication by race or educational attainment. This is consistent with our prior work demonstrating that racial and ethnic minorities were no less likely to consider bariatric surgery if the treatment were recommended by their doctor [9]. However, our other work did suggest that clinicians may be less likely to recommend bariatric surgery to their medically eligible minority patients as compared to their Caucasian patients. Whether this may be the case for pharmacotherapy is unclear since this was not explicitly queried in our current study [9].

Our study also found that patients with diabetes but not other comorbidities were more likely to consider weight loss medication after adjusting for QOL. This may reflect a stronger link between diabetes and obesity perceived by patients. Our result is consistent with our earlier data showing that diabetes but not other comorbid conditions was associated with a higher likelihood of considering weight loss surgery [9]. Nevertheless, having diabetes contributed only modestly to the variation in patient preferences regarding pharmacotherapy as reflected by the trivial change in model C-statistic when diabetes status was added to the model.

In contrast, lower QOL scores, especially in the domains of self-esteem and sex life, were associated with increased willingness to take a weight loss medication and appeared to be a stronger predictor than individual comorbidities. This is consistent with other studies showing that patients seeking treatment for obesity tend to have lower health-related QOL [9,17]. Our findings are also consistent with our previous research demonstrating that impairments in specific QOL domains are often more important to patients and stronger drivers of diminished well-being than measures of overall QOL [18]. Hence, given their importance to patients, clinicians need to consider QOL benefits when counseling patients about the risks and benefits of various obesity treatments.

This study is the first to our knowledge to systematically characterize demographic factors associated with the likelihood of primary care patients with obesity considering weight loss pharmacotherapy. This information may aid outpatient weight loss counseling by increasing awareness of gender and patient specific preferences. The fact that many patients with obesity appear to be interested in pursuing weight loss medication may also support public health initiatives in providing equitable access to weight loss pharmacotherapy. As our study characterizes patients who are willing to pursue weight loss medications, future studies may include retrospective analyses on actual use of weight loss medications among various demographic groups. Further investigation on specific reasons why patients choose whether or not to use weight loss medication may also be helpful.

This study has important limitations. The sample size was modest and potentially underpowered to detect small differences across different subgroups. Our sample was also limited to practices in Boston, which limits generalizability; although, by design, we oversampled racial and ethnic subjects to ensure diverse representation. Finally, our study examined patients’ hypothetical willingness to take weight loss medications rather than their actual adherence to treatment if offered.

Conclusion

In this sample of obese primary care patients, we found that the majority of patients were willing to take a daily medication to lose weight; however, patients had expectations for weight loss that far exceeded the level achievable by patients in pharmaceutical trials of these agents. Men and patients with diabetes were more likely to be willing to pursue weight loss medication; however, lower weight-related QOL, especially low self-esteem and impaired sexual function, appeared to be a stronger correlate of willingness to consider pharmacotherapy than comorbid diagnoses.

Corresponding author: Christina C. Wee, MD, MPH, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215, cwee@bidmc.harvard.edu.

Funding/support: This study was funded by the National Institute of Diabetes, Digestive and Kidney Diseases (R01 DK073302, PI Wee). Dr. Wee is also supported by an NIH midcareer mentorship award (K24DK087932). The sponsor had no role in the design or conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.

Financial disclosures: None reported.

From Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.

Abstracts

• Objective: To identify patient factors associated with willingness to take daily weight loss medication and weight loss expectations using these medications.
• Methods: A random sample of 331 primary care patients aged 18–65 years with a BMI ≥ 35 kg/m² were recruited from 4 diverse primary care practices in Boston, MA. We conducted telephone interviews and chart reviews to assess patients’ willingness to take a weight loss medication and their expectations for weight loss. We used sequential logistic regression models to identify demographic, clinical, and quality of life (QOL) factors associated with this willingness.
• Results: Of 331 subjects, 69% were women, 35% were white, 35% were black, and 25% were Hispanic; 249 (75%) of patients were willing to take a daily weight loss medication if recommended by their doctor but required a median weight loss of 15% to 24%; only 17% of patients were willing to take a medication for ≤ 10% weight loss. Men were significantly more willing than women (1.2 [95% CI 1.0–1.4]). Diabetes was the only comorbidity associated with willingness to consider pharmacotherapy (1.2 [1.0–1.3]) but only modestly improved model performance (C-statistic increased from 0.59 to 0.60). In contrast, lower QOL, especially low self-esteem and sex life, were stronger correlates (C-statistic 0.72).
• Conclusion: A majority of obese primary care patients were willing to take a daily weight loss pill; however, most required more than 10% weight loss to consider pharmacotherapy worthwhile. Poor QOL, especially low self-esteem and poor sex life, were stronger correlates than having diabetes.

Key words: obesity; primary care; weight loss medication.

In the United States, obesity continues to be unrelentingly prevalent, affecting more than one-third of adults (34.9%) [1]. This statistic has ominous implications when considering that obesity is a risk factor for numerous chronic diseases, such as coronary heart disease, diabetes, sleep apnea, osteoarthritis, and some types of cancers [2]. Moreover, it is associated with increased risk of all-cause and cardiovascular disease mortality. Promisingly, an initial 5% to 10% weight loss over 6 months has been associated with improvement in LDL, HDL, triglycerides, glucose, hemoglobin A1C, diabetes risk, blood pressure, and medication use [2]. Therefore, although patients may not be able to achieve their ideal body weight or normal BMI, modest weight loss can still have beneficial health effects.

Weight loss medications are effective adjunctive therapies in helping patients lose up to 10% of their body weight on average when combined with diet and exercise [3–5]. There are currently 5 medications approved by the Food and Drug Administration for long-term use for weight loss: orlistat, lorcaserin, phentermine-topiramate, bupropion-naltrexone, and liraglutide. Despite their proven efficacy, there are barriers to initiating a long-term weight loss medication. Insurance reimbursement is limited for these medications, thus resulting in high out-of-pocket cost for patients that they may be unable or unwilling to pay [6]. There may also be safety concerns given that several weight loss medications, including fenfluramine, sibutramine, and rimonabant, have been withdrawn from the market because of adverse effects [7]. Thus, in deciding whether to initiate a pharmacologic weight loss regimen, patients must believe that the weight loss benefits will exceed the potential risks.

Little is known, however, about patients’ willingness to take weight loss medications or the minimum weight loss they expect to lose to make pharmacotherapy worthwhile. Only a few studies have investigated patient willingness to adopt pharmacotherapy as part of a weight loss regimen, and only one investigated obese patients in the United States [8]. In this context, we surveyed a sociodemographically diverse group of primary care patients with moderate to severe obesity to examine patient characteristics associated with willingness to pursue weight loss pharmacotherapy. We also aimed to evaluate how much weight patients expected to lose in order to make taking a daily medication worth the effort. Characterizing patients seen in primary care who are willing to adopt pharmacotherapy to lose weight may guide weight loss counseling in the primary care setting. Furthermore, determining whether patients have realistic weight loss expectations can help clinicians better counsel their patients on weight loss goals.

Methods

Study Sample

We recruited 337 subjects from 4 diverse primary care practices in Boston, Massachusetts: a large hospital-based academic practice, a community practice in a working-class suburb, a community practice in an affluent suburb, and a health center serving a predominantly socially disadvantaged population. The primary goal of the parent study was to understand the preferences of patients for weight loss treatment, especially bariatric surgery. Therefore, to be included, patients needed to have a BMI ≥ 35 kg/m² at the time of recruitment, been seen in clinic within the past year, be aged 18–65 years, and be English or Spanish speaking. By design, African-American and Hispanic patients were oversampled from an electronic list of potentially eligible patient groups so that we could examine for racial differences in treatment preferences. Study details have been previously described [9].

Data Collection and Measures

Trained interviewers conducted a 45- to 60-minute telephone interview with each participant in either English or Spanish. To assess willingness to use a daily weight loss medication, subjects were asked, “If your doctor recommended it, would you be willing to take a pill or medication every day in order to lose weight?” Those who answered affirmatively were then asked the minimum amount of weight they would have to lose to make taking a pill everyday worthwhile.

Subjects were also asked about demographic information (age, race, education, marital status) and comorbid health conditions commonly associated with obesity (diabetes mellitus, hypertension, asthma, obstructive sleep apnea, GERD, depression, anxiety, back pain, and cardiovascular problems). We assessed quality of life (QOL) using the Impact of Weight on Quality of Life-Lite (IWQOL-Lite), a 31-item instrument designed specifically to assess the impact of obesity on QOL capturing 5 domains (physical function, self-esteem, sexual life, public distress, and work). Subjects were asked to rate a series of statements beginning with “Because of my weight…” as “always true,” “usually true,” “sometimes true,” “rarely true,” or “never true.” Global and domain scores ranged from 0 to 100; higher scores reflected better QOL [10].

Data Analysis

We used descriptive statistics to characterize the proportion of subjects willing to use a daily weight loss medication and the weight loss required for patients to be willing to consider pharmacotherapy. We used a stepwise logistic model to examine demographic, QOL, and clinical factors associated with the willingness to take a weight loss medication as the outcome, with an entry criteria of P value of 0.1 and an exit criteria of 0.05. Log-Poisson distribution using the sandwich estimator was used to obtain relative risks for each significant variable. Adjusted models included age, BMI, sex, and race and any significant comorbidities. We added overall QOL score and individual QOL scores in subsequent models to examine the relative influence of overall vs. domain-specific QOL. Statistical analyses were conducted with SAS (SAS Institute, Cary, NC). We considered the change in model C-statistic when specific variables were added to the model to determine the importance of these factors in contributing to patients’ willingness to consider pharmacotherapy; larger changes in model C-statistic signifies a greater contribution.

Results

Table 2 displays sequentially adjusted models examining various demographic, clinical, and QOL factors associated with willingness to take a weight loss medication. 

Discussion

In our study, we found that a large proportion (75%) of primary care patients with at least moderate obesity were willing to take a daily weight loss medication if their doctor recommended it. After full adjustment, men, those with lower quality of life (QOL), and patients with diabetes were more likely to pursue weight loss pharmacotherapy than their counterparts. Moreover, QOL appeared more important than comorbid diagnoses in contributing to whether patients would consider taking a weight loss medication. Most patients expected to lose more than 10% of their weight to make taking a daily medication worthwhile.

Few studies have examined patients’ willingness to take a medication to lose weight. Tan et al [11] found that only about half of their surveyed outpatients were likely to take a medication to lose weight; however, approximately a quarter of the patients in that study were of normal BMI. In contrast, our study interviewed patients with at least a BMI of 35 kg/m² and the majority of these patients reported a willingness to take a weight loss medication. Nevertheless, patients appear to have unrealistic expectations of the weight loss potential of pharmacotherapy. Only a minority of patients in our study would be willing to take a weight loss medication if the weight loss was no more than 10%, a level that is more consistent with the outcomes achievable in most clinical trials of weight loss medications [12]. Prior studies have also shown that patients often have unrealistic weight loss expectations and are unable to achieve their ideal body weight using diet, exercise, or pharmacotherapy [13,14]. Doyle et al found that percentage of weight loss was the most important treatment attribute when considering weight loss pharmacotherapy when compared to cost, health improvements, side effects, diet and exercise requirements, and method of medication administration [8]. Thus it is important to educate patients on realistic goal setting and the benefits of modest weight loss when considering pharmacotherapy. The weight loss preferences expressed in our study may also influence the weight loss outcomes targets pursued in pharmaceutical development. Interestingly, after full adjustment, BMI did not correlate with willingness to take a weight loss medication. Given that all patients in our study had a BMI of ≥ 35 kg/m², this may imply that variations beyond this BMI threshold did not significantly affect a patient’s willingness to use pharmacotherapy. In contrast, weight-related QOL was an important correlate.

Men were slightly more likely than women to be willing to take a weight loss medication, which is interesting since men have been shown to be less likely to participate in behavioral weight loss programs and diets [15]. One reason may be that many weight loss programs are delivered in group settings which may deter men from participating. Whether this hypothetical willingness to undergo pharmacotherapy would translate to actual use is unclear, especially since there are barriers to pharmacotherapy including out-of-pocket costs. In a prior study in the United Kingdom, women were more likely to have reported prior weight loss medication use than men [16].

Our study did not find differences in willingness to pursue weight loss medication by race or educational attainment. This is consistent with our prior work demonstrating that racial and ethnic minorities were no less likely to consider bariatric surgery if the treatment were recommended by their doctor [9]. However, our other work did suggest that clinicians may be less likely to recommend bariatric surgery to their medically eligible minority patients as compared to their Caucasian patients. Whether this may be the case for pharmacotherapy is unclear since this was not explicitly queried in our current study [9].

Our study also found that patients with diabetes but not other comorbidities were more likely to consider weight loss medication after adjusting for QOL. This may reflect a stronger link between diabetes and obesity perceived by patients. Our result is consistent with our earlier data showing that diabetes but not other comorbid conditions was associated with a higher likelihood of considering weight loss surgery [9]. Nevertheless, having diabetes contributed only modestly to the variation in patient preferences regarding pharmacotherapy as reflected by the trivial change in model C-statistic when diabetes status was added to the model.

In contrast, lower QOL scores, especially in the domains of self-esteem and sex life, were associated with increased willingness to take a weight loss medication and appeared to be a stronger predictor than individual comorbidities. This is consistent with other studies showing that patients seeking treatment for obesity tend to have lower health-related QOL [9,17]. Our findings are also consistent with our previous research demonstrating that impairments in specific QOL domains are often more important to patients and stronger drivers of diminished well-being than measures of overall QOL [18]. Hence, given their importance to patients, clinicians need to consider QOL benefits when counseling patients about the risks and benefits of various obesity treatments.

This study is the first to our knowledge to systematically characterize demographic factors associated with the likelihood of primary care patients with obesity considering weight loss pharmacotherapy. This information may aid outpatient weight loss counseling by increasing awareness of gender and patient specific preferences. The fact that many patients with obesity appear to be interested in pursuing weight loss medication may also support public health initiatives in providing equitable access to weight loss pharmacotherapy. As our study characterizes patients who are willing to pursue weight loss medications, future studies may include retrospective analyses on actual use of weight loss medications among various demographic groups. Further investigation on specific reasons why patients choose whether or not to use weight loss medication may also be helpful.

This study has important limitations. The sample size was modest and potentially underpowered to detect small differences across different subgroups. Our sample was also limited to practices in Boston, which limits generalizability; although, by design, we oversampled racial and ethnic subjects to ensure diverse representation. Finally, our study examined patients’ hypothetical willingness to take weight loss medications rather than their actual adherence to treatment if offered.

Conclusion

In this sample of obese primary care patients, we found that the majority of patients were willing to take a daily medication to lose weight; however, patients had expectations for weight loss that far exceeded the level achievable by patients in pharmaceutical trials of these agents. Men and patients with diabetes were more likely to be willing to pursue weight loss medication; however, lower weight-related QOL, especially low self-esteem and impaired sexual function, appeared to be a stronger correlate of willingness to consider pharmacotherapy than comorbid diagnoses.

Corresponding author: Christina C. Wee, MD, MPH, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215, cwee@bidmc.harvard.edu.

Funding/support: This study was funded by the National Institute of Diabetes, Digestive and Kidney Diseases (R01 DK073302, PI Wee). Dr. Wee is also supported by an NIH midcareer mentorship award (K24DK087932). The sponsor had no role in the design or conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.

Financial disclosures: None reported.

From Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.

Abstracts

• Objective: To identify patient factors associated with willingness to take daily weight loss medication and weight loss expectations using these medications.
• Methods: A random sample of 331 primary care patients aged 18–65 years with a BMI ≥ 35 kg/m² were recruited from 4 diverse primary care practices in Boston, MA. We conducted telephone interviews and chart reviews to assess patients’ willingness to take a weight loss medication and their expectations for weight loss. We used sequential logistic regression models to identify demographic, clinical, and quality of life (QOL) factors associated with this willingness.
• Results: Of 331 subjects, 69% were women, 35% were white, 35% were black, and 25% were Hispanic; 249 (75%) of patients were willing to take a daily weight loss medication if recommended by their doctor but required a median weight loss of 15% to 24%; only 17% of patients were willing to take a medication for ≤ 10% weight loss. Men were significantly more willing than women (1.2 [95% CI 1.0–1.4]). Diabetes was the only comorbidity associated with willingness to consider pharmacotherapy (1.2 [1.0–1.3]) but only modestly improved model performance (C-statistic increased from 0.59 to 0.60). In contrast, lower QOL, especially low self-esteem and sex life, were stronger correlates (C-statistic 0.72).
• Conclusion: A majority of obese primary care patients were willing to take a daily weight loss pill; however, most required more than 10% weight loss to consider pharmacotherapy worthwhile. Poor QOL, especially low self-esteem and poor sex life, were stronger correlates than having diabetes.

Key words: obesity; primary care; weight loss medication.

In the United States, obesity continues to be unrelentingly prevalent, affecting more than one-third of adults (34.9%) [1]. This statistic has ominous implications when considering that obesity is a risk factor for numerous chronic diseases, such as coronary heart disease, diabetes, sleep apnea, osteoarthritis, and some types of cancers [2]. Moreover, it is associated with increased risk of all-cause and cardiovascular disease mortality. Promisingly, an initial 5% to 10% weight loss over 6 months has been associated with improvement in LDL, HDL, triglycerides, glucose, hemoglobin A1C, diabetes risk, blood pressure, and medication use [2]. Therefore, although patients may not be able to achieve their ideal body weight or normal BMI, modest weight loss can still have beneficial health effects.

Weight loss medications are effective adjunctive therapies in helping patients lose up to 10% of their body weight on average when combined with diet and exercise [3–5]. There are currently 5 medications approved by the Food and Drug Administration for long-term use for weight loss: orlistat, lorcaserin, phentermine-topiramate, bupropion-naltrexone, and liraglutide. Despite their proven efficacy, there are barriers to initiating a long-term weight loss medication. Insurance reimbursement is limited for these medications, thus resulting in high out-of-pocket cost for patients that they may be unable or unwilling to pay [6]. There may also be safety concerns given that several weight loss medications, including fenfluramine, sibutramine, and rimonabant, have been withdrawn from the market because of adverse effects [7]. Thus, in deciding whether to initiate a pharmacologic weight loss regimen, patients must believe that the weight loss benefits will exceed the potential risks.

Little is known, however, about patients’ willingness to take weight loss medications or the minimum weight loss they expect to lose to make pharmacotherapy worthwhile. Only a few studies have investigated patient willingness to adopt pharmacotherapy as part of a weight loss regimen, and only one investigated obese patients in the United States [8]. In this context, we surveyed a sociodemographically diverse group of primary care patients with moderate to severe obesity to examine patient characteristics associated with willingness to pursue weight loss pharmacotherapy. We also aimed to evaluate how much weight patients expected to lose in order to make taking a daily medication worth the effort. Characterizing patients seen in primary care who are willing to adopt pharmacotherapy to lose weight may guide weight loss counseling in the primary care setting. Furthermore, determining whether patients have realistic weight loss expectations can help clinicians better counsel their patients on weight loss goals.

Methods

Study Sample

We recruited 337 subjects from 4 diverse primary care practices in Boston, Massachusetts: a large hospital-based academic practice, a community practice in a working-class suburb, a community practice in an affluent suburb, and a health center serving a predominantly socially disadvantaged population. The primary goal of the parent study was to understand the preferences of patients for weight loss treatment, especially bariatric surgery. Therefore, to be included, patients needed to have a BMI ≥ 35 kg/m² at the time of recruitment, been seen in clinic within the past year, be aged 18–65 years, and be English or Spanish speaking. By design, African-American and Hispanic patients were oversampled from an electronic list of potentially eligible patient groups so that we could examine for racial differences in treatment preferences. Study details have been previously described [9].

Data Collection and Measures

Trained interviewers conducted a 45- to 60-minute telephone interview with each participant in either English or Spanish. To assess willingness to use a daily weight loss medication, subjects were asked, “If your doctor recommended it, would you be willing to take a pill or medication every day in order to lose weight?” Those who answered affirmatively were then asked the minimum amount of weight they would have to lose to make taking a pill everyday worthwhile.

Subjects were also asked about demographic information (age, race, education, marital status) and comorbid health conditions commonly associated with obesity (diabetes mellitus, hypertension, asthma, obstructive sleep apnea, GERD, depression, anxiety, back pain, and cardiovascular problems). We assessed quality of life (QOL) using the Impact of Weight on Quality of Life-Lite (IWQOL-Lite), a 31-item instrument designed specifically to assess the impact of obesity on QOL capturing 5 domains (physical function, self-esteem, sexual life, public distress, and work). Subjects were asked to rate a series of statements beginning with “Because of my weight…” as “always true,” “usually true,” “sometimes true,” “rarely true,” or “never true.” Global and domain scores ranged from 0 to 100; higher scores reflected better QOL [10].

Data Analysis

We used descriptive statistics to characterize the proportion of subjects willing to use a daily weight loss medication and the weight loss required for patients to be willing to consider pharmacotherapy. We used a stepwise logistic model to examine demographic, QOL, and clinical factors associated with the willingness to take a weight loss medication as the outcome, with an entry criteria of P value of 0.1 and an exit criteria of 0.05. Log-Poisson distribution using the sandwich estimator was used to obtain relative risks for each significant variable. Adjusted models included age, BMI, sex, and race and any significant comorbidities. We added overall QOL score and individual QOL scores in subsequent models to examine the relative influence of overall vs. domain-specific QOL. Statistical analyses were conducted with SAS (SAS Institute, Cary, NC). We considered the change in model C-statistic when specific variables were added to the model to determine the importance of these factors in contributing to patients’ willingness to consider pharmacotherapy; larger changes in model C-statistic signifies a greater contribution.

Results

Table 2 displays sequentially adjusted models examining various demographic, clinical, and QOL factors associated with willingness to take a weight loss medication. 

Discussion

In our study, we found that a large proportion (75%) of primary care patients with at least moderate obesity were willing to take a daily weight loss medication if their doctor recommended it. After full adjustment, men, those with lower quality of life (QOL), and patients with diabetes were more likely to pursue weight loss pharmacotherapy than their counterparts. Moreover, QOL appeared more important than comorbid diagnoses in contributing to whether patients would consider taking a weight loss medication. Most patients expected to lose more than 10% of their weight to make taking a daily medication worthwhile.

Few studies have examined patients’ willingness to take a medication to lose weight. Tan et al [11] found that only about half of their surveyed outpatients were likely to take a medication to lose weight; however, approximately a quarter of the patients in that study were of normal BMI. In contrast, our study interviewed patients with at least a BMI of 35 kg/m² and the majority of these patients reported a willingness to take a weight loss medication. Nevertheless, patients appear to have unrealistic expectations of the weight loss potential of pharmacotherapy. Only a minority of patients in our study would be willing to take a weight loss medication if the weight loss was no more than 10%, a level that is more consistent with the outcomes achievable in most clinical trials of weight loss medications [12]. Prior studies have also shown that patients often have unrealistic weight loss expectations and are unable to achieve their ideal body weight using diet, exercise, or pharmacotherapy [13,14]. Doyle et al found that percentage of weight loss was the most important treatment attribute when considering weight loss pharmacotherapy when compared to cost, health improvements, side effects, diet and exercise requirements, and method of medication administration [8]. Thus it is important to educate patients on realistic goal setting and the benefits of modest weight loss when considering pharmacotherapy. The weight loss preferences expressed in our study may also influence the weight loss outcomes targets pursued in pharmaceutical development. Interestingly, after full adjustment, BMI did not correlate with willingness to take a weight loss medication. Given that all patients in our study had a BMI of ≥ 35 kg/m², this may imply that variations beyond this BMI threshold did not significantly affect a patient’s willingness to use pharmacotherapy. In contrast, weight-related QOL was an important correlate.

Men were slightly more likely than women to be willing to take a weight loss medication, which is interesting since men have been shown to be less likely to participate in behavioral weight loss programs and diets [15]. One reason may be that many weight loss programs are delivered in group settings which may deter men from participating. Whether this hypothetical willingness to undergo pharmacotherapy would translate to actual use is unclear, especially since there are barriers to pharmacotherapy including out-of-pocket costs. In a prior study in the United Kingdom, women were more likely to have reported prior weight loss medication use than men [16].

Our study did not find differences in willingness to pursue weight loss medication by race or educational attainment. This is consistent with our prior work demonstrating that racial and ethnic minorities were no less likely to consider bariatric surgery if the treatment were recommended by their doctor [9]. However, our other work did suggest that clinicians may be less likely to recommend bariatric surgery to their medically eligible minority patients as compared to their Caucasian patients. Whether this may be the case for pharmacotherapy is unclear since this was not explicitly queried in our current study [9].

Our study also found that patients with diabetes but not other comorbidities were more likely to consider weight loss medication after adjusting for QOL. This may reflect a stronger link between diabetes and obesity perceived by patients. Our result is consistent with our earlier data showing that diabetes but not other comorbid conditions was associated with a higher likelihood of considering weight loss surgery [9]. Nevertheless, having diabetes contributed only modestly to the variation in patient preferences regarding pharmacotherapy as reflected by the trivial change in model C-statistic when diabetes status was added to the model.

In contrast, lower QOL scores, especially in the domains of self-esteem and sex life, were associated with increased willingness to take a weight loss medication and appeared to be a stronger predictor than individual comorbidities. This is consistent with other studies showing that patients seeking treatment for obesity tend to have lower health-related QOL [9,17]. Our findings are also consistent with our previous research demonstrating that impairments in specific QOL domains are often more important to patients and stronger drivers of diminished well-being than measures of overall QOL [18]. Hence, given their importance to patients, clinicians need to consider QOL benefits when counseling patients about the risks and benefits of various obesity treatments.

This study is the first to our knowledge to systematically characterize demographic factors associated with the likelihood of primary care patients with obesity considering weight loss pharmacotherapy. This information may aid outpatient weight loss counseling by increasing awareness of gender and patient specific preferences. The fact that many patients with obesity appear to be interested in pursuing weight loss medication may also support public health initiatives in providing equitable access to weight loss pharmacotherapy. As our study characterizes patients who are willing to pursue weight loss medications, future studies may include retrospective analyses on actual use of weight loss medications among various demographic groups. Further investigation on specific reasons why patients choose whether or not to use weight loss medication may also be helpful.

This study has important limitations. The sample size was modest and potentially underpowered to detect small differences across different subgroups. Our sample was also limited to practices in Boston, which limits generalizability; although, by design, we oversampled racial and ethnic subjects to ensure diverse representation. Finally, our study examined patients’ hypothetical willingness to take weight loss medications rather than their actual adherence to treatment if offered.

Conclusion

In this sample of obese primary care patients, we found that the majority of patients were willing to take a daily medication to lose weight; however, patients had expectations for weight loss that far exceeded the level achievable by patients in pharmaceutical trials of these agents. Men and patients with diabetes were more likely to be willing to pursue weight loss medication; however, lower weight-related QOL, especially low self-esteem and impaired sexual function, appeared to be a stronger correlate of willingness to consider pharmacotherapy than comorbid diagnoses.

Corresponding author: Christina C. Wee, MD, MPH, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215, cwee@bidmc.harvard.edu.

Funding/support: This study was funded by the National Institute of Diabetes, Digestive and Kidney Diseases (R01 DK073302, PI Wee). Dr. Wee is also supported by an NIH midcareer mentorship award (K24DK087932). The sponsor had no role in the design or conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.

Financial disclosures: None reported.

VANCOUVER—Pediatric multiple sclerosis (MS) presents unique concerns, making appropriate treatment especially important, according to an overview presented at the 45th Annual Meeting of the Child Neurology Society. Currently, disease-modifying therapies with FDA approval in adult MS have not been approved for the treatment of pediatric MS. In addition, brain growth and cognition are adversely affected in pediatric MS. Furthermore, children with MS tend to become disabled at a younger age, compared with adults.

Diagnosis and Initiation of Therapy

Neurologists should be prepared to engage with children and their families to ensure the most efficacious treatment. “Whenever you are having that conversation or you are considering starting the disease-modifying therapy, you need to balance the need to treat the disease with the idea that you are going to be starting a therapy for a lifetime,” said Dr. Lotze.

Disease-modifying therapies target the inflammatory aspects of pediatric-onset MS and should be initiated in children with a confirmed diagnosis, said Dr. Lotze. Children with clinically isolated syndrome who appear to be at high risk for MS and children with positive oligoclonal bands or elevated IgG index may also need to begin a disease-modifying therapy. Distinguishing between MS, acute disseminated encephalomyelitis (ADEM), and neuromyelitis optica (NMO) poses challenges, especially in children under age 10. Certain interferons can exacerbate NMO and may be harmful in children with ADEM or multiphasic ADEM.

Setting Goals

Neurologists are encouraged to counsel patients about the purpose and side effects of treatment, as well as to establish reasonable expectations for treatment. Additionally, children and families should be aware that another attack may occur during treatment and should be informed about what to do if it does.

No therapy is 100% efficacious in pediatric or adult MS, said Dr. Lotze. Research suggests that 50% of adults have no evidence of disease activity (NEDA) at two years of the disease. After seven years, however, 7% of these adults meet NEDA criteria. As a result, minimal disease progression (defined as less than one attack per year, fewer than three new lesions on a yearly MRI, and no progression in disability) may be a more attainable goal. “We would like to see a drug in a single individual or patient that is effective in achieving NEDA. If that is not possible … you might find that ultimately what you can go for is minimal disease progression,” said Dr. Lotze. He added that there appears to be no clear difference in terms of long-term outcome between children with MS who achieve NEDA and those who achieve minimal disease progression.

First-Line Therapies and Follow-Up Appointments

First-line agents for pediatric MS are the injectable drugs known as platform therapies. The International Pediatric MS Society Group (IPMSSG) recommends that all patients start first-line therapy (ie, interferon β or glatiramer acetate) soon after diagnosis.

Positive results from phase IV observational studies suggest that interferon β and glatiramer acetate are safe and efficacious treatments in pediatric MS. When studied in populations ranging in age from 12 to 17, these therapies decreased relapse rate, stabilized disability, and reduced accrual of new lesions. However, injectable treatments are associated with flu-like symptoms and injection-site reactions. Neurologists should start pediatric patients on interferon β with 25% to 50% of full dosing and titrate to a full adult dosing over four to six weeks. When initiating glatiramer acetate, neurologists should start children with a full adult dosing, 20 mg subcutaneous daily or 40 mg subcutaneous three times per week.

Follow-up appointments should occur every three to six months to assess adherence and determine efficacy of treatment. Neurologists are advised to ask patients whether they are comfortable with taking shots. Patients with needle anxiety, a common problem in pediatric MS, may need assistance from a child psychologist or child life specialist. Asking patients how often the patient or family forgets to take the disease-modifying therapy is also necessary, said Dr. Lotze. In addition, the transition from pediatric to adult care should be addressed in follow-up discussions. Teens must understand that certain disease-modifying therapies are contraindicated for pregnant patients. They also should be aware of how alcohol and other drugs interact with treatment.

Treatment Failure

Research indicates that approximately 30% of patients with pediatric-onset MS will not respond to the first-line therapies, and numerous variables may explain why. Age and disease duration can influence treatment efficacy, as can the number of relapses and the level of disease activity before treatment initiation. Patients who are nonadherent because of side effects and who continue to struggle with needle anxiety may experience treatment failure. The IPMSSG defines treatment failure as adherence to treatment for at least six months with no reduction in relapse rate or in new MRI T2 or contrast-enhancing lesions, or with two or more relapses within a 12-month period.

Second-Line Therapies

Trials of several oral agents are currently under way. The IPMSSG, however, urges neurologists to use extreme caution when considering nonplatform therapies for pediatric patients.

Fingolimod is a second-line drug for pediatric MS that blocks the egress of lymphocytes from the lymph nodes. A small percentage of patients taking this oral agent may develop bradycardia. Monitoring is required for the first six hours of treatment to ensure that the patient has no side effects. Some adverse effects associated with the drug include: first dose bradycardia, macular edema, and herpetic infections.

Dimethyl fumarate is an Nrf2 antioxidant pathway modulator that is associated with adverse effects such as flushing and gastrointestinal upset, said Dr. Lotze. Low-dose aspirin may help with flushing, and a proton pump inhibitor can help to manage the gastrointestinal upset. This treatment requires patients to undergo monitoring for blood count and liver function, as does fingolimod.

Teriflunomide, a pyrimidine synthesis inhibitor, is a Pregnancy Category X drug because it increases the risk of birth defects. Rituximab, an anti-CD20 chimeric monoclonal antibody, is gaining popularity for treating MS. Studies suggest that ocrelizumab may be well tolerated in pediatric MS. Natlizumamb, cladribine, and alemtuzumab are typically used to treat more aggressive forms of MS.

Neurologists rarely prescribe cyclophosphamide or mitoxantrone in pediatric MS. Cyclophosphamide has no formal FDA approval for adult MS or pediatric-onset MS and is associated with increased risks of bladder cancer, secondary leukemia, and infertility. Mitoxantrone is FDA-approved for adults with aggressive relapsing-remitting MS and secondary progressive MS. It is associated with increased cancer risk, however, and is highly cardiotoxic.

“After you have initiated a second-line agent, you need to continue to monitor aspects of disease control, including relapse rate, disability, MRI changes, and other adverse events. If you continue to see breakthrough disease, then you may need to consider … changing to another agent or moving to a more aggressive therapy such as rituximab or natalizumab,” said Dr. Lotze.

—Erica Tricarico

Suggested Reading

Chitnis T, Ghezzi A, Bajer-Korneck B, et al. Pediatric multiple sclerosis: Escalation and emerging treatments. Neurology. 2016;87(9 Suppl 2):S10 3-S109.

Jancic J, Nikolic B, Ivancevic N, et al. Multiple sclerosis in pediatrics: Current concepts and treatment options. Neurol Ther. 2016:5(2):131-143.

VANCOUVER—Pediatric multiple sclerosis (MS) presents unique concerns, making appropriate treatment especially important, according to an overview presented at the 45th Annual Meeting of the Child Neurology Society. Currently, disease-modifying therapies with FDA approval in adult MS have not been approved for the treatment of pediatric MS. In addition, brain growth and cognition are adversely affected in pediatric MS. Furthermore, children with MS tend to become disabled at a younger age, compared with adults.

Diagnosis and Initiation of Therapy

Neurologists should be prepared to engage with children and their families to ensure the most efficacious treatment. “Whenever you are having that conversation or you are considering starting the disease-modifying therapy, you need to balance the need to treat the disease with the idea that you are going to be starting a therapy for a lifetime,” said Dr. Lotze.

Disease-modifying therapies target the inflammatory aspects of pediatric-onset MS and should be initiated in children with a confirmed diagnosis, said Dr. Lotze. Children with clinically isolated syndrome who appear to be at high risk for MS and children with positive oligoclonal bands or elevated IgG index may also need to begin a disease-modifying therapy. Distinguishing between MS, acute disseminated encephalomyelitis (ADEM), and neuromyelitis optica (NMO) poses challenges, especially in children under age 10. Certain interferons can exacerbate NMO and may be harmful in children with ADEM or multiphasic ADEM.

Setting Goals

Neurologists are encouraged to counsel patients about the purpose and side effects of treatment, as well as to establish reasonable expectations for treatment. Additionally, children and families should be aware that another attack may occur during treatment and should be informed about what to do if it does.

No therapy is 100% efficacious in pediatric or adult MS, said Dr. Lotze. Research suggests that 50% of adults have no evidence of disease activity (NEDA) at two years of the disease. After seven years, however, 7% of these adults meet NEDA criteria. As a result, minimal disease progression (defined as less than one attack per year, fewer than three new lesions on a yearly MRI, and no progression in disability) may be a more attainable goal. “We would like to see a drug in a single individual or patient that is effective in achieving NEDA. If that is not possible … you might find that ultimately what you can go for is minimal disease progression,” said Dr. Lotze. He added that there appears to be no clear difference in terms of long-term outcome between children with MS who achieve NEDA and those who achieve minimal disease progression.

First-Line Therapies and Follow-Up Appointments

First-line agents for pediatric MS are the injectable drugs known as platform therapies. The International Pediatric MS Society Group (IPMSSG) recommends that all patients start first-line therapy (ie, interferon β or glatiramer acetate) soon after diagnosis.

Positive results from phase IV observational studies suggest that interferon β and glatiramer acetate are safe and efficacious treatments in pediatric MS. When studied in populations ranging in age from 12 to 17, these therapies decreased relapse rate, stabilized disability, and reduced accrual of new lesions. However, injectable treatments are associated with flu-like symptoms and injection-site reactions. Neurologists should start pediatric patients on interferon β with 25% to 50% of full dosing and titrate to a full adult dosing over four to six weeks. When initiating glatiramer acetate, neurologists should start children with a full adult dosing, 20 mg subcutaneous daily or 40 mg subcutaneous three times per week.

Follow-up appointments should occur every three to six months to assess adherence and determine efficacy of treatment. Neurologists are advised to ask patients whether they are comfortable with taking shots. Patients with needle anxiety, a common problem in pediatric MS, may need assistance from a child psychologist or child life specialist. Asking patients how often the patient or family forgets to take the disease-modifying therapy is also necessary, said Dr. Lotze. In addition, the transition from pediatric to adult care should be addressed in follow-up discussions. Teens must understand that certain disease-modifying therapies are contraindicated for pregnant patients. They also should be aware of how alcohol and other drugs interact with treatment.

Treatment Failure

Research indicates that approximately 30% of patients with pediatric-onset MS will not respond to the first-line therapies, and numerous variables may explain why. Age and disease duration can influence treatment efficacy, as can the number of relapses and the level of disease activity before treatment initiation. Patients who are nonadherent because of side effects and who continue to struggle with needle anxiety may experience treatment failure. The IPMSSG defines treatment failure as adherence to treatment for at least six months with no reduction in relapse rate or in new MRI T2 or contrast-enhancing lesions, or with two or more relapses within a 12-month period.

Second-Line Therapies

Trials of several oral agents are currently under way. The IPMSSG, however, urges neurologists to use extreme caution when considering nonplatform therapies for pediatric patients.

Fingolimod is a second-line drug for pediatric MS that blocks the egress of lymphocytes from the lymph nodes. A small percentage of patients taking this oral agent may develop bradycardia. Monitoring is required for the first six hours of treatment to ensure that the patient has no side effects. Some adverse effects associated with the drug include: first dose bradycardia, macular edema, and herpetic infections.

Dimethyl fumarate is an Nrf2 antioxidant pathway modulator that is associated with adverse effects such as flushing and gastrointestinal upset, said Dr. Lotze. Low-dose aspirin may help with flushing, and a proton pump inhibitor can help to manage the gastrointestinal upset. This treatment requires patients to undergo monitoring for blood count and liver function, as does fingolimod.

Teriflunomide, a pyrimidine synthesis inhibitor, is a Pregnancy Category X drug because it increases the risk of birth defects. Rituximab, an anti-CD20 chimeric monoclonal antibody, is gaining popularity for treating MS. Studies suggest that ocrelizumab may be well tolerated in pediatric MS. Natlizumamb, cladribine, and alemtuzumab are typically used to treat more aggressive forms of MS.

Neurologists rarely prescribe cyclophosphamide or mitoxantrone in pediatric MS. Cyclophosphamide has no formal FDA approval for adult MS or pediatric-onset MS and is associated with increased risks of bladder cancer, secondary leukemia, and infertility. Mitoxantrone is FDA-approved for adults with aggressive relapsing-remitting MS and secondary progressive MS. It is associated with increased cancer risk, however, and is highly cardiotoxic.

“After you have initiated a second-line agent, you need to continue to monitor aspects of disease control, including relapse rate, disability, MRI changes, and other adverse events. If you continue to see breakthrough disease, then you may need to consider … changing to another agent or moving to a more aggressive therapy such as rituximab or natalizumab,” said Dr. Lotze.

—Erica Tricarico

Suggested Reading

Chitnis T, Ghezzi A, Bajer-Korneck B, et al. Pediatric multiple sclerosis: Escalation and emerging treatments. Neurology. 2016;87(9 Suppl 2):S10 3-S109.

Jancic J, Nikolic B, Ivancevic N, et al. Multiple sclerosis in pediatrics: Current concepts and treatment options. Neurol Ther. 2016:5(2):131-143.

VANCOUVER—Pediatric multiple sclerosis (MS) presents unique concerns, making appropriate treatment especially important, according to an overview presented at the 45th Annual Meeting of the Child Neurology Society. Currently, disease-modifying therapies with FDA approval in adult MS have not been approved for the treatment of pediatric MS. In addition, brain growth and cognition are adversely affected in pediatric MS. Furthermore, children with MS tend to become disabled at a younger age, compared with adults.

Diagnosis and Initiation of Therapy

Neurologists should be prepared to engage with children and their families to ensure the most efficacious treatment. “Whenever you are having that conversation or you are considering starting the disease-modifying therapy, you need to balance the need to treat the disease with the idea that you are going to be starting a therapy for a lifetime,” said Dr. Lotze.

Disease-modifying therapies target the inflammatory aspects of pediatric-onset MS and should be initiated in children with a confirmed diagnosis, said Dr. Lotze. Children with clinically isolated syndrome who appear to be at high risk for MS and children with positive oligoclonal bands or elevated IgG index may also need to begin a disease-modifying therapy. Distinguishing between MS, acute disseminated encephalomyelitis (ADEM), and neuromyelitis optica (NMO) poses challenges, especially in children under age 10. Certain interferons can exacerbate NMO and may be harmful in children with ADEM or multiphasic ADEM.

Setting Goals

Neurologists are encouraged to counsel patients about the purpose and side effects of treatment, as well as to establish reasonable expectations for treatment. Additionally, children and families should be aware that another attack may occur during treatment and should be informed about what to do if it does.

No therapy is 100% efficacious in pediatric or adult MS, said Dr. Lotze. Research suggests that 50% of adults have no evidence of disease activity (NEDA) at two years of the disease. After seven years, however, 7% of these adults meet NEDA criteria. As a result, minimal disease progression (defined as less than one attack per year, fewer than three new lesions on a yearly MRI, and no progression in disability) may be a more attainable goal. “We would like to see a drug in a single individual or patient that is effective in achieving NEDA. If that is not possible … you might find that ultimately what you can go for is minimal disease progression,” said Dr. Lotze. He added that there appears to be no clear difference in terms of long-term outcome between children with MS who achieve NEDA and those who achieve minimal disease progression.

First-Line Therapies and Follow-Up Appointments

First-line agents for pediatric MS are the injectable drugs known as platform therapies. The International Pediatric MS Society Group (IPMSSG) recommends that all patients start first-line therapy (ie, interferon β or glatiramer acetate) soon after diagnosis.

Positive results from phase IV observational studies suggest that interferon β and glatiramer acetate are safe and efficacious treatments in pediatric MS. When studied in populations ranging in age from 12 to 17, these therapies decreased relapse rate, stabilized disability, and reduced accrual of new lesions. However, injectable treatments are associated with flu-like symptoms and injection-site reactions. Neurologists should start pediatric patients on interferon β with 25% to 50% of full dosing and titrate to a full adult dosing over four to six weeks. When initiating glatiramer acetate, neurologists should start children with a full adult dosing, 20 mg subcutaneous daily or 40 mg subcutaneous three times per week.

Follow-up appointments should occur every three to six months to assess adherence and determine efficacy of treatment. Neurologists are advised to ask patients whether they are comfortable with taking shots. Patients with needle anxiety, a common problem in pediatric MS, may need assistance from a child psychologist or child life specialist. Asking patients how often the patient or family forgets to take the disease-modifying therapy is also necessary, said Dr. Lotze. In addition, the transition from pediatric to adult care should be addressed in follow-up discussions. Teens must understand that certain disease-modifying therapies are contraindicated for pregnant patients. They also should be aware of how alcohol and other drugs interact with treatment.

Treatment Failure

Research indicates that approximately 30% of patients with pediatric-onset MS will not respond to the first-line therapies, and numerous variables may explain why. Age and disease duration can influence treatment efficacy, as can the number of relapses and the level of disease activity before treatment initiation. Patients who are nonadherent because of side effects and who continue to struggle with needle anxiety may experience treatment failure. The IPMSSG defines treatment failure as adherence to treatment for at least six months with no reduction in relapse rate or in new MRI T2 or contrast-enhancing lesions, or with two or more relapses within a 12-month period.

Second-Line Therapies

Trials of several oral agents are currently under way. The IPMSSG, however, urges neurologists to use extreme caution when considering nonplatform therapies for pediatric patients.

Fingolimod is a second-line drug for pediatric MS that blocks the egress of lymphocytes from the lymph nodes. A small percentage of patients taking this oral agent may develop bradycardia. Monitoring is required for the first six hours of treatment to ensure that the patient has no side effects. Some adverse effects associated with the drug include: first dose bradycardia, macular edema, and herpetic infections.

Dimethyl fumarate is an Nrf2 antioxidant pathway modulator that is associated with adverse effects such as flushing and gastrointestinal upset, said Dr. Lotze. Low-dose aspirin may help with flushing, and a proton pump inhibitor can help to manage the gastrointestinal upset. This treatment requires patients to undergo monitoring for blood count and liver function, as does fingolimod.

Teriflunomide, a pyrimidine synthesis inhibitor, is a Pregnancy Category X drug because it increases the risk of birth defects. Rituximab, an anti-CD20 chimeric monoclonal antibody, is gaining popularity for treating MS. Studies suggest that ocrelizumab may be well tolerated in pediatric MS. Natlizumamb, cladribine, and alemtuzumab are typically used to treat more aggressive forms of MS.

Neurologists rarely prescribe cyclophosphamide or mitoxantrone in pediatric MS. Cyclophosphamide has no formal FDA approval for adult MS or pediatric-onset MS and is associated with increased risks of bladder cancer, secondary leukemia, and infertility. Mitoxantrone is FDA-approved for adults with aggressive relapsing-remitting MS and secondary progressive MS. It is associated with increased cancer risk, however, and is highly cardiotoxic.

“After you have initiated a second-line agent, you need to continue to monitor aspects of disease control, including relapse rate, disability, MRI changes, and other adverse events. If you continue to see breakthrough disease, then you may need to consider … changing to another agent or moving to a more aggressive therapy such as rituximab or natalizumab,” said Dr. Lotze.

—Erica Tricarico

Suggested Reading

Chitnis T, Ghezzi A, Bajer-Korneck B, et al. Pediatric multiple sclerosis: Escalation and emerging treatments. Neurology. 2016;87(9 Suppl 2):S10 3-S109.

Jancic J, Nikolic B, Ivancevic N, et al. Multiple sclerosis in pediatrics: Current concepts and treatment options. Neurol Ther. 2016:5(2):131-143.

Varicella-zoster virus (VZV) causes varicella as a primary infection. It is a highly contagious disease characterized by a widespread papulovesicular eruption with fever and malaise.^1,2 After the primary infection, the virus remains latent within the sensory dorsal root ganglia and can reactivate as herpes zoster (HZ).^1-5 Herpes zoster is characterized by unilateral radicular pain and a vesicular rash in a dermatomal pattern.^1,2 It is most common in adults, especially elderly and immunocompromised patients, but rarely occurs in children. Herpes zoster is most often seen in individuals previously infected with VZV, but it also has occurred in individuals without known varicella infection,^1-17 possibly because these individuals had a prior subclinical VZV infection.

A live attenuated VZV vaccine was created after isolation of the virus from a child in Japan.² Since the introduction of the vaccine in 1995 in the United States, the incidence of VZV and HZ has declined.⁵ Herpes zoster rates after vaccination vary from 14 to 19 per 100,000 individuals.^3,5 Breakthrough disease with the wild-type strain does occur in vaccinated children, but vaccine-strain HZ also has been reported.^1-5 The risk for HZ caused by reactivated VZV vaccine in healthy children is unknown. We present a case of HZ in an otherwise healthy 19-month-old boy with no known varicella exposure who received the VZV vaccine at 13 months of age.

Case Report

An otherwise healthy 19-month-old boy presented to the dermatology clinic with a rash that began 2 days prior on the right groin and spread to the right leg. The patient’s mother denied that the child had been febrile and noted that the rash did not appear to bother him in any way. The patient was up-to-date on his vaccinations and received the first dose of the varicella series 6 months prior to presentation. He had no personal history of varicella, no exposure to sick contacts with varicella, and no known exposure to the virus. He was otherwise completely healthy with no signs or symptoms of immunocompromise.

Physical examination revealed grouped vesicles on an erythematous base on the right thigh, right sacrum, and lower abdomen that did not cross the midline (Figure). There were no other pertinent physical examination findings. The eruption was most consistent with HZ but concern remained for herpes simplex virus (HSV) or impetigo. A bacterial culture and polymerase chain reaction assay for VZV and HSV from skin swabs was ordered. The patient was prescribed acyclovir 20 mg/kg every 6 hours for 5 days. Laboratory testing revealed a positive result for VZV on polymerase chain reaction and a negative result for HSV. The majority of the patient’s lesions had crusted after 2 days of treatment with acyclovir, and the rash had nearly resolved 1 week after presentation. Subsequent evaluation with a complete blood cell count with differential and basic metabolic profile was normal. Levels of IgG, IgA, and IgM also were normal; IgE was slightly elevated.

Comment

Herpes zoster in children is an uncommon clinical entity. Most children with HZ are immunocompromised, have a history of varicella, or were exposed to varicella during gestation.⁸ With the introduction of the live VZV vaccine, the incidence of HZ has declined, but reactivation of the live vaccine leading to HZ infection is possible. The vaccine is 90% effective, and breakthrough varicella has been reported in 15% to 20% of vaccinated patients.^1-17 The cause of HZ in vaccinated children is unclear due to the potential for either wild-type or vaccine-strain VZV to induce HZ.

Twenty-two cases of HZ in healthy children after vaccination were identified with a PubMed search of articles indexed for MEDLINE using the search terms herpes zoster infection after vaccination and herpes zoster infection AND immunocompetent AND vaccination in separate searches for all English-language studies (Table). The search was limited to immunocompetent children and adolescents who were 18 years or younger with no history of varicella or exposure to varicella during gestation.

The mean age for HZ infection was 5.3 years. The average time between vaccination and HZ infection was 3.3 years. There was a spread of dermatomal patterns with cases in the first division of the trigeminal nerve, cervical, thoracic, lumbar, and sacral distributions. Of the 22 cases of HZ we reviewed, 16 underwent genotype testing to determine the source of the infection. The Oka vaccine strain virus was identified in 8 (50%) cases, while wild-type virus was found in 8 (50%) cases.^{1,2,4,5,7,8,10,11,13,14,16} Twelve cases were treated with acyclovir.^{2,3,5,6,9-12,14-17} The method of delivery, either oral or intravenous, and the length of treatment depended on the severity of the disease. Patients with meningoencephalitis and HZ ophthalmicus received intravenous acyclovir more often and also had a longer course of acyclovir compared to those individuals with involvement limited to the skin.

This review found HZ occurs from reactivation of wild-type or Oka vaccine-strain VZV in immunocompetent children.^1-17 It shows that subclinical varicella infection is not the only explanation for HZ in a healthy vaccinated child. It is currently not clear why some healthy children experience HZ from vaccine-strain VZV. When HZ presents in a vaccinated immunocompetent child without a history of varicella infection or exposure, the possibility for vaccine strain–induced HZ should be considered.

Varicella-zoster virus (VZV) causes varicella as a primary infection. It is a highly contagious disease characterized by a widespread papulovesicular eruption with fever and malaise.^1,2 After the primary infection, the virus remains latent within the sensory dorsal root ganglia and can reactivate as herpes zoster (HZ).^1-5 Herpes zoster is characterized by unilateral radicular pain and a vesicular rash in a dermatomal pattern.^1,2 It is most common in adults, especially elderly and immunocompromised patients, but rarely occurs in children. Herpes zoster is most often seen in individuals previously infected with VZV, but it also has occurred in individuals without known varicella infection,^1-17 possibly because these individuals had a prior subclinical VZV infection.

A live attenuated VZV vaccine was created after isolation of the virus from a child in Japan.² Since the introduction of the vaccine in 1995 in the United States, the incidence of VZV and HZ has declined.⁵ Herpes zoster rates after vaccination vary from 14 to 19 per 100,000 individuals.^3,5 Breakthrough disease with the wild-type strain does occur in vaccinated children, but vaccine-strain HZ also has been reported.^1-5 The risk for HZ caused by reactivated VZV vaccine in healthy children is unknown. We present a case of HZ in an otherwise healthy 19-month-old boy with no known varicella exposure who received the VZV vaccine at 13 months of age.

Case Report

An otherwise healthy 19-month-old boy presented to the dermatology clinic with a rash that began 2 days prior on the right groin and spread to the right leg. The patient’s mother denied that the child had been febrile and noted that the rash did not appear to bother him in any way. The patient was up-to-date on his vaccinations and received the first dose of the varicella series 6 months prior to presentation. He had no personal history of varicella, no exposure to sick contacts with varicella, and no known exposure to the virus. He was otherwise completely healthy with no signs or symptoms of immunocompromise.

Physical examination revealed grouped vesicles on an erythematous base on the right thigh, right sacrum, and lower abdomen that did not cross the midline (Figure). There were no other pertinent physical examination findings. The eruption was most consistent with HZ but concern remained for herpes simplex virus (HSV) or impetigo. A bacterial culture and polymerase chain reaction assay for VZV and HSV from skin swabs was ordered. The patient was prescribed acyclovir 20 mg/kg every 6 hours for 5 days. Laboratory testing revealed a positive result for VZV on polymerase chain reaction and a negative result for HSV. The majority of the patient’s lesions had crusted after 2 days of treatment with acyclovir, and the rash had nearly resolved 1 week after presentation. Subsequent evaluation with a complete blood cell count with differential and basic metabolic profile was normal. Levels of IgG, IgA, and IgM also were normal; IgE was slightly elevated.

Comment

Herpes zoster in children is an uncommon clinical entity. Most children with HZ are immunocompromised, have a history of varicella, or were exposed to varicella during gestation.⁸ With the introduction of the live VZV vaccine, the incidence of HZ has declined, but reactivation of the live vaccine leading to HZ infection is possible. The vaccine is 90% effective, and breakthrough varicella has been reported in 15% to 20% of vaccinated patients.^1-17 The cause of HZ in vaccinated children is unclear due to the potential for either wild-type or vaccine-strain VZV to induce HZ.

Twenty-two cases of HZ in healthy children after vaccination were identified with a PubMed search of articles indexed for MEDLINE using the search terms herpes zoster infection after vaccination and herpes zoster infection AND immunocompetent AND vaccination in separate searches for all English-language studies (Table). The search was limited to immunocompetent children and adolescents who were 18 years or younger with no history of varicella or exposure to varicella during gestation.

The mean age for HZ infection was 5.3 years. The average time between vaccination and HZ infection was 3.3 years. There was a spread of dermatomal patterns with cases in the first division of the trigeminal nerve, cervical, thoracic, lumbar, and sacral distributions. Of the 22 cases of HZ we reviewed, 16 underwent genotype testing to determine the source of the infection. The Oka vaccine strain virus was identified in 8 (50%) cases, while wild-type virus was found in 8 (50%) cases.^{1,2,4,5,7,8,10,11,13,14,16} Twelve cases were treated with acyclovir.^{2,3,5,6,9-12,14-17} The method of delivery, either oral or intravenous, and the length of treatment depended on the severity of the disease. Patients with meningoencephalitis and HZ ophthalmicus received intravenous acyclovir more often and also had a longer course of acyclovir compared to those individuals with involvement limited to the skin.

This review found HZ occurs from reactivation of wild-type or Oka vaccine-strain VZV in immunocompetent children.^1-17 It shows that subclinical varicella infection is not the only explanation for HZ in a healthy vaccinated child. It is currently not clear why some healthy children experience HZ from vaccine-strain VZV. When HZ presents in a vaccinated immunocompetent child without a history of varicella infection or exposure, the possibility for vaccine strain–induced HZ should be considered.

Varicella-zoster virus (VZV) causes varicella as a primary infection. It is a highly contagious disease characterized by a widespread papulovesicular eruption with fever and malaise.^1,2 After the primary infection, the virus remains latent within the sensory dorsal root ganglia and can reactivate as herpes zoster (HZ).^1-5 Herpes zoster is characterized by unilateral radicular pain and a vesicular rash in a dermatomal pattern.^1,2 It is most common in adults, especially elderly and immunocompromised patients, but rarely occurs in children. Herpes zoster is most often seen in individuals previously infected with VZV, but it also has occurred in individuals without known varicella infection,^1-17 possibly because these individuals had a prior subclinical VZV infection.

A live attenuated VZV vaccine was created after isolation of the virus from a child in Japan.² Since the introduction of the vaccine in 1995 in the United States, the incidence of VZV and HZ has declined.⁵ Herpes zoster rates after vaccination vary from 14 to 19 per 100,000 individuals.^3,5 Breakthrough disease with the wild-type strain does occur in vaccinated children, but vaccine-strain HZ also has been reported.^1-5 The risk for HZ caused by reactivated VZV vaccine in healthy children is unknown. We present a case of HZ in an otherwise healthy 19-month-old boy with no known varicella exposure who received the VZV vaccine at 13 months of age.

Case Report

An otherwise healthy 19-month-old boy presented to the dermatology clinic with a rash that began 2 days prior on the right groin and spread to the right leg. The patient’s mother denied that the child had been febrile and noted that the rash did not appear to bother him in any way. The patient was up-to-date on his vaccinations and received the first dose of the varicella series 6 months prior to presentation. He had no personal history of varicella, no exposure to sick contacts with varicella, and no known exposure to the virus. He was otherwise completely healthy with no signs or symptoms of immunocompromise.

Physical examination revealed grouped vesicles on an erythematous base on the right thigh, right sacrum, and lower abdomen that did not cross the midline (Figure). There were no other pertinent physical examination findings. The eruption was most consistent with HZ but concern remained for herpes simplex virus (HSV) or impetigo. A bacterial culture and polymerase chain reaction assay for VZV and HSV from skin swabs was ordered. The patient was prescribed acyclovir 20 mg/kg every 6 hours for 5 days. Laboratory testing revealed a positive result for VZV on polymerase chain reaction and a negative result for HSV. The majority of the patient’s lesions had crusted after 2 days of treatment with acyclovir, and the rash had nearly resolved 1 week after presentation. Subsequent evaluation with a complete blood cell count with differential and basic metabolic profile was normal. Levels of IgG, IgA, and IgM also were normal; IgE was slightly elevated.

Comment

Herpes zoster in children is an uncommon clinical entity. Most children with HZ are immunocompromised, have a history of varicella, or were exposed to varicella during gestation.⁸ With the introduction of the live VZV vaccine, the incidence of HZ has declined, but reactivation of the live vaccine leading to HZ infection is possible. The vaccine is 90% effective, and breakthrough varicella has been reported in 15% to 20% of vaccinated patients.^1-17 The cause of HZ in vaccinated children is unclear due to the potential for either wild-type or vaccine-strain VZV to induce HZ.

Twenty-two cases of HZ in healthy children after vaccination were identified with a PubMed search of articles indexed for MEDLINE using the search terms herpes zoster infection after vaccination and herpes zoster infection AND immunocompetent AND vaccination in separate searches for all English-language studies (Table). The search was limited to immunocompetent children and adolescents who were 18 years or younger with no history of varicella or exposure to varicella during gestation.

The mean age for HZ infection was 5.3 years. The average time between vaccination and HZ infection was 3.3 years. There was a spread of dermatomal patterns with cases in the first division of the trigeminal nerve, cervical, thoracic, lumbar, and sacral distributions. Of the 22 cases of HZ we reviewed, 16 underwent genotype testing to determine the source of the infection. The Oka vaccine strain virus was identified in 8 (50%) cases, while wild-type virus was found in 8 (50%) cases.^{1,2,4,5,7,8,10,11,13,14,16} Twelve cases were treated with acyclovir.^{2,3,5,6,9-12,14-17} The method of delivery, either oral or intravenous, and the length of treatment depended on the severity of the disease. Patients with meningoencephalitis and HZ ophthalmicus received intravenous acyclovir more often and also had a longer course of acyclovir compared to those individuals with involvement limited to the skin.

This review found HZ occurs from reactivation of wild-type or Oka vaccine-strain VZV in immunocompetent children.^1-17 It shows that subclinical varicella infection is not the only explanation for HZ in a healthy vaccinated child. It is currently not clear why some healthy children experience HZ from vaccine-strain VZV. When HZ presents in a vaccinated immunocompetent child without a history of varicella infection or exposure, the possibility for vaccine strain–induced HZ should be considered.

From the Department of Neuropsychiatry and Behavioral Sceince, University of South Carolina School of Medicine, Columbia, SC.

Abstract

• Objective: To review the identification, clinical assessment and treatment of patients with late-life depression.
• Methods: Review of the literature.
• Results: Depressive symptoms are present in up to 1 in 4 older adults. Comprehensive evaluation of depressive symptoms in this population often requires a multidisciplinary and collaborative approach between primary care, mental health, and other ancillary providers. Key aspects include a detailed history, physical and mental status examinations, cognitive and functional status assessment, and suicide risk assessment. Treatment options include anti-depressants, psychotherapy, and electroconvulsive therapy.
• Conclusion: A systematic approach to evaluating depressive symptoms in the elderly can enhance timely recognition and treatment.

Key words: Late-life depression; clinical assessment; antidepressants; psychotherapy; electroconvulsive therapy.

The U.S. population is aging, and with this comes the potential for increased health care needs. In 2014, there were over 46 million Americans age 65 and over (14.5% of the U.S. population). This number is projected to increase to 88 million by the year 2050 [1]. One in 4 older adults suffers with depressive symptoms that cause distress and functional impairment [2]. The World Health Organization Global Burden of Disease Study found depressive disorders to be the leading cause of disability-adjusted life years (DALYs) and the second leading cause of years lived with disability (YLDs). The burden of disease due to depressive disorders increased by 37.5% between 1990 and 2010, and 10.4% was attributable to aging [3]. These figures underscore the importance of accurate assessment and treatment of depression in the elderly. In this article, we review the identification, clinical assessment, and treatment of patients with late-life depression.

Diagnostic Criteria

Prevalence

It is estimated that 1% to 4% of community-dwelling adults age 65 and older suffer from MDD, with women more likely to be affected than men (prevalence of 4.4% vs. 2.7) [2,5–7]. This estimate is low compared with lifetime prevalence of almost 20% in the general adult population [8]. However, when depressive symptoms that do not meet criteria for MDD are considered, prevalence rates increase up to 25% [2,9]. These estimates also vary by clinical setting, with the highest rates (up to 40%) among elderly patients in long-term care facilities [10,11]. While individuals with subsyndromal depression may experience fewer symptoms than those with MDD, clinically significant distress persists, impacting health and functional status. Depression is associated with overall poor social or occupational functioning, cognitive decline, increased health care utilization and cost, increased morbidity and mortality from medical illness, and increased suicide mortality [5,9,10,12].

Identifying LLD

Accurate identification of LLD also requires recognition of the differences in the presentation of LLD compared with onset in earlier life. Depression in younger adults is often marked by depressed mood and loss of interest [18]. In contrast, older adults may present with increased anger or irritability [5]. Younger adults are more likely to report suicidal thoughts while older patients report feelings of hopelessness and thoughts of death [18]. LLD is often characterized by increased somatic complaints, hypochondriasis, or pain [5,18,19]. Another major difference lies in the presentation of cognitive difficulties. Younger patients typically complain of poor concentration or indecisiveness. Geriatric patients may present with cognitive changes including objective findings of slower processing speed and executive dysfunction on neuropsychological testing [17].

Depression rating scales may aid in identification of LLD. They are not a substitute for clinical diagnosis but can be useful as screening tools. Two commonly utilized depression rating scales are the Geriatric Depression Scale (GDS) and the Patient Health Questionnaire-9 (PHQ-9). GDS is a 30-item instrument developed specifically for older adults. Shorter 15-item, 5-item, and 4-item versions exist. The scale utilizes a Yes/No format and can be self- or clinician-administered [20]. One advantage of the GDS lies in its focus on psychological and cognitive aspects of depression rather than neurovegetative symptoms that may overlap with medical illnesses common in older adults [21]. The PHQ-9 is a 9-item self- or clinician-administered screening tool designed for use in primary care settings and has also been validated in geriatric populations [22,23]. The 9 items on this scale correspond to the DSM-5 criteria for major depression. A shorter 2-item version (PHQ-2) has also been validated, and a positive screen on this test should prompt administration of the full-length version. Both versions have approximately 80% sensitivity and specificity in detecting depression. An added advantage of PHQ-9 over GDS is that it can be useful in monitoring treatment response over time [22,23]

Comprehensive Assessment of LLD

The comprehensive assessment of patients with LLD can be carried out by health professionals in both mental health or primary care settings. In a multidisciplinary approach, psychiatrists and mental health professionals have collaborated with primary care providers using depression care managers with successful outcomes in managing depression in older adults [24,25]. Complete evaluation of a patient with suspected LLD begins with a history and physical and mental status examination. Other essential components of the evaluation include assessment of cognition, functional status, and suicide risk. Laboratory and neuroimaging studies may be necessary as well. Due to the comprehensive nature of this assessment, a multidisciplinary approach with collaboration between primary care, psychiatry, psychology, and ancillary services such as social work may be necessary. Multiple patient interactions may be required to complete a thorough evaluation.

History and Mental Status Examination

As with many other psychiatric illnesses, LLD is a clinical diagnosis. A careful history should be obtained initially utilizing open-ended questions. This should be followed by more directed questions as indicated to elicit the presence of depressive symptoms. The history should be obtained from the patient. A relevant collateral informant can be invaluable in the assessment, especially in cases where there is a comorbid neurocognitive disorder. However, the patient’s informed consent must be obtained prior to obtaining collateral information whenever possible. Psychosocial stressors that may have precipitated or may be perpetuating symptoms should be explored. Such stressors may include recent changes in living situation, loss of social support, recent deaths, or financial difficulties. Biological precipitants also need to be explored including presence of physical illness, depressogenic medications, and comorbid alcohol or other substance use. The patient’s past psychiatric history, psychiatric hospitalizations, and past medication trials should be ascertained. Any family history of depression, other psychiatric disorders, substance use disorders, and suicide attempts should be documented. A full mental status exam including cognitive assessment should be completed [21,26].

Cognitive Assessment

Cognitive impairment can be associated with LLD and may be due to the underlying depression or represent a comorbid neurocognitive disorder. Furthermore, the burden of medical illness as well as cerebrovascular and cardiovascular risk factors have been linked to executive dysfunction and reduced processing speed in individuals with LDD [27,28]. Distinguishing between these can be challenging; however, chronology of symptom onset is often helpful. Depression is more likely the etiology of cognitive impairment when depressive symptoms precede onset of cognitive deficits. This type of cognitive impairment is termed dementia syndrome of depression and may improve with treatment of depression [5]. Some patients may progress to develop major cognitive decline, and it remains unclear whether LLD represents a risk factor or prodrome to developing a major neurocognitive disorder [29]. On the other hand, if depression develops later in the course of cognitive decline, there may be an underlying neurocognitive disorder [17]. Up to 20% of individuals with major neurocognitive disorder due to Alzheimer’s disease also have major depression [11]. For these reasons, concomitant assessment of cognition is essential to the evaluation of the older adult presenting with depressive symptoms [30]. Cognitive domains that may be affected include learning and memory, language, attention, perceptual motor abilities, social cognition, and executive function [4]. Many of these domains can be assessed during the mental status examination, with brief cognitive screening tools, or with formal neuropsychological testing.

While there are numerous cognitive screening tools, some commonly used, brief tools include the Mini-Cog, the Folstein Mini-Mental State Exam (MMSE), and the Montreal Cognitive Assessment (MoCA). The Mini-Cog consists of a 3-item registration, delayed recall, and clock drawing test and has several advantages over other screening tools. It is a brief test (taking approximately 3 minutes to administer) with good sensitivity and specificity of 80% or greater. Compared with other cognitive screening tools, it is less influenced by level of education, language, or cultural background [31–33]. The MMSE is a longer screening tool consisting of 19 items and requires about 10 minutes to administer. Unlike the Mini-Cog, performance on the MMSE can be affected by level of education and cultural background. However, the MMSE can be administered serially to monitor changes in cognition over time [34,35]. The MoCA is a 10-minute cognitive screening tool first developed to detect mild cognitive impairment (MCI) [36]. The MoCA consists of 7 subscore sections covering visuospatial/executive function, naming, memory (delayed recall), attention, language, abstraction, and orientation. The total score is 30, and 1 point is added to the score if the testing subject has less than high school/12 years of education. The MoCA has demonstrated better sensitivity than the MMSE for the detection of MCI [36]. Elderly patients with depression often perform poorly on these cognitive screening tests due to apathy and poor effort.

Functional Assessment

The diagnosis of LLD requires that symptoms cause significant distress or interfere with functioning. A functional assessment is especially important in the evaluation of the older adult in that it allows clinicians to determine an individual’s ability to live independently and attend to daily needs. Basic activities of daily living (ADLs) include bathing, dressing, grooming, toileting, and self-transferring. Instrumental activities of daily living (IADLs) include more complex daily activities such as preparing meals, administering medications, driving, managing finances, and using simple electronics such as the telephone or remote control [26]. Impairment in IADLs is associated with increased depression severity. Conversely, the severity of depressive symptoms along with associated cognitive impairment predicts IADL impairment [37]. The Philadelphia Multilevel Assessment Instrument is a tool that can aid in the assessment of ADLs and IADLs and has been utilized in studies examining disability in depressed elderly patients [37,38]. Other available scales to quantify functional status include OARS Physical Activities of Daily Living, OARS Instrumental Activities of Daily Living Scale, and Direct Assessment of Functional Status Scale [26].

Suicide Assessment

Assessment for suicidality is an integral part of all psychiatric evaluations and is especially important in the evaluation of the depressed older adult. According to the Centers for Disease Control and Prevention, the suicide rate for individuals age 65 and older is 16.6 per 100,000, a figure that is comparable to that for individuals 18–64 years of age [39]. Non-Hispanic Caucasian males age 85 and older have the highest rate of completed suicide (56.5 per 100,000), underscoring the importance of a thorough suicide assessment [39]. Suicidality can range from passive thoughts of death and wishing that one were not alive, to active thoughts of self-harm with plan and intent. A Canadian study found 2% of community-dwelling adults age 55 and older had suicidal thoughts over a 12-month period and, of these, 28% had major depression [40]. A suicide assessment begins with inquiring about the presence of suicidal thoughts, plans, and intent. The 3 most frequently used methods of completed suicide in the elderly are firearms (28%), hanging (24%) and poisoning (21%) [41]. Access to weapons or other lethal means of self-harm such has hoarding of medications should be ascertained.

A complete suicide assessment requires attention to suicide risk factors, protective factors, and warning signs of impending suicide. Risk factors for suicide in the older adult include mood disorders, chronic medical illnesses and associated functional impairment, chronic pain, and psychosocial factors such as social isolation [42]. Mood disorders are present in 54% to 87% of cases of completed suicide, with major depression being the most common [42]. Chronic medical illness and pain can result in functional impairment leading to feelings of excessive guilt or being a burden to loved ones. Protective factors such as social connectedness, spirituality, religious beliefs, and cultural attitudes against suicide may serve as buffers against these risk factors [43]. Warning signs of impending suicide may indicate preparations for suicide and include feelings of hopelessness or lack of purpose, feeling trapped, talking about death, threatening suicide, agitation, social withdrawal, increased substance use and reckless behavior. Warning signs should prompt action to ensure the safety of the individual [44,45].

Physical Examination, Laboratory Studies, and Neuroimaging

Evaluation of LLD is not complete without a physical examination and ancillary studies to identify underlying medical conditions possibly contributing to or mimicking depressive symptoms. Routine laboratory studies include complete blood count, complete metabolic panel, thyroid studies, and urine drug screen. Signs and symptoms of underlying medical conditions may necessitate further laboratory studies [46]. Neuroimaging may reveal signs of cerebrovascular disease which can predispose, precipitate, or perpetuate depression in older adults [47].

Treatment

Treatment of LLD can take many forms and occur in various settings. Geriatric psychiatrists have expertise in the assessment and treatment of mental illness in the elderly. Workforce estimates for 2010 revealed 1 geriatric psychiatrist per 10,000 adults age 75 and over. This figure is estimated to decrease to 0.5 per 10,000 by the year 2030, underscoring the importance of increasing the knowledge base of clinicians across specialties who provide care to the depressed elderly [48]. The primary care setting is often the locus of care for depression in older adults; however, studies suggest that patients are often left untreated or undertreated [49]. Collaborative care models whereby mental health care is integrated into primary care have been shown to improve outcomes. The Prevention of Suicide in Primary Care Elderly: Collaborative Trial (PROSPECT) study found that use of care managers to assist primary care providers in identification of depression, offer algorithm-based treatment recommendations, monitor symptoms and medication side effects, and provide follow-up yielded improvement in outcomes. Patients in the intervention group were more likely to receive pharmacotherapy or psychotherapy, achieve remission, and showed greater decline in suicidal ideation [50]. Similar results were found in the Improving Mood-Promoting Access to Collaborative Treatment (IMPACT) study in which intervention patients treated under a collaborative care model showed lower depression severity, less functional impairment, and greater reduction in depressive symptoms [25].

Just as a collaborative care model can lead to improved outcomes, the overall strategy of treating depression must be multifaceted. The biopsychosocial model of disease first described in the 1970s emphasizes biological and psychosocial determinants of illness that must be addressed when treatment is considered [51]. This includes nonmodifiable biological factors such as age, gender, and genetic predisposition that may affect treatment options, as well as modifiable biological factors such as comorbid medical illness, medications, or substance use disorders. Psychological factors that can affect depressive symptoms include coping skills and defense mechanisms in the face of stressful life events. Social factors including the role of culture, environment, and family dynamics in disease presentation must be considered as well [52].

Pharmacologic Treatment of LLD

The primary pharmacologic treatment for depression is antidepressants. Treatment consists of 3 phases—acute, continuation, and maintenance. In the acute phase, the goal is remission of current symptoms and restoration of function. The continuation phase, extending up to 6 months after remission, aims to prevent relapse back into a depressive episode. Maintenance therapy is geared at preventing recurrence of future depressive episodes [53]. Studies have found a 50% risk of relapse after 1 episode of depression and 80% after 2 episodes. Up to 20% will develop chronic symptoms. For this reason, maintenance therapy is often necessary for recurrent depression [54].

While cognitive impairment may affect antidepressant efficacy, age does not appear to be a determinant. Gildengers et al examined antidepressant response in young, middle, and older-old patients and found no significant difference in response rates [59]. Early onset versus late onset of first depressive episode also does not predict antidepressant response in patients age 55 and over [60]. There is scant evidence for efficacy of antidepressants in depressed patients with neurocognitive disorders. A 2002 Cochrane review with 4 studies in the meta-analysis (n = 137) concluded that there was weak support for antidepressant efficacy in this population [61]. A 2011 meta-analysis with 330 participants also yielded inconclusive results [62]. The paucity of evidence for antidepressant efficacy in depressed patients with neurocognitive disorders should prompt careful consideration of potential benefits versus adverse effects.

Antidepressants are generally well tolerated in older adults. Side effects vary by medication and contribute to discontinuation in up to 25% of new users (versus 22% for new users who discontinue for reasons other than side effects) [63]. Potential adverse effects shared by most SSRIs and SNRIs include GI disturbance (nausea, diarrhea or constipation), sexual dysfunction, headache, and sleep disturbance [64,65]. In addition, abrupt discontinuation can precipitate serotonin withdrawal syndrome characterized by sensory disturbance (paresthesia, tremor, and irritability) as well as headache, lightheadedness, diaphoresis, insomnia, and agitation. Other medication-specific side effects include risk of seizure with bupropion and sedation with mirtazapine [65].

Despite superiority of antidepressants to placebo in treating depression, up to one-third of patients may not respond to a trial of antidepressants. Sequential treatment protocols such as switching to a different antidepressant or augmentation can increase the proportion of antidepressant responders [66–68]. Studies have found particularly favorable response to augmentation with lithium, with one study achieving a 33% remission rate in treatment- resistant geriatric depression [67,69]. Other pharmacologic augmentation strategies include the addition of mood stabilizers such as lamotrigine, antipsychotics (aripiprazole, olanzapine, quetiapine, and risperidone), and psychostimulants [70–73]. Electroconvulsive therapy (ECT) is a nonpharmacologic option for treatment-resistant depression that will be reviewed later.

Psychotherapeutic and Psychosocial Interventions

Psychotherapeutic interventions have demonstrated efficacy in the treatment of geriatric depression, including but not limited to cognitive behavioral therapy (CBT), interpersonal therapy (IPT), problem-solving therapy (PST), reminiscence and life review, and brief psychodynamic psychotherapy [74]. Some older adults may prefer psychotherapy to pharmacologic treatment (57% vs. 43%) [75]. Potential benefits of psychotherapy include ability to directly address psychosocial stressors that may precipitate or perpetuate depressive symptoms. In addition, psychotherapy is associated with few to no side effects and avoids drug interactions. Barriers to employing psychotherapy may include cost and access to trained psychotherapists [76]. Efficacy of several psychotherapeutic approaches in the care of older depressed adults has been examined. CBT, brief psychodynamic psychotherapy, and IPT will be briefly reviewed here.

CBT. Cognitive therapy was first described by Aaron Beck in the 1960s [77]. It is a highly structured therapy built on the premise that beliefs and assumptions an individual holds can influence emotions and behavior. CBT aims to identify maladaptive belief systems, test the validity of these cognitive distortions, and help individuals formulate more realistic cognitions [78]. Symptom improvement results from addressing these cognitive aspects as well as integration of behavioral activation and skills training to overcome maladaptive behavioral patterns [78]. CBT approaches have been applied to older adults with depression and results show acceptability [79] and efficacy in this population [80–82]. A 2008 Cochrane review (n = 153) found CBT to be superior to waitlist controls [82].

Brief psychodynamic psychotherapy. Brief psychodynamic psychotherapy, unlike highly structured CBT, aims to alter behavior by examining how past experiences and unresolved conflicts influence current emotions and behavior. While studies on application to the treatment of geriatric depression are scarce, limited data demonstrate efficacy in treating geriatric depression [81] and no significant difference in outcomes when compared to CBT [82].

IPT. Like CBT, IPT is a structured time-limited psychotherapeutic treatment approach first developed in the late 1960s by Klerman and Weissman [83]. IPT focuses on the impact of interpersonal relationships on depressive symptoms and examines 4 domains: interpersonal conflict, interpersonal deficits, role transitions, and grief [74].

Studies have shown efficacy of IPT in reducing depressive symptoms in the elderly when compared to usual care [84]. Reynolds et al found IPT combined with nortriptyline (a tricyclic antidepressant) to be superior to either nortriptyline alone or IPT alone in preventing recurrent depressive episodes [85]. Interestingly, a similar study investigating the efficacy of IPT in combination with paroxetine (an SSRI) failed to show added benefit of IPT in preventing recurrence, suggesting that further studies are needed [86].

Psychosocial interventions are integral in the care of the elderly depressed patient. Studies have shown positive benefits of aerobic exercise on depressive symptoms [87]. Yoga, Tai Chi, and other mindfulness-based exercises can increase sense of emotional and physical wellbeing [88–90]. Spirituality, religious beliefs, and involvement with a faith group may be protective against development of mental illness while at the same time provide avenues for increased social connectedness [91]. These and other avenues for socialization should be encouraged as part of the treatment plan for older depressed patients [92]

Electroconvulsive Therapy

ECT is indicated for the treatment of mood and psychotic disorders and has demonstrated efficacy in the treatment of severe depression [93]. It is typically initiated when patients fail to respond to pharmacotherapy and psychotherapy. Circumstances in which ECT can be considered first-line treatment include situations that require a rapid response (severe inanition, weight loss, or suicidality), situations where risks of ECT are lower than that of alternative treatments, previous positive response to ECT, or strong patient preference [94]. ECT is performed under general anesthesia and involves the induction of a generalized tonic-clonic seizure, which is theorized to enhance serotonergic, noradrenergic, and dopaminergic neurotransmission. A typical course of ECT involves treatments 3 times a week for an average of 6 to 12 treatments in total [95]. Elderly patients and those suffering from severe depression with psychotic features respond more robustly to ECT [93,96]. Estimated remission rates after an ECT series have been higher than 80% [93], making this modality the most effective treatment for severe depression to date.

Conclusion

As the population continues to age, clinicians are increasingly likely to encounter patients with late-life depression. A thorough evaluation includes not only assessment of depressive symptoms, but also cognitive, functional, and suicide assessment. Treatment options include pharmaco-therapy, psychotherapy, and in some cases electroconvulsive therapy. Utilization of assessment and treatment nuances unique to the geriatric population, with a multidisciplinary and collaborative approach involving primary care, mental health, and other ancillary providers, will serve to ultimately enhance patient care.

Corresponding author: Corresponding author: Juliet Glover, MD, Dept. of Neuropsychiatry and Behavioral Science, Univ. of South Carolina School of Medicine, 15 Medical Park, Suite 301, Columbia, SC 29203, Juliet.Glover@uscmed.sc.edu.

Financial disclosures: None reported.

Author contributions: conception and design, JAG, SS; drafting of article, JAG, SS; critical revision of the article, JAG, SS.

From the Department of Neuropsychiatry and Behavioral Sceince, University of South Carolina School of Medicine, Columbia, SC.

Abstract

• Objective: To review the identification, clinical assessment and treatment of patients with late-life depression.
• Methods: Review of the literature.
• Results: Depressive symptoms are present in up to 1 in 4 older adults. Comprehensive evaluation of depressive symptoms in this population often requires a multidisciplinary and collaborative approach between primary care, mental health, and other ancillary providers. Key aspects include a detailed history, physical and mental status examinations, cognitive and functional status assessment, and suicide risk assessment. Treatment options include anti-depressants, psychotherapy, and electroconvulsive therapy.
• Conclusion: A systematic approach to evaluating depressive symptoms in the elderly can enhance timely recognition and treatment.

Key words: Late-life depression; clinical assessment; antidepressants; psychotherapy; electroconvulsive therapy.

The U.S. population is aging, and with this comes the potential for increased health care needs. In 2014, there were over 46 million Americans age 65 and over (14.5% of the U.S. population). This number is projected to increase to 88 million by the year 2050 [1]. One in 4 older adults suffers with depressive symptoms that cause distress and functional impairment [2]. The World Health Organization Global Burden of Disease Study found depressive disorders to be the leading cause of disability-adjusted life years (DALYs) and the second leading cause of years lived with disability (YLDs). The burden of disease due to depressive disorders increased by 37.5% between 1990 and 2010, and 10.4% was attributable to aging [3]. These figures underscore the importance of accurate assessment and treatment of depression in the elderly. In this article, we review the identification, clinical assessment, and treatment of patients with late-life depression.

Diagnostic Criteria

Prevalence

It is estimated that 1% to 4% of community-dwelling adults age 65 and older suffer from MDD, with women more likely to be affected than men (prevalence of 4.4% vs. 2.7) [2,5–7]. This estimate is low compared with lifetime prevalence of almost 20% in the general adult population [8]. However, when depressive symptoms that do not meet criteria for MDD are considered, prevalence rates increase up to 25% [2,9]. These estimates also vary by clinical setting, with the highest rates (up to 40%) among elderly patients in long-term care facilities [10,11]. While individuals with subsyndromal depression may experience fewer symptoms than those with MDD, clinically significant distress persists, impacting health and functional status. Depression is associated with overall poor social or occupational functioning, cognitive decline, increased health care utilization and cost, increased morbidity and mortality from medical illness, and increased suicide mortality [5,9,10,12].

Identifying LLD

Accurate identification of LLD also requires recognition of the differences in the presentation of LLD compared with onset in earlier life. Depression in younger adults is often marked by depressed mood and loss of interest [18]. In contrast, older adults may present with increased anger or irritability [5]. Younger adults are more likely to report suicidal thoughts while older patients report feelings of hopelessness and thoughts of death [18]. LLD is often characterized by increased somatic complaints, hypochondriasis, or pain [5,18,19]. Another major difference lies in the presentation of cognitive difficulties. Younger patients typically complain of poor concentration or indecisiveness. Geriatric patients may present with cognitive changes including objective findings of slower processing speed and executive dysfunction on neuropsychological testing [17].

Depression rating scales may aid in identification of LLD. They are not a substitute for clinical diagnosis but can be useful as screening tools. Two commonly utilized depression rating scales are the Geriatric Depression Scale (GDS) and the Patient Health Questionnaire-9 (PHQ-9). GDS is a 30-item instrument developed specifically for older adults. Shorter 15-item, 5-item, and 4-item versions exist. The scale utilizes a Yes/No format and can be self- or clinician-administered [20]. One advantage of the GDS lies in its focus on psychological and cognitive aspects of depression rather than neurovegetative symptoms that may overlap with medical illnesses common in older adults [21]. The PHQ-9 is a 9-item self- or clinician-administered screening tool designed for use in primary care settings and has also been validated in geriatric populations [22,23]. The 9 items on this scale correspond to the DSM-5 criteria for major depression. A shorter 2-item version (PHQ-2) has also been validated, and a positive screen on this test should prompt administration of the full-length version. Both versions have approximately 80% sensitivity and specificity in detecting depression. An added advantage of PHQ-9 over GDS is that it can be useful in monitoring treatment response over time [22,23]

Comprehensive Assessment of LLD

The comprehensive assessment of patients with LLD can be carried out by health professionals in both mental health or primary care settings. In a multidisciplinary approach, psychiatrists and mental health professionals have collaborated with primary care providers using depression care managers with successful outcomes in managing depression in older adults [24,25]. Complete evaluation of a patient with suspected LLD begins with a history and physical and mental status examination. Other essential components of the evaluation include assessment of cognition, functional status, and suicide risk. Laboratory and neuroimaging studies may be necessary as well. Due to the comprehensive nature of this assessment, a multidisciplinary approach with collaboration between primary care, psychiatry, psychology, and ancillary services such as social work may be necessary. Multiple patient interactions may be required to complete a thorough evaluation.

History and Mental Status Examination

As with many other psychiatric illnesses, LLD is a clinical diagnosis. A careful history should be obtained initially utilizing open-ended questions. This should be followed by more directed questions as indicated to elicit the presence of depressive symptoms. The history should be obtained from the patient. A relevant collateral informant can be invaluable in the assessment, especially in cases where there is a comorbid neurocognitive disorder. However, the patient’s informed consent must be obtained prior to obtaining collateral information whenever possible. Psychosocial stressors that may have precipitated or may be perpetuating symptoms should be explored. Such stressors may include recent changes in living situation, loss of social support, recent deaths, or financial difficulties. Biological precipitants also need to be explored including presence of physical illness, depressogenic medications, and comorbid alcohol or other substance use. The patient’s past psychiatric history, psychiatric hospitalizations, and past medication trials should be ascertained. Any family history of depression, other psychiatric disorders, substance use disorders, and suicide attempts should be documented. A full mental status exam including cognitive assessment should be completed [21,26].

Cognitive Assessment

Cognitive impairment can be associated with LLD and may be due to the underlying depression or represent a comorbid neurocognitive disorder. Furthermore, the burden of medical illness as well as cerebrovascular and cardiovascular risk factors have been linked to executive dysfunction and reduced processing speed in individuals with LDD [27,28]. Distinguishing between these can be challenging; however, chronology of symptom onset is often helpful. Depression is more likely the etiology of cognitive impairment when depressive symptoms precede onset of cognitive deficits. This type of cognitive impairment is termed dementia syndrome of depression and may improve with treatment of depression [5]. Some patients may progress to develop major cognitive decline, and it remains unclear whether LLD represents a risk factor or prodrome to developing a major neurocognitive disorder [29]. On the other hand, if depression develops later in the course of cognitive decline, there may be an underlying neurocognitive disorder [17]. Up to 20% of individuals with major neurocognitive disorder due to Alzheimer’s disease also have major depression [11]. For these reasons, concomitant assessment of cognition is essential to the evaluation of the older adult presenting with depressive symptoms [30]. Cognitive domains that may be affected include learning and memory, language, attention, perceptual motor abilities, social cognition, and executive function [4]. Many of these domains can be assessed during the mental status examination, with brief cognitive screening tools, or with formal neuropsychological testing.

While there are numerous cognitive screening tools, some commonly used, brief tools include the Mini-Cog, the Folstein Mini-Mental State Exam (MMSE), and the Montreal Cognitive Assessment (MoCA). The Mini-Cog consists of a 3-item registration, delayed recall, and clock drawing test and has several advantages over other screening tools. It is a brief test (taking approximately 3 minutes to administer) with good sensitivity and specificity of 80% or greater. Compared with other cognitive screening tools, it is less influenced by level of education, language, or cultural background [31–33]. The MMSE is a longer screening tool consisting of 19 items and requires about 10 minutes to administer. Unlike the Mini-Cog, performance on the MMSE can be affected by level of education and cultural background. However, the MMSE can be administered serially to monitor changes in cognition over time [34,35]. The MoCA is a 10-minute cognitive screening tool first developed to detect mild cognitive impairment (MCI) [36]. The MoCA consists of 7 subscore sections covering visuospatial/executive function, naming, memory (delayed recall), attention, language, abstraction, and orientation. The total score is 30, and 1 point is added to the score if the testing subject has less than high school/12 years of education. The MoCA has demonstrated better sensitivity than the MMSE for the detection of MCI [36]. Elderly patients with depression often perform poorly on these cognitive screening tests due to apathy and poor effort.

Functional Assessment

The diagnosis of LLD requires that symptoms cause significant distress or interfere with functioning. A functional assessment is especially important in the evaluation of the older adult in that it allows clinicians to determine an individual’s ability to live independently and attend to daily needs. Basic activities of daily living (ADLs) include bathing, dressing, grooming, toileting, and self-transferring. Instrumental activities of daily living (IADLs) include more complex daily activities such as preparing meals, administering medications, driving, managing finances, and using simple electronics such as the telephone or remote control [26]. Impairment in IADLs is associated with increased depression severity. Conversely, the severity of depressive symptoms along with associated cognitive impairment predicts IADL impairment [37]. The Philadelphia Multilevel Assessment Instrument is a tool that can aid in the assessment of ADLs and IADLs and has been utilized in studies examining disability in depressed elderly patients [37,38]. Other available scales to quantify functional status include OARS Physical Activities of Daily Living, OARS Instrumental Activities of Daily Living Scale, and Direct Assessment of Functional Status Scale [26].

Suicide Assessment

Assessment for suicidality is an integral part of all psychiatric evaluations and is especially important in the evaluation of the depressed older adult. According to the Centers for Disease Control and Prevention, the suicide rate for individuals age 65 and older is 16.6 per 100,000, a figure that is comparable to that for individuals 18–64 years of age [39]. Non-Hispanic Caucasian males age 85 and older have the highest rate of completed suicide (56.5 per 100,000), underscoring the importance of a thorough suicide assessment [39]. Suicidality can range from passive thoughts of death and wishing that one were not alive, to active thoughts of self-harm with plan and intent. A Canadian study found 2% of community-dwelling adults age 55 and older had suicidal thoughts over a 12-month period and, of these, 28% had major depression [40]. A suicide assessment begins with inquiring about the presence of suicidal thoughts, plans, and intent. The 3 most frequently used methods of completed suicide in the elderly are firearms (28%), hanging (24%) and poisoning (21%) [41]. Access to weapons or other lethal means of self-harm such has hoarding of medications should be ascertained.

A complete suicide assessment requires attention to suicide risk factors, protective factors, and warning signs of impending suicide. Risk factors for suicide in the older adult include mood disorders, chronic medical illnesses and associated functional impairment, chronic pain, and psychosocial factors such as social isolation [42]. Mood disorders are present in 54% to 87% of cases of completed suicide, with major depression being the most common [42]. Chronic medical illness and pain can result in functional impairment leading to feelings of excessive guilt or being a burden to loved ones. Protective factors such as social connectedness, spirituality, religious beliefs, and cultural attitudes against suicide may serve as buffers against these risk factors [43]. Warning signs of impending suicide may indicate preparations for suicide and include feelings of hopelessness or lack of purpose, feeling trapped, talking about death, threatening suicide, agitation, social withdrawal, increased substance use and reckless behavior. Warning signs should prompt action to ensure the safety of the individual [44,45].

Physical Examination, Laboratory Studies, and Neuroimaging

Evaluation of LLD is not complete without a physical examination and ancillary studies to identify underlying medical conditions possibly contributing to or mimicking depressive symptoms. Routine laboratory studies include complete blood count, complete metabolic panel, thyroid studies, and urine drug screen. Signs and symptoms of underlying medical conditions may necessitate further laboratory studies [46]. Neuroimaging may reveal signs of cerebrovascular disease which can predispose, precipitate, or perpetuate depression in older adults [47].

Treatment

Treatment of LLD can take many forms and occur in various settings. Geriatric psychiatrists have expertise in the assessment and treatment of mental illness in the elderly. Workforce estimates for 2010 revealed 1 geriatric psychiatrist per 10,000 adults age 75 and over. This figure is estimated to decrease to 0.5 per 10,000 by the year 2030, underscoring the importance of increasing the knowledge base of clinicians across specialties who provide care to the depressed elderly [48]. The primary care setting is often the locus of care for depression in older adults; however, studies suggest that patients are often left untreated or undertreated [49]. Collaborative care models whereby mental health care is integrated into primary care have been shown to improve outcomes. The Prevention of Suicide in Primary Care Elderly: Collaborative Trial (PROSPECT) study found that use of care managers to assist primary care providers in identification of depression, offer algorithm-based treatment recommendations, monitor symptoms and medication side effects, and provide follow-up yielded improvement in outcomes. Patients in the intervention group were more likely to receive pharmacotherapy or psychotherapy, achieve remission, and showed greater decline in suicidal ideation [50]. Similar results were found in the Improving Mood-Promoting Access to Collaborative Treatment (IMPACT) study in which intervention patients treated under a collaborative care model showed lower depression severity, less functional impairment, and greater reduction in depressive symptoms [25].

Just as a collaborative care model can lead to improved outcomes, the overall strategy of treating depression must be multifaceted. The biopsychosocial model of disease first described in the 1970s emphasizes biological and psychosocial determinants of illness that must be addressed when treatment is considered [51]. This includes nonmodifiable biological factors such as age, gender, and genetic predisposition that may affect treatment options, as well as modifiable biological factors such as comorbid medical illness, medications, or substance use disorders. Psychological factors that can affect depressive symptoms include coping skills and defense mechanisms in the face of stressful life events. Social factors including the role of culture, environment, and family dynamics in disease presentation must be considered as well [52].

Pharmacologic Treatment of LLD

The primary pharmacologic treatment for depression is antidepressants. Treatment consists of 3 phases—acute, continuation, and maintenance. In the acute phase, the goal is remission of current symptoms and restoration of function. The continuation phase, extending up to 6 months after remission, aims to prevent relapse back into a depressive episode. Maintenance therapy is geared at preventing recurrence of future depressive episodes [53]. Studies have found a 50% risk of relapse after 1 episode of depression and 80% after 2 episodes. Up to 20% will develop chronic symptoms. For this reason, maintenance therapy is often necessary for recurrent depression [54].

While cognitive impairment may affect antidepressant efficacy, age does not appear to be a determinant. Gildengers et al examined antidepressant response in young, middle, and older-old patients and found no significant difference in response rates [59]. Early onset versus late onset of first depressive episode also does not predict antidepressant response in patients age 55 and over [60]. There is scant evidence for efficacy of antidepressants in depressed patients with neurocognitive disorders. A 2002 Cochrane review with 4 studies in the meta-analysis (n = 137) concluded that there was weak support for antidepressant efficacy in this population [61]. A 2011 meta-analysis with 330 participants also yielded inconclusive results [62]. The paucity of evidence for antidepressant efficacy in depressed patients with neurocognitive disorders should prompt careful consideration of potential benefits versus adverse effects.

Antidepressants are generally well tolerated in older adults. Side effects vary by medication and contribute to discontinuation in up to 25% of new users (versus 22% for new users who discontinue for reasons other than side effects) [63]. Potential adverse effects shared by most SSRIs and SNRIs include GI disturbance (nausea, diarrhea or constipation), sexual dysfunction, headache, and sleep disturbance [64,65]. In addition, abrupt discontinuation can precipitate serotonin withdrawal syndrome characterized by sensory disturbance (paresthesia, tremor, and irritability) as well as headache, lightheadedness, diaphoresis, insomnia, and agitation. Other medication-specific side effects include risk of seizure with bupropion and sedation with mirtazapine [65].

Despite superiority of antidepressants to placebo in treating depression, up to one-third of patients may not respond to a trial of antidepressants. Sequential treatment protocols such as switching to a different antidepressant or augmentation can increase the proportion of antidepressant responders [66–68]. Studies have found particularly favorable response to augmentation with lithium, with one study achieving a 33% remission rate in treatment- resistant geriatric depression [67,69]. Other pharmacologic augmentation strategies include the addition of mood stabilizers such as lamotrigine, antipsychotics (aripiprazole, olanzapine, quetiapine, and risperidone), and psychostimulants [70–73]. Electroconvulsive therapy (ECT) is a nonpharmacologic option for treatment-resistant depression that will be reviewed later.

Psychotherapeutic and Psychosocial Interventions

Psychotherapeutic interventions have demonstrated efficacy in the treatment of geriatric depression, including but not limited to cognitive behavioral therapy (CBT), interpersonal therapy (IPT), problem-solving therapy (PST), reminiscence and life review, and brief psychodynamic psychotherapy [74]. Some older adults may prefer psychotherapy to pharmacologic treatment (57% vs. 43%) [75]. Potential benefits of psychotherapy include ability to directly address psychosocial stressors that may precipitate or perpetuate depressive symptoms. In addition, psychotherapy is associated with few to no side effects and avoids drug interactions. Barriers to employing psychotherapy may include cost and access to trained psychotherapists [76]. Efficacy of several psychotherapeutic approaches in the care of older depressed adults has been examined. CBT, brief psychodynamic psychotherapy, and IPT will be briefly reviewed here.

CBT. Cognitive therapy was first described by Aaron Beck in the 1960s [77]. It is a highly structured therapy built on the premise that beliefs and assumptions an individual holds can influence emotions and behavior. CBT aims to identify maladaptive belief systems, test the validity of these cognitive distortions, and help individuals formulate more realistic cognitions [78]. Symptom improvement results from addressing these cognitive aspects as well as integration of behavioral activation and skills training to overcome maladaptive behavioral patterns [78]. CBT approaches have been applied to older adults with depression and results show acceptability [79] and efficacy in this population [80–82]. A 2008 Cochrane review (n = 153) found CBT to be superior to waitlist controls [82].

Brief psychodynamic psychotherapy. Brief psychodynamic psychotherapy, unlike highly structured CBT, aims to alter behavior by examining how past experiences and unresolved conflicts influence current emotions and behavior. While studies on application to the treatment of geriatric depression are scarce, limited data demonstrate efficacy in treating geriatric depression [81] and no significant difference in outcomes when compared to CBT [82].

IPT. Like CBT, IPT is a structured time-limited psychotherapeutic treatment approach first developed in the late 1960s by Klerman and Weissman [83]. IPT focuses on the impact of interpersonal relationships on depressive symptoms and examines 4 domains: interpersonal conflict, interpersonal deficits, role transitions, and grief [74].

Studies have shown efficacy of IPT in reducing depressive symptoms in the elderly when compared to usual care [84]. Reynolds et al found IPT combined with nortriptyline (a tricyclic antidepressant) to be superior to either nortriptyline alone or IPT alone in preventing recurrent depressive episodes [85]. Interestingly, a similar study investigating the efficacy of IPT in combination with paroxetine (an SSRI) failed to show added benefit of IPT in preventing recurrence, suggesting that further studies are needed [86].

Psychosocial interventions are integral in the care of the elderly depressed patient. Studies have shown positive benefits of aerobic exercise on depressive symptoms [87]. Yoga, Tai Chi, and other mindfulness-based exercises can increase sense of emotional and physical wellbeing [88–90]. Spirituality, religious beliefs, and involvement with a faith group may be protective against development of mental illness while at the same time provide avenues for increased social connectedness [91]. These and other avenues for socialization should be encouraged as part of the treatment plan for older depressed patients [92]

Electroconvulsive Therapy

ECT is indicated for the treatment of mood and psychotic disorders and has demonstrated efficacy in the treatment of severe depression [93]. It is typically initiated when patients fail to respond to pharmacotherapy and psychotherapy. Circumstances in which ECT can be considered first-line treatment include situations that require a rapid response (severe inanition, weight loss, or suicidality), situations where risks of ECT are lower than that of alternative treatments, previous positive response to ECT, or strong patient preference [94]. ECT is performed under general anesthesia and involves the induction of a generalized tonic-clonic seizure, which is theorized to enhance serotonergic, noradrenergic, and dopaminergic neurotransmission. A typical course of ECT involves treatments 3 times a week for an average of 6 to 12 treatments in total [95]. Elderly patients and those suffering from severe depression with psychotic features respond more robustly to ECT [93,96]. Estimated remission rates after an ECT series have been higher than 80% [93], making this modality the most effective treatment for severe depression to date.

Conclusion

As the population continues to age, clinicians are increasingly likely to encounter patients with late-life depression. A thorough evaluation includes not only assessment of depressive symptoms, but also cognitive, functional, and suicide assessment. Treatment options include pharmaco-therapy, psychotherapy, and in some cases electroconvulsive therapy. Utilization of assessment and treatment nuances unique to the geriatric population, with a multidisciplinary and collaborative approach involving primary care, mental health, and other ancillary providers, will serve to ultimately enhance patient care.

Corresponding author: Corresponding author: Juliet Glover, MD, Dept. of Neuropsychiatry and Behavioral Science, Univ. of South Carolina School of Medicine, 15 Medical Park, Suite 301, Columbia, SC 29203, Juliet.Glover@uscmed.sc.edu.

Financial disclosures: None reported.

Author contributions: conception and design, JAG, SS; drafting of article, JAG, SS; critical revision of the article, JAG, SS.

From the Department of Neuropsychiatry and Behavioral Sceince, University of South Carolina School of Medicine, Columbia, SC.

Abstract

• Objective: To review the identification, clinical assessment and treatment of patients with late-life depression.
• Methods: Review of the literature.
• Results: Depressive symptoms are present in up to 1 in 4 older adults. Comprehensive evaluation of depressive symptoms in this population often requires a multidisciplinary and collaborative approach between primary care, mental health, and other ancillary providers. Key aspects include a detailed history, physical and mental status examinations, cognitive and functional status assessment, and suicide risk assessment. Treatment options include anti-depressants, psychotherapy, and electroconvulsive therapy.
• Conclusion: A systematic approach to evaluating depressive symptoms in the elderly can enhance timely recognition and treatment.

Key words: Late-life depression; clinical assessment; antidepressants; psychotherapy; electroconvulsive therapy.

The U.S. population is aging, and with this comes the potential for increased health care needs. In 2014, there were over 46 million Americans age 65 and over (14.5% of the U.S. population). This number is projected to increase to 88 million by the year 2050 [1]. One in 4 older adults suffers with depressive symptoms that cause distress and functional impairment [2]. The World Health Organization Global Burden of Disease Study found depressive disorders to be the leading cause of disability-adjusted life years (DALYs) and the second leading cause of years lived with disability (YLDs). The burden of disease due to depressive disorders increased by 37.5% between 1990 and 2010, and 10.4% was attributable to aging [3]. These figures underscore the importance of accurate assessment and treatment of depression in the elderly. In this article, we review the identification, clinical assessment, and treatment of patients with late-life depression.

Diagnostic Criteria

Prevalence

It is estimated that 1% to 4% of community-dwelling adults age 65 and older suffer from MDD, with women more likely to be affected than men (prevalence of 4.4% vs. 2.7) [2,5–7]. This estimate is low compared with lifetime prevalence of almost 20% in the general adult population [8]. However, when depressive symptoms that do not meet criteria for MDD are considered, prevalence rates increase up to 25% [2,9]. These estimates also vary by clinical setting, with the highest rates (up to 40%) among elderly patients in long-term care facilities [10,11]. While individuals with subsyndromal depression may experience fewer symptoms than those with MDD, clinically significant distress persists, impacting health and functional status. Depression is associated with overall poor social or occupational functioning, cognitive decline, increased health care utilization and cost, increased morbidity and mortality from medical illness, and increased suicide mortality [5,9,10,12].

Identifying LLD

Accurate identification of LLD also requires recognition of the differences in the presentation of LLD compared with onset in earlier life. Depression in younger adults is often marked by depressed mood and loss of interest [18]. In contrast, older adults may present with increased anger or irritability [5]. Younger adults are more likely to report suicidal thoughts while older patients report feelings of hopelessness and thoughts of death [18]. LLD is often characterized by increased somatic complaints, hypochondriasis, or pain [5,18,19]. Another major difference lies in the presentation of cognitive difficulties. Younger patients typically complain of poor concentration or indecisiveness. Geriatric patients may present with cognitive changes including objective findings of slower processing speed and executive dysfunction on neuropsychological testing [17].

Depression rating scales may aid in identification of LLD. They are not a substitute for clinical diagnosis but can be useful as screening tools. Two commonly utilized depression rating scales are the Geriatric Depression Scale (GDS) and the Patient Health Questionnaire-9 (PHQ-9). GDS is a 30-item instrument developed specifically for older adults. Shorter 15-item, 5-item, and 4-item versions exist. The scale utilizes a Yes/No format and can be self- or clinician-administered [20]. One advantage of the GDS lies in its focus on psychological and cognitive aspects of depression rather than neurovegetative symptoms that may overlap with medical illnesses common in older adults [21]. The PHQ-9 is a 9-item self- or clinician-administered screening tool designed for use in primary care settings and has also been validated in geriatric populations [22,23]. The 9 items on this scale correspond to the DSM-5 criteria for major depression. A shorter 2-item version (PHQ-2) has also been validated, and a positive screen on this test should prompt administration of the full-length version. Both versions have approximately 80% sensitivity and specificity in detecting depression. An added advantage of PHQ-9 over GDS is that it can be useful in monitoring treatment response over time [22,23]

Comprehensive Assessment of LLD

The comprehensive assessment of patients with LLD can be carried out by health professionals in both mental health or primary care settings. In a multidisciplinary approach, psychiatrists and mental health professionals have collaborated with primary care providers using depression care managers with successful outcomes in managing depression in older adults [24,25]. Complete evaluation of a patient with suspected LLD begins with a history and physical and mental status examination. Other essential components of the evaluation include assessment of cognition, functional status, and suicide risk. Laboratory and neuroimaging studies may be necessary as well. Due to the comprehensive nature of this assessment, a multidisciplinary approach with collaboration between primary care, psychiatry, psychology, and ancillary services such as social work may be necessary. Multiple patient interactions may be required to complete a thorough evaluation.

History and Mental Status Examination

As with many other psychiatric illnesses, LLD is a clinical diagnosis. A careful history should be obtained initially utilizing open-ended questions. This should be followed by more directed questions as indicated to elicit the presence of depressive symptoms. The history should be obtained from the patient. A relevant collateral informant can be invaluable in the assessment, especially in cases where there is a comorbid neurocognitive disorder. However, the patient’s informed consent must be obtained prior to obtaining collateral information whenever possible. Psychosocial stressors that may have precipitated or may be perpetuating symptoms should be explored. Such stressors may include recent changes in living situation, loss of social support, recent deaths, or financial difficulties. Biological precipitants also need to be explored including presence of physical illness, depressogenic medications, and comorbid alcohol or other substance use. The patient’s past psychiatric history, psychiatric hospitalizations, and past medication trials should be ascertained. Any family history of depression, other psychiatric disorders, substance use disorders, and suicide attempts should be documented. A full mental status exam including cognitive assessment should be completed [21,26].

Cognitive Assessment

Cognitive impairment can be associated with LLD and may be due to the underlying depression or represent a comorbid neurocognitive disorder. Furthermore, the burden of medical illness as well as cerebrovascular and cardiovascular risk factors have been linked to executive dysfunction and reduced processing speed in individuals with LDD [27,28]. Distinguishing between these can be challenging; however, chronology of symptom onset is often helpful. Depression is more likely the etiology of cognitive impairment when depressive symptoms precede onset of cognitive deficits. This type of cognitive impairment is termed dementia syndrome of depression and may improve with treatment of depression [5]. Some patients may progress to develop major cognitive decline, and it remains unclear whether LLD represents a risk factor or prodrome to developing a major neurocognitive disorder [29]. On the other hand, if depression develops later in the course of cognitive decline, there may be an underlying neurocognitive disorder [17]. Up to 20% of individuals with major neurocognitive disorder due to Alzheimer’s disease also have major depression [11]. For these reasons, concomitant assessment of cognition is essential to the evaluation of the older adult presenting with depressive symptoms [30]. Cognitive domains that may be affected include learning and memory, language, attention, perceptual motor abilities, social cognition, and executive function [4]. Many of these domains can be assessed during the mental status examination, with brief cognitive screening tools, or with formal neuropsychological testing.

While there are numerous cognitive screening tools, some commonly used, brief tools include the Mini-Cog, the Folstein Mini-Mental State Exam (MMSE), and the Montreal Cognitive Assessment (MoCA). The Mini-Cog consists of a 3-item registration, delayed recall, and clock drawing test and has several advantages over other screening tools. It is a brief test (taking approximately 3 minutes to administer) with good sensitivity and specificity of 80% or greater. Compared with other cognitive screening tools, it is less influenced by level of education, language, or cultural background [31–33]. The MMSE is a longer screening tool consisting of 19 items and requires about 10 minutes to administer. Unlike the Mini-Cog, performance on the MMSE can be affected by level of education and cultural background. However, the MMSE can be administered serially to monitor changes in cognition over time [34,35]. The MoCA is a 10-minute cognitive screening tool first developed to detect mild cognitive impairment (MCI) [36]. The MoCA consists of 7 subscore sections covering visuospatial/executive function, naming, memory (delayed recall), attention, language, abstraction, and orientation. The total score is 30, and 1 point is added to the score if the testing subject has less than high school/12 years of education. The MoCA has demonstrated better sensitivity than the MMSE for the detection of MCI [36]. Elderly patients with depression often perform poorly on these cognitive screening tests due to apathy and poor effort.

Functional Assessment

The diagnosis of LLD requires that symptoms cause significant distress or interfere with functioning. A functional assessment is especially important in the evaluation of the older adult in that it allows clinicians to determine an individual’s ability to live independently and attend to daily needs. Basic activities of daily living (ADLs) include bathing, dressing, grooming, toileting, and self-transferring. Instrumental activities of daily living (IADLs) include more complex daily activities such as preparing meals, administering medications, driving, managing finances, and using simple electronics such as the telephone or remote control [26]. Impairment in IADLs is associated with increased depression severity. Conversely, the severity of depressive symptoms along with associated cognitive impairment predicts IADL impairment [37]. The Philadelphia Multilevel Assessment Instrument is a tool that can aid in the assessment of ADLs and IADLs and has been utilized in studies examining disability in depressed elderly patients [37,38]. Other available scales to quantify functional status include OARS Physical Activities of Daily Living, OARS Instrumental Activities of Daily Living Scale, and Direct Assessment of Functional Status Scale [26].

Suicide Assessment

Assessment for suicidality is an integral part of all psychiatric evaluations and is especially important in the evaluation of the depressed older adult. According to the Centers for Disease Control and Prevention, the suicide rate for individuals age 65 and older is 16.6 per 100,000, a figure that is comparable to that for individuals 18–64 years of age [39]. Non-Hispanic Caucasian males age 85 and older have the highest rate of completed suicide (56.5 per 100,000), underscoring the importance of a thorough suicide assessment [39]. Suicidality can range from passive thoughts of death and wishing that one were not alive, to active thoughts of self-harm with plan and intent. A Canadian study found 2% of community-dwelling adults age 55 and older had suicidal thoughts over a 12-month period and, of these, 28% had major depression [40]. A suicide assessment begins with inquiring about the presence of suicidal thoughts, plans, and intent. The 3 most frequently used methods of completed suicide in the elderly are firearms (28%), hanging (24%) and poisoning (21%) [41]. Access to weapons or other lethal means of self-harm such has hoarding of medications should be ascertained.

A complete suicide assessment requires attention to suicide risk factors, protective factors, and warning signs of impending suicide. Risk factors for suicide in the older adult include mood disorders, chronic medical illnesses and associated functional impairment, chronic pain, and psychosocial factors such as social isolation [42]. Mood disorders are present in 54% to 87% of cases of completed suicide, with major depression being the most common [42]. Chronic medical illness and pain can result in functional impairment leading to feelings of excessive guilt or being a burden to loved ones. Protective factors such as social connectedness, spirituality, religious beliefs, and cultural attitudes against suicide may serve as buffers against these risk factors [43]. Warning signs of impending suicide may indicate preparations for suicide and include feelings of hopelessness or lack of purpose, feeling trapped, talking about death, threatening suicide, agitation, social withdrawal, increased substance use and reckless behavior. Warning signs should prompt action to ensure the safety of the individual [44,45].

Physical Examination, Laboratory Studies, and Neuroimaging

Evaluation of LLD is not complete without a physical examination and ancillary studies to identify underlying medical conditions possibly contributing to or mimicking depressive symptoms. Routine laboratory studies include complete blood count, complete metabolic panel, thyroid studies, and urine drug screen. Signs and symptoms of underlying medical conditions may necessitate further laboratory studies [46]. Neuroimaging may reveal signs of cerebrovascular disease which can predispose, precipitate, or perpetuate depression in older adults [47].

Treatment

Treatment of LLD can take many forms and occur in various settings. Geriatric psychiatrists have expertise in the assessment and treatment of mental illness in the elderly. Workforce estimates for 2010 revealed 1 geriatric psychiatrist per 10,000 adults age 75 and over. This figure is estimated to decrease to 0.5 per 10,000 by the year 2030, underscoring the importance of increasing the knowledge base of clinicians across specialties who provide care to the depressed elderly [48]. The primary care setting is often the locus of care for depression in older adults; however, studies suggest that patients are often left untreated or undertreated [49]. Collaborative care models whereby mental health care is integrated into primary care have been shown to improve outcomes. The Prevention of Suicide in Primary Care Elderly: Collaborative Trial (PROSPECT) study found that use of care managers to assist primary care providers in identification of depression, offer algorithm-based treatment recommendations, monitor symptoms and medication side effects, and provide follow-up yielded improvement in outcomes. Patients in the intervention group were more likely to receive pharmacotherapy or psychotherapy, achieve remission, and showed greater decline in suicidal ideation [50]. Similar results were found in the Improving Mood-Promoting Access to Collaborative Treatment (IMPACT) study in which intervention patients treated under a collaborative care model showed lower depression severity, less functional impairment, and greater reduction in depressive symptoms [25].

Just as a collaborative care model can lead to improved outcomes, the overall strategy of treating depression must be multifaceted. The biopsychosocial model of disease first described in the 1970s emphasizes biological and psychosocial determinants of illness that must be addressed when treatment is considered [51]. This includes nonmodifiable biological factors such as age, gender, and genetic predisposition that may affect treatment options, as well as modifiable biological factors such as comorbid medical illness, medications, or substance use disorders. Psychological factors that can affect depressive symptoms include coping skills and defense mechanisms in the face of stressful life events. Social factors including the role of culture, environment, and family dynamics in disease presentation must be considered as well [52].

Pharmacologic Treatment of LLD

The primary pharmacologic treatment for depression is antidepressants. Treatment consists of 3 phases—acute, continuation, and maintenance. In the acute phase, the goal is remission of current symptoms and restoration of function. The continuation phase, extending up to 6 months after remission, aims to prevent relapse back into a depressive episode. Maintenance therapy is geared at preventing recurrence of future depressive episodes [53]. Studies have found a 50% risk of relapse after 1 episode of depression and 80% after 2 episodes. Up to 20% will develop chronic symptoms. For this reason, maintenance therapy is often necessary for recurrent depression [54].

While cognitive impairment may affect antidepressant efficacy, age does not appear to be a determinant. Gildengers et al examined antidepressant response in young, middle, and older-old patients and found no significant difference in response rates [59]. Early onset versus late onset of first depressive episode also does not predict antidepressant response in patients age 55 and over [60]. There is scant evidence for efficacy of antidepressants in depressed patients with neurocognitive disorders. A 2002 Cochrane review with 4 studies in the meta-analysis (n = 137) concluded that there was weak support for antidepressant efficacy in this population [61]. A 2011 meta-analysis with 330 participants also yielded inconclusive results [62]. The paucity of evidence for antidepressant efficacy in depressed patients with neurocognitive disorders should prompt careful consideration of potential benefits versus adverse effects.

Antidepressants are generally well tolerated in older adults. Side effects vary by medication and contribute to discontinuation in up to 25% of new users (versus 22% for new users who discontinue for reasons other than side effects) [63]. Potential adverse effects shared by most SSRIs and SNRIs include GI disturbance (nausea, diarrhea or constipation), sexual dysfunction, headache, and sleep disturbance [64,65]. In addition, abrupt discontinuation can precipitate serotonin withdrawal syndrome characterized by sensory disturbance (paresthesia, tremor, and irritability) as well as headache, lightheadedness, diaphoresis, insomnia, and agitation. Other medication-specific side effects include risk of seizure with bupropion and sedation with mirtazapine [65].

Despite superiority of antidepressants to placebo in treating depression, up to one-third of patients may not respond to a trial of antidepressants. Sequential treatment protocols such as switching to a different antidepressant or augmentation can increase the proportion of antidepressant responders [66–68]. Studies have found particularly favorable response to augmentation with lithium, with one study achieving a 33% remission rate in treatment- resistant geriatric depression [67,69]. Other pharmacologic augmentation strategies include the addition of mood stabilizers such as lamotrigine, antipsychotics (aripiprazole, olanzapine, quetiapine, and risperidone), and psychostimulants [70–73]. Electroconvulsive therapy (ECT) is a nonpharmacologic option for treatment-resistant depression that will be reviewed later.

Psychotherapeutic and Psychosocial Interventions

Psychotherapeutic interventions have demonstrated efficacy in the treatment of geriatric depression, including but not limited to cognitive behavioral therapy (CBT), interpersonal therapy (IPT), problem-solving therapy (PST), reminiscence and life review, and brief psychodynamic psychotherapy [74]. Some older adults may prefer psychotherapy to pharmacologic treatment (57% vs. 43%) [75]. Potential benefits of psychotherapy include ability to directly address psychosocial stressors that may precipitate or perpetuate depressive symptoms. In addition, psychotherapy is associated with few to no side effects and avoids drug interactions. Barriers to employing psychotherapy may include cost and access to trained psychotherapists [76]. Efficacy of several psychotherapeutic approaches in the care of older depressed adults has been examined. CBT, brief psychodynamic psychotherapy, and IPT will be briefly reviewed here.

CBT. Cognitive therapy was first described by Aaron Beck in the 1960s [77]. It is a highly structured therapy built on the premise that beliefs and assumptions an individual holds can influence emotions and behavior. CBT aims to identify maladaptive belief systems, test the validity of these cognitive distortions, and help individuals formulate more realistic cognitions [78]. Symptom improvement results from addressing these cognitive aspects as well as integration of behavioral activation and skills training to overcome maladaptive behavioral patterns [78]. CBT approaches have been applied to older adults with depression and results show acceptability [79] and efficacy in this population [80–82]. A 2008 Cochrane review (n = 153) found CBT to be superior to waitlist controls [82].

Brief psychodynamic psychotherapy. Brief psychodynamic psychotherapy, unlike highly structured CBT, aims to alter behavior by examining how past experiences and unresolved conflicts influence current emotions and behavior. While studies on application to the treatment of geriatric depression are scarce, limited data demonstrate efficacy in treating geriatric depression [81] and no significant difference in outcomes when compared to CBT [82].

IPT. Like CBT, IPT is a structured time-limited psychotherapeutic treatment approach first developed in the late 1960s by Klerman and Weissman [83]. IPT focuses on the impact of interpersonal relationships on depressive symptoms and examines 4 domains: interpersonal conflict, interpersonal deficits, role transitions, and grief [74].

Studies have shown efficacy of IPT in reducing depressive symptoms in the elderly when compared to usual care [84]. Reynolds et al found IPT combined with nortriptyline (a tricyclic antidepressant) to be superior to either nortriptyline alone or IPT alone in preventing recurrent depressive episodes [85]. Interestingly, a similar study investigating the efficacy of IPT in combination with paroxetine (an SSRI) failed to show added benefit of IPT in preventing recurrence, suggesting that further studies are needed [86].

Psychosocial interventions are integral in the care of the elderly depressed patient. Studies have shown positive benefits of aerobic exercise on depressive symptoms [87]. Yoga, Tai Chi, and other mindfulness-based exercises can increase sense of emotional and physical wellbeing [88–90]. Spirituality, religious beliefs, and involvement with a faith group may be protective against development of mental illness while at the same time provide avenues for increased social connectedness [91]. These and other avenues for socialization should be encouraged as part of the treatment plan for older depressed patients [92]

Electroconvulsive Therapy

ECT is indicated for the treatment of mood and psychotic disorders and has demonstrated efficacy in the treatment of severe depression [93]. It is typically initiated when patients fail to respond to pharmacotherapy and psychotherapy. Circumstances in which ECT can be considered first-line treatment include situations that require a rapid response (severe inanition, weight loss, or suicidality), situations where risks of ECT are lower than that of alternative treatments, previous positive response to ECT, or strong patient preference [94]. ECT is performed under general anesthesia and involves the induction of a generalized tonic-clonic seizure, which is theorized to enhance serotonergic, noradrenergic, and dopaminergic neurotransmission. A typical course of ECT involves treatments 3 times a week for an average of 6 to 12 treatments in total [95]. Elderly patients and those suffering from severe depression with psychotic features respond more robustly to ECT [93,96]. Estimated remission rates after an ECT series have been higher than 80% [93], making this modality the most effective treatment for severe depression to date.

Conclusion

As the population continues to age, clinicians are increasingly likely to encounter patients with late-life depression. A thorough evaluation includes not only assessment of depressive symptoms, but also cognitive, functional, and suicide assessment. Treatment options include pharmaco-therapy, psychotherapy, and in some cases electroconvulsive therapy. Utilization of assessment and treatment nuances unique to the geriatric population, with a multidisciplinary and collaborative approach involving primary care, mental health, and other ancillary providers, will serve to ultimately enhance patient care.

Corresponding author: Corresponding author: Juliet Glover, MD, Dept. of Neuropsychiatry and Behavioral Science, Univ. of South Carolina School of Medicine, 15 Medical Park, Suite 301, Columbia, SC 29203, Juliet.Glover@uscmed.sc.edu.

Financial disclosures: None reported.

Author contributions: conception and design, JAG, SS; drafting of article, JAG, SS; critical revision of the article, JAG, SS.

Topical management of acne vulgaris (AV) incorporates a variety of agents with diverse modes of action (MOAs), including retinoids and antibiotics.^1-3 The first topical retinoid developed for acne therapy was tretinoin, available in the United States since 1971.^2,4 Topical retinoids, including tretinoin, exhibit multiple pharmacologic effects that are believed to correlate with efficacy for acne treatment,^1,2,4,5 such as the reduction of inflammatory and comedonal lesions and contribution to dermal matrix remodeling.^1,2,4-9 The predominant topical antibiotic used for acne treatment, often in combination with benzoyl peroxide (BP) and/or a topical retinoid, is clindamycin. Clindamycin is a lincosamide antibiotic that is closely related to erythromycin, a member of the macrolide antibiotic category.^1,3,10 Available data support that over time topical clindamycin has sustained greater efficacy in reducing AV lesions than topical erythromycin; the latter also has been shown to exhibit a greater prevalence of Propionibacterium acnes resistance than clindamycin.^1,3,10-12

Combination gel formulations of clindamycin phosphate 1.2%–tretinoin 0.025% (CP-Tret) are approved by the US Food and Drug Administration and available in the United States for once-daily treatment of AV in patients 12 years of age and older.^13-15 Large-scale randomized controlled trials (RCTs) have demonstrated both efficacy and safety for these formulations.^16,17 This article reviews important considerations related to both individual active ingredients (clindamycin phosphate [CP] and tretinoin [Tret]), formulation characteristics, and data from pivotal RCTs with a CP-Tret gel that has more recently been reintroduced into the US marketplace for acne therapy (Veltin, Aqua Pharmaceuticals).

What is the rationale behind combining CP and Tret in a single combination formulation?

Clindamycin is a lincosamide antibiotic that has been used for the treatment of AV for approximately 5 decades.^1,3,10,17 The main MOA of clindamycin in the treatment of AV is believed to be reduction of P acnes; however, anti-inflammatory effects maypotentially play some role in AV lesion reduction.^{3,10,12,17-19} Multiple RCTs completed over approximately 3 decades and inclusive of more than 2000 participants treated topically with clindamycin as monotherapy have shown that the efficacy of this agent in reducing AV lesions has remained consistent overall,^3,20-24 unlike topical erythromycin, which did not sustain its efficacy over a similar comparative time period.²⁰ Importantly, these data are based on RCTs designed to evaluate the efficacy and safety of individual agents, including topical clindamycin; however, topical antibiotic therapy is not recommended as monotherapy for AV treatment due to emergence of antibiotic-resistant bacterial strains.^{1,3,11,12,25-28} Although the prevalence of resistant strains of P acnes is lower in the United States and many other countries for clindamycin versus erythromycin, the magnitude of clindamycin-resistant P acnes strains increases and response to clindamycin therapy may decrease when this agent is used alone.^{12,25-27,29,30} Therefore, it is recommended that a BP formulation that exhibits the ability to adequately reduce P acnes counts be used concurrently with antibiotic therapy for AV to reduce the emergence and proliferation of antibiotic-resistant P acnes organisms; short-contact BP therapy using a high-concentration (9.8%) emollient foam formulation and sufficient contact time (ie, 2 minutes) prior to washing off also has been shown to markedly reduce truncal P acnes organism counts.^{1,3,10-12,25-33} The Table depicts the major characteristics of clindamycin related to its use for treatment of AV.

Tretinoin has been used extensively for the treatment of AV since its introduction in the United States in 1971.^1,2,4,5 The proposed MOAs of topical retinoids, including tretinoin, based on available data include a variety of pharmacologic effects such as inhibition of follicular hyperkeratosis (decreased microcomedone formation), modulation of keratinocyte differentiation, anti-inflammatory properties, and inhibition of dermal matrix degradation (Figure).^{1,2,4,5,14,34,35} Topical retinoids, including tretinoin, have been shown to reduce both inflammatory and comedonal acne lesions, likely due to multiple MOAs, and are devoid of antibiotic properties.^2,4-8,16 Available data support that topical combination therapy for AV with a retinoid and a topical antimicrobial agent augments the therapeutic benefit as compared to use of either agent alone.^{1-4,12,15,16,28,31,32}

The rationale for incorporating both clindamycin and tretinoin together into one topical formulation includes combining different MOAs that appear to correlate with suppression of AV lesion formation and to improve patient adherence through once-daily application of a single topical product.^16,31,32,36 Importantly, formulation researchers were able to combine CP-Tret into a specific aqueous gel formulation that maintained the stability of both active ingredients and proved to be effective and safe in preliminary studies completed in participants with AV.^16,23,37-39 This aqueous formulation incorporated a limited number of excipients with low to negligible potential for cutaneous irritation or allergenicity, including anhydrous citric acid (chelating agent, preservative, emulsifier, acidulent), butylated hydroxytoluene (antioxidant), carbomer homopolymer type C (thickening agent, dispersing agent, biocompatible gel matrix), edetate disodium (chelating agent), laureth 4 (emulsifier, dissolution agent), methylparaben (preservative), propylene glycol (low-concentration humectant), purified water (diluent), and tromethamine (buffer, permeability enhancer).¹⁴

What are the clinical data evaluating the efficacy and tolerability/safety of the specific aqueous-based gel formulation of CP-Tret?

An aqueous-based gel formulation (referred to in the literature as a hydrogel) of CP-Tret is devoid of alcohol and contains the excipients described above.¹⁴ This formulation was shown to be efficacious, well tolerated, and safe in smaller clinical studies of participants with AV.^23,37-39 Two large-scale phase 3 studies were completed (N=2219), powered to compare the efficacy and tolerability/safety of CP-Tret hydrogel (n=634) versus CP hydrogel (n=635), Tret hydrogel (n=635), and vehicle hydrogel (n=315) in participants with facial AV. All 4 study drug formulations in both studies—CP-Tret, CP, Tret, vehicle—used the same hydrogel vehicle, hereafter referred to simply as gel.¹⁶

In both trials, participants 12 years of age and older with AV were randomized to active drug groups versus vehicle (2:2:2:1 randomization), each applied once daily at bedtime for 12 weeks.¹⁶ The baseline demographics among all 4 study groups were well matched, with approximately two-thirds of white participants and one-third Asian (2%–3%), black (19%–21%), or Hispanic (9%–10%). Approximately half of enrolled participants were 16 years of age or younger (mean age [range], 19.0–20.2 years). Enrolled participants in each study group presented at baseline predominantly with facial AV of mild (grade 2 [20%–23% of enrolled participants]) or moderate (grade 3 [60%–62% of enrolled participants]) severity based on a protocol-mandated, 6-point investigator static global assessment scale. Investigator static global assessment scores and acne lesion counts, including noninflammatory (comedonal), inflammatory (papules, pustules), and total AV lesions, were evaluated at baseline and weeks 2, 4, 8, and 12 (end of study [EOS]). Among the 4 study groups at baseline, the range of mean lesion counts was 27.7 to 29.3 for noninflammatory lesions, 26.0 to 26.4 for inflammatory lesions, and 76.4 to 78.3 for total lesions. All enrolled participants met protocol-mandated, standardized, inclusion, exclusion, and prestudy washout period criteria.¹⁶

The primary efficacy end points determined based on intention-to-treat analysis were the percentage reduction in all 3 lesion counts at EOS compared to baseline and the proportion of participants who achieved scores of clear (grade 0) or almost clear (grade 1) at EOS. The secondary end point parameter was time to 50% reduction in total lesion counts.¹⁶

The study efficacy outcomes were as follows: The mean percentage reduction in inflammatory lesions at EOS versus baseline was significantly higher in the CP-Tret group than in each of the other 3 groups (CP-Tret, 53.4%; CP, 47.5%; Tret, 43.3%; vehicle, 30.3%)(P<.005).¹⁶ The mean percentage reduction in noninflammatory lesions at EOS versus baseline was significantly higher in the CP-Tret group than in each of the other 3 groups (CP-Tret, 45.2%; CP, 31.6%; Tret, 37.9%; vehicle, 18.5%)(P≤.0004). The mean percentage reduction in total AV lesions at EOS versus baseline was significantly higher in the CP-Tret group than in each of the other 3 groups (CP-Tret, 48.7%; CP, 38.3%; Tret, 40.3%; vehicle, 23.2%)(P≤.0001). The median time to 50% reduction in total AV lesion counts was significantly faster with CP-Tret (8 weeks) compared to the other 3 groups (CP, 12 weeks [P<.0001]; Tret, 12 weeks [P<.001]; vehicle, not reached by EOS [P<.0001]). The consistency of results, methodologies, and overall study characteristics between the 2 phase 3 RCTs allowed for accurate pooling of data.¹⁶

Tolerability and safety assessments were completed at each visit for all enrolled participants. No adverse events (AEs) were noted in approximately 90% of enrolled participants.¹⁶ The most common AEs noted over the course of the study were mild to moderate application-site reactions (eg, dryness, erythema, burning, pruritus, desquamation), mostly correlated with the 2 groups containing tretinoin—CP-Tret and Tret—which is not unanticipated with topical retinoid use; 1.2% of these participants withdrew from the study due to such application-site AEs. No serious AEs or systemic safety signals emerged during the study.¹⁶

What summarizing statements can be made about CP-Tret gel from these study results that may be helpful to clinicians treating patients with AV?

The gel formulation of CP-Tret incorporates active ingredients that target different pathophysiologic cascades in AV, providing antimicrobial, anti-inflammatory, and anticomedonal effects.

Applied once daily, CP-Tret gel demonstrated the ability to achieve complete or near-complete clearance of comedonal and papulopustular facial AV lesions of mild to moderate severity in approximately 40% of participants within 12 weeks of use in 2 large-scale RCTs.¹⁶ The ability to achieve a median 50% reduction in total lesions by 8 weeks of use provides relevant information for patients regarding reasonable expectations with therapy.

The favorable cutaneous tolerability profile and low number of AEs demonstrated with CP-Tret gel are major considerations, especially as skin tolerability reactions can impede patient adherence with treatment. Any issues that interfere with achieving a favorable therapeutic outcome can lead to patients giving up with their therapy.

The large number of patients with skin of color treated with CP-Tret gel (n=209) in the 2 phase 3 RCTs is important, as the spectrum of racial origins, skin types, and skin colors seen in dermatology practices is diversifying across the United States. Both clinicians and patients with skin of color are often concerned about the sequelae of medication-induced skin irritation, which can lead to ensuing dyschromia.

Concerns related to potential development of clindamycin-resistant P acnes with CP-Tret gel may be addressed by concurrent use of BP, including with leave-on or short-contact therapy.

Although phase 3 RCTs evaluate therapeutic agents as monotherapy, in real world clinical practice, combination topical regimens using different individual products are common to optimize therapeutic outcomes. Advantages of the CP-Tret gel formulation, if a clinician desires to use it along with another topical product, are once-daily use and the low risk for cutaneous irritation.

Topical management of acne vulgaris (AV) incorporates a variety of agents with diverse modes of action (MOAs), including retinoids and antibiotics.^1-3 The first topical retinoid developed for acne therapy was tretinoin, available in the United States since 1971.^2,4 Topical retinoids, including tretinoin, exhibit multiple pharmacologic effects that are believed to correlate with efficacy for acne treatment,^1,2,4,5 such as the reduction of inflammatory and comedonal lesions and contribution to dermal matrix remodeling.^1,2,4-9 The predominant topical antibiotic used for acne treatment, often in combination with benzoyl peroxide (BP) and/or a topical retinoid, is clindamycin. Clindamycin is a lincosamide antibiotic that is closely related to erythromycin, a member of the macrolide antibiotic category.^1,3,10 Available data support that over time topical clindamycin has sustained greater efficacy in reducing AV lesions than topical erythromycin; the latter also has been shown to exhibit a greater prevalence of Propionibacterium acnes resistance than clindamycin.^1,3,10-12

Combination gel formulations of clindamycin phosphate 1.2%–tretinoin 0.025% (CP-Tret) are approved by the US Food and Drug Administration and available in the United States for once-daily treatment of AV in patients 12 years of age and older.^13-15 Large-scale randomized controlled trials (RCTs) have demonstrated both efficacy and safety for these formulations.^16,17 This article reviews important considerations related to both individual active ingredients (clindamycin phosphate [CP] and tretinoin [Tret]), formulation characteristics, and data from pivotal RCTs with a CP-Tret gel that has more recently been reintroduced into the US marketplace for acne therapy (Veltin, Aqua Pharmaceuticals).

What is the rationale behind combining CP and Tret in a single combination formulation?

Clindamycin is a lincosamide antibiotic that has been used for the treatment of AV for approximately 5 decades.^1,3,10,17 The main MOA of clindamycin in the treatment of AV is believed to be reduction of P acnes; however, anti-inflammatory effects maypotentially play some role in AV lesion reduction.^{3,10,12,17-19} Multiple RCTs completed over approximately 3 decades and inclusive of more than 2000 participants treated topically with clindamycin as monotherapy have shown that the efficacy of this agent in reducing AV lesions has remained consistent overall,^3,20-24 unlike topical erythromycin, which did not sustain its efficacy over a similar comparative time period.²⁰ Importantly, these data are based on RCTs designed to evaluate the efficacy and safety of individual agents, including topical clindamycin; however, topical antibiotic therapy is not recommended as monotherapy for AV treatment due to emergence of antibiotic-resistant bacterial strains.^{1,3,11,12,25-28} Although the prevalence of resistant strains of P acnes is lower in the United States and many other countries for clindamycin versus erythromycin, the magnitude of clindamycin-resistant P acnes strains increases and response to clindamycin therapy may decrease when this agent is used alone.^{12,25-27,29,30} Therefore, it is recommended that a BP formulation that exhibits the ability to adequately reduce P acnes counts be used concurrently with antibiotic therapy for AV to reduce the emergence and proliferation of antibiotic-resistant P acnes organisms; short-contact BP therapy using a high-concentration (9.8%) emollient foam formulation and sufficient contact time (ie, 2 minutes) prior to washing off also has been shown to markedly reduce truncal P acnes organism counts.^{1,3,10-12,25-33} The Table depicts the major characteristics of clindamycin related to its use for treatment of AV.

Tretinoin has been used extensively for the treatment of AV since its introduction in the United States in 1971.^1,2,4,5 The proposed MOAs of topical retinoids, including tretinoin, based on available data include a variety of pharmacologic effects such as inhibition of follicular hyperkeratosis (decreased microcomedone formation), modulation of keratinocyte differentiation, anti-inflammatory properties, and inhibition of dermal matrix degradation (Figure).^{1,2,4,5,14,34,35} Topical retinoids, including tretinoin, have been shown to reduce both inflammatory and comedonal acne lesions, likely due to multiple MOAs, and are devoid of antibiotic properties.^2,4-8,16 Available data support that topical combination therapy for AV with a retinoid and a topical antimicrobial agent augments the therapeutic benefit as compared to use of either agent alone.^{1-4,12,15,16,28,31,32}

The rationale for incorporating both clindamycin and tretinoin together into one topical formulation includes combining different MOAs that appear to correlate with suppression of AV lesion formation and to improve patient adherence through once-daily application of a single topical product.^16,31,32,36 Importantly, formulation researchers were able to combine CP-Tret into a specific aqueous gel formulation that maintained the stability of both active ingredients and proved to be effective and safe in preliminary studies completed in participants with AV.^16,23,37-39 This aqueous formulation incorporated a limited number of excipients with low to negligible potential for cutaneous irritation or allergenicity, including anhydrous citric acid (chelating agent, preservative, emulsifier, acidulent), butylated hydroxytoluene (antioxidant), carbomer homopolymer type C (thickening agent, dispersing agent, biocompatible gel matrix), edetate disodium (chelating agent), laureth 4 (emulsifier, dissolution agent), methylparaben (preservative), propylene glycol (low-concentration humectant), purified water (diluent), and tromethamine (buffer, permeability enhancer).¹⁴

What are the clinical data evaluating the efficacy and tolerability/safety of the specific aqueous-based gel formulation of CP-Tret?

An aqueous-based gel formulation (referred to in the literature as a hydrogel) of CP-Tret is devoid of alcohol and contains the excipients described above.¹⁴ This formulation was shown to be efficacious, well tolerated, and safe in smaller clinical studies of participants with AV.^23,37-39 Two large-scale phase 3 studies were completed (N=2219), powered to compare the efficacy and tolerability/safety of CP-Tret hydrogel (n=634) versus CP hydrogel (n=635), Tret hydrogel (n=635), and vehicle hydrogel (n=315) in participants with facial AV. All 4 study drug formulations in both studies—CP-Tret, CP, Tret, vehicle—used the same hydrogel vehicle, hereafter referred to simply as gel.¹⁶

In both trials, participants 12 years of age and older with AV were randomized to active drug groups versus vehicle (2:2:2:1 randomization), each applied once daily at bedtime for 12 weeks.¹⁶ The baseline demographics among all 4 study groups were well matched, with approximately two-thirds of white participants and one-third Asian (2%–3%), black (19%–21%), or Hispanic (9%–10%). Approximately half of enrolled participants were 16 years of age or younger (mean age [range], 19.0–20.2 years). Enrolled participants in each study group presented at baseline predominantly with facial AV of mild (grade 2 [20%–23% of enrolled participants]) or moderate (grade 3 [60%–62% of enrolled participants]) severity based on a protocol-mandated, 6-point investigator static global assessment scale. Investigator static global assessment scores and acne lesion counts, including noninflammatory (comedonal), inflammatory (papules, pustules), and total AV lesions, were evaluated at baseline and weeks 2, 4, 8, and 12 (end of study [EOS]). Among the 4 study groups at baseline, the range of mean lesion counts was 27.7 to 29.3 for noninflammatory lesions, 26.0 to 26.4 for inflammatory lesions, and 76.4 to 78.3 for total lesions. All enrolled participants met protocol-mandated, standardized, inclusion, exclusion, and prestudy washout period criteria.¹⁶

The primary efficacy end points determined based on intention-to-treat analysis were the percentage reduction in all 3 lesion counts at EOS compared to baseline and the proportion of participants who achieved scores of clear (grade 0) or almost clear (grade 1) at EOS. The secondary end point parameter was time to 50% reduction in total lesion counts.¹⁶

The study efficacy outcomes were as follows: The mean percentage reduction in inflammatory lesions at EOS versus baseline was significantly higher in the CP-Tret group than in each of the other 3 groups (CP-Tret, 53.4%; CP, 47.5%; Tret, 43.3%; vehicle, 30.3%)(P<.005).¹⁶ The mean percentage reduction in noninflammatory lesions at EOS versus baseline was significantly higher in the CP-Tret group than in each of the other 3 groups (CP-Tret, 45.2%; CP, 31.6%; Tret, 37.9%; vehicle, 18.5%)(P≤.0004). The mean percentage reduction in total AV lesions at EOS versus baseline was significantly higher in the CP-Tret group than in each of the other 3 groups (CP-Tret, 48.7%; CP, 38.3%; Tret, 40.3%; vehicle, 23.2%)(P≤.0001). The median time to 50% reduction in total AV lesion counts was significantly faster with CP-Tret (8 weeks) compared to the other 3 groups (CP, 12 weeks [P<.0001]; Tret, 12 weeks [P<.001]; vehicle, not reached by EOS [P<.0001]). The consistency of results, methodologies, and overall study characteristics between the 2 phase 3 RCTs allowed for accurate pooling of data.¹⁶

Tolerability and safety assessments were completed at each visit for all enrolled participants. No adverse events (AEs) were noted in approximately 90% of enrolled participants.¹⁶ The most common AEs noted over the course of the study were mild to moderate application-site reactions (eg, dryness, erythema, burning, pruritus, desquamation), mostly correlated with the 2 groups containing tretinoin—CP-Tret and Tret—which is not unanticipated with topical retinoid use; 1.2% of these participants withdrew from the study due to such application-site AEs. No serious AEs or systemic safety signals emerged during the study.¹⁶

What summarizing statements can be made about CP-Tret gel from these study results that may be helpful to clinicians treating patients with AV?

The gel formulation of CP-Tret incorporates active ingredients that target different pathophysiologic cascades in AV, providing antimicrobial, anti-inflammatory, and anticomedonal effects.

Applied once daily, CP-Tret gel demonstrated the ability to achieve complete or near-complete clearance of comedonal and papulopustular facial AV lesions of mild to moderate severity in approximately 40% of participants within 12 weeks of use in 2 large-scale RCTs.¹⁶ The ability to achieve a median 50% reduction in total lesions by 8 weeks of use provides relevant information for patients regarding reasonable expectations with therapy.

The favorable cutaneous tolerability profile and low number of AEs demonstrated with CP-Tret gel are major considerations, especially as skin tolerability reactions can impede patient adherence with treatment. Any issues that interfere with achieving a favorable therapeutic outcome can lead to patients giving up with their therapy.

The large number of patients with skin of color treated with CP-Tret gel (n=209) in the 2 phase 3 RCTs is important, as the spectrum of racial origins, skin types, and skin colors seen in dermatology practices is diversifying across the United States. Both clinicians and patients with skin of color are often concerned about the sequelae of medication-induced skin irritation, which can lead to ensuing dyschromia.

Concerns related to potential development of clindamycin-resistant P acnes with CP-Tret gel may be addressed by concurrent use of BP, including with leave-on or short-contact therapy.

Although phase 3 RCTs evaluate therapeutic agents as monotherapy, in real world clinical practice, combination topical regimens using different individual products are common to optimize therapeutic outcomes. Advantages of the CP-Tret gel formulation, if a clinician desires to use it along with another topical product, are once-daily use and the low risk for cutaneous irritation.

Topical management of acne vulgaris (AV) incorporates a variety of agents with diverse modes of action (MOAs), including retinoids and antibiotics.^1-3 The first topical retinoid developed for acne therapy was tretinoin, available in the United States since 1971.^2,4 Topical retinoids, including tretinoin, exhibit multiple pharmacologic effects that are believed to correlate with efficacy for acne treatment,^1,2,4,5 such as the reduction of inflammatory and comedonal lesions and contribution to dermal matrix remodeling.^1,2,4-9 The predominant topical antibiotic used for acne treatment, often in combination with benzoyl peroxide (BP) and/or a topical retinoid, is clindamycin. Clindamycin is a lincosamide antibiotic that is closely related to erythromycin, a member of the macrolide antibiotic category.^1,3,10 Available data support that over time topical clindamycin has sustained greater efficacy in reducing AV lesions than topical erythromycin; the latter also has been shown to exhibit a greater prevalence of Propionibacterium acnes resistance than clindamycin.^1,3,10-12

Combination gel formulations of clindamycin phosphate 1.2%–tretinoin 0.025% (CP-Tret) are approved by the US Food and Drug Administration and available in the United States for once-daily treatment of AV in patients 12 years of age and older.^13-15 Large-scale randomized controlled trials (RCTs) have demonstrated both efficacy and safety for these formulations.^16,17 This article reviews important considerations related to both individual active ingredients (clindamycin phosphate [CP] and tretinoin [Tret]), formulation characteristics, and data from pivotal RCTs with a CP-Tret gel that has more recently been reintroduced into the US marketplace for acne therapy (Veltin, Aqua Pharmaceuticals).

What is the rationale behind combining CP and Tret in a single combination formulation?

Clindamycin is a lincosamide antibiotic that has been used for the treatment of AV for approximately 5 decades.^1,3,10,17 The main MOA of clindamycin in the treatment of AV is believed to be reduction of P acnes; however, anti-inflammatory effects maypotentially play some role in AV lesion reduction.^{3,10,12,17-19} Multiple RCTs completed over approximately 3 decades and inclusive of more than 2000 participants treated topically with clindamycin as monotherapy have shown that the efficacy of this agent in reducing AV lesions has remained consistent overall,^3,20-24 unlike topical erythromycin, which did not sustain its efficacy over a similar comparative time period.²⁰ Importantly, these data are based on RCTs designed to evaluate the efficacy and safety of individual agents, including topical clindamycin; however, topical antibiotic therapy is not recommended as monotherapy for AV treatment due to emergence of antibiotic-resistant bacterial strains.^{1,3,11,12,25-28} Although the prevalence of resistant strains of P acnes is lower in the United States and many other countries for clindamycin versus erythromycin, the magnitude of clindamycin-resistant P acnes strains increases and response to clindamycin therapy may decrease when this agent is used alone.^{12,25-27,29,30} Therefore, it is recommended that a BP formulation that exhibits the ability to adequately reduce P acnes counts be used concurrently with antibiotic therapy for AV to reduce the emergence and proliferation of antibiotic-resistant P acnes organisms; short-contact BP therapy using a high-concentration (9.8%) emollient foam formulation and sufficient contact time (ie, 2 minutes) prior to washing off also has been shown to markedly reduce truncal P acnes organism counts.^{1,3,10-12,25-33} The Table depicts the major characteristics of clindamycin related to its use for treatment of AV.

Tretinoin has been used extensively for the treatment of AV since its introduction in the United States in 1971.^1,2,4,5 The proposed MOAs of topical retinoids, including tretinoin, based on available data include a variety of pharmacologic effects such as inhibition of follicular hyperkeratosis (decreased microcomedone formation), modulation of keratinocyte differentiation, anti-inflammatory properties, and inhibition of dermal matrix degradation (Figure).^{1,2,4,5,14,34,35} Topical retinoids, including tretinoin, have been shown to reduce both inflammatory and comedonal acne lesions, likely due to multiple MOAs, and are devoid of antibiotic properties.^2,4-8,16 Available data support that topical combination therapy for AV with a retinoid and a topical antimicrobial agent augments the therapeutic benefit as compared to use of either agent alone.^{1-4,12,15,16,28,31,32}

The rationale for incorporating both clindamycin and tretinoin together into one topical formulation includes combining different MOAs that appear to correlate with suppression of AV lesion formation and to improve patient adherence through once-daily application of a single topical product.^16,31,32,36 Importantly, formulation researchers were able to combine CP-Tret into a specific aqueous gel formulation that maintained the stability of both active ingredients and proved to be effective and safe in preliminary studies completed in participants with AV.^16,23,37-39 This aqueous formulation incorporated a limited number of excipients with low to negligible potential for cutaneous irritation or allergenicity, including anhydrous citric acid (chelating agent, preservative, emulsifier, acidulent), butylated hydroxytoluene (antioxidant), carbomer homopolymer type C (thickening agent, dispersing agent, biocompatible gel matrix), edetate disodium (chelating agent), laureth 4 (emulsifier, dissolution agent), methylparaben (preservative), propylene glycol (low-concentration humectant), purified water (diluent), and tromethamine (buffer, permeability enhancer).¹⁴

What are the clinical data evaluating the efficacy and tolerability/safety of the specific aqueous-based gel formulation of CP-Tret?

An aqueous-based gel formulation (referred to in the literature as a hydrogel) of CP-Tret is devoid of alcohol and contains the excipients described above.¹⁴ This formulation was shown to be efficacious, well tolerated, and safe in smaller clinical studies of participants with AV.^23,37-39 Two large-scale phase 3 studies were completed (N=2219), powered to compare the efficacy and tolerability/safety of CP-Tret hydrogel (n=634) versus CP hydrogel (n=635), Tret hydrogel (n=635), and vehicle hydrogel (n=315) in participants with facial AV. All 4 study drug formulations in both studies—CP-Tret, CP, Tret, vehicle—used the same hydrogel vehicle, hereafter referred to simply as gel.¹⁶

In both trials, participants 12 years of age and older with AV were randomized to active drug groups versus vehicle (2:2:2:1 randomization), each applied once daily at bedtime for 12 weeks.¹⁶ The baseline demographics among all 4 study groups were well matched, with approximately two-thirds of white participants and one-third Asian (2%–3%), black (19%–21%), or Hispanic (9%–10%). Approximately half of enrolled participants were 16 years of age or younger (mean age [range], 19.0–20.2 years). Enrolled participants in each study group presented at baseline predominantly with facial AV of mild (grade 2 [20%–23% of enrolled participants]) or moderate (grade 3 [60%–62% of enrolled participants]) severity based on a protocol-mandated, 6-point investigator static global assessment scale. Investigator static global assessment scores and acne lesion counts, including noninflammatory (comedonal), inflammatory (papules, pustules), and total AV lesions, were evaluated at baseline and weeks 2, 4, 8, and 12 (end of study [EOS]). Among the 4 study groups at baseline, the range of mean lesion counts was 27.7 to 29.3 for noninflammatory lesions, 26.0 to 26.4 for inflammatory lesions, and 76.4 to 78.3 for total lesions. All enrolled participants met protocol-mandated, standardized, inclusion, exclusion, and prestudy washout period criteria.¹⁶

The primary efficacy end points determined based on intention-to-treat analysis were the percentage reduction in all 3 lesion counts at EOS compared to baseline and the proportion of participants who achieved scores of clear (grade 0) or almost clear (grade 1) at EOS. The secondary end point parameter was time to 50% reduction in total lesion counts.¹⁶

The study efficacy outcomes were as follows: The mean percentage reduction in inflammatory lesions at EOS versus baseline was significantly higher in the CP-Tret group than in each of the other 3 groups (CP-Tret, 53.4%; CP, 47.5%; Tret, 43.3%; vehicle, 30.3%)(P<.005).¹⁶ The mean percentage reduction in noninflammatory lesions at EOS versus baseline was significantly higher in the CP-Tret group than in each of the other 3 groups (CP-Tret, 45.2%; CP, 31.6%; Tret, 37.9%; vehicle, 18.5%)(P≤.0004). The mean percentage reduction in total AV lesions at EOS versus baseline was significantly higher in the CP-Tret group than in each of the other 3 groups (CP-Tret, 48.7%; CP, 38.3%; Tret, 40.3%; vehicle, 23.2%)(P≤.0001). The median time to 50% reduction in total AV lesion counts was significantly faster with CP-Tret (8 weeks) compared to the other 3 groups (CP, 12 weeks [P<.0001]; Tret, 12 weeks [P<.001]; vehicle, not reached by EOS [P<.0001]). The consistency of results, methodologies, and overall study characteristics between the 2 phase 3 RCTs allowed for accurate pooling of data.¹⁶

Tolerability and safety assessments were completed at each visit for all enrolled participants. No adverse events (AEs) were noted in approximately 90% of enrolled participants.¹⁶ The most common AEs noted over the course of the study were mild to moderate application-site reactions (eg, dryness, erythema, burning, pruritus, desquamation), mostly correlated with the 2 groups containing tretinoin—CP-Tret and Tret—which is not unanticipated with topical retinoid use; 1.2% of these participants withdrew from the study due to such application-site AEs. No serious AEs or systemic safety signals emerged during the study.¹⁶

What summarizing statements can be made about CP-Tret gel from these study results that may be helpful to clinicians treating patients with AV?

The gel formulation of CP-Tret incorporates active ingredients that target different pathophysiologic cascades in AV, providing antimicrobial, anti-inflammatory, and anticomedonal effects.

Applied once daily, CP-Tret gel demonstrated the ability to achieve complete or near-complete clearance of comedonal and papulopustular facial AV lesions of mild to moderate severity in approximately 40% of participants within 12 weeks of use in 2 large-scale RCTs.¹⁶ The ability to achieve a median 50% reduction in total lesions by 8 weeks of use provides relevant information for patients regarding reasonable expectations with therapy.

The favorable cutaneous tolerability profile and low number of AEs demonstrated with CP-Tret gel are major considerations, especially as skin tolerability reactions can impede patient adherence with treatment. Any issues that interfere with achieving a favorable therapeutic outcome can lead to patients giving up with their therapy.

The large number of patients with skin of color treated with CP-Tret gel (n=209) in the 2 phase 3 RCTs is important, as the spectrum of racial origins, skin types, and skin colors seen in dermatology practices is diversifying across the United States. Both clinicians and patients with skin of color are often concerned about the sequelae of medication-induced skin irritation, which can lead to ensuing dyschromia.

Concerns related to potential development of clindamycin-resistant P acnes with CP-Tret gel may be addressed by concurrent use of BP, including with leave-on or short-contact therapy.

Although phase 3 RCTs evaluate therapeutic agents as monotherapy, in real world clinical practice, combination topical regimens using different individual products are common to optimize therapeutic outcomes. Advantages of the CP-Tret gel formulation, if a clinician desires to use it along with another topical product, are once-daily use and the low risk for cutaneous irritation.

What does your patient need to know?

When a patient presents with a history of genital warts (GWs), find out when and where the lesions started; where the lesions are currently located; what new lesions have developed; what treatments have been administered (eg, physician applied, prescription) and which one(s) worked; what side effects to treatments have been experienced and at what dose; does a partner(s) have similar lesions; is there a history of other sexually transmitted diseases or genital cancer; is he/she immunocompromised (eg, human immunodeficiency virus, transplant, medications); and what is his/her sexual orientation.

Once all of the information has been gathered and the entire anogenital region has been examined, a treatment plan can be formulated. If the patient is immunocompromised or is a man who has sex with men, the risk for anogenital malignancy due to human papillomavirus (HPV) is higher, and GWs, which can be coinfected with oncogenic HPV types, should be treated more aggressively. If the patient is still getting new lesions, use of only a destructive method such as cryotherapy will likely lead to suboptimal results.

Any patients with GWs in the anal region but particularly those in high-risk groups such as men who have sex with men and human immunodeficiency virus–infected patients should have an anoscopy to evaluate for lesions on the anal mucosa and in the rectum.

What are your go-to treatments?

Prior treatments need to be taken into account; make sure to understand any side effects and how he/she applied the prior treatment before eliminating it as a viable option. Treatment usually depends on the number of lesions, surface area, anatomic locations involved, and size of the lesions. I start with a 2-pronged approach—a debulking therapy and a patient-applied topical therapy—which allows me to physically remove some of the lesions, typically the larger ones, and then have the patient apply a topical medication at home that will treat the smaller lesions as well as help to clear or decrease the burden of HPV virus on the skin. I use cryotherapy as a debulking agent, but curettage or podophyllin 25% also can be used in the office. I use imiquimod cream 5% as a first-line topical agent at the recommended dose of 3 times weekly; however, if after the first 2 weeks the patient has little response or too much irritation, I titrate the dose so that the patient has mild inflammation on the skin. The dose ultimately can range from daily to once weekly. Some patients who can only tolerate imiquimod once or twice weekly may require zinc oxide paste for the inguinal folds and scrotum to protect from irritation. Alternate topical medications for GWs include sinecatechins ointment 15% or cidofovir ointment 2%.

How do you keep patients compliant?

Start the visit with open communication about the disease, where it came from, what the risks are if it is not treated, and how we can best treat it to make sure we minimize those risks. I explain all of the treatment options as well as our role in treating these lesions and minimizing the risk for disease progression.

What do you do if they refuse treatment?

Most patients with GWs are motivated to be treated. If pain is a concern, such as with cryotherapy, I recommend topical treatments.

What patient resources do you recommend?

The American Academy of Dermatology (https://www.aad.org/public/diseases/contagious-skin-diseases/genital-warts), Harvard Medical School patient education center (Boston, Massachusetts)(http://www.patienteducationcenter.org/articles/genital-warts/), and American Family Physician (http://www.aafp.org/afp/2004/1215/p2345.html) provide patient materials that I recommend.

What does your patient need to know?

When a patient presents with a history of genital warts (GWs), find out when and where the lesions started; where the lesions are currently located; what new lesions have developed; what treatments have been administered (eg, physician applied, prescription) and which one(s) worked; what side effects to treatments have been experienced and at what dose; does a partner(s) have similar lesions; is there a history of other sexually transmitted diseases or genital cancer; is he/she immunocompromised (eg, human immunodeficiency virus, transplant, medications); and what is his/her sexual orientation.

Once all of the information has been gathered and the entire anogenital region has been examined, a treatment plan can be formulated. If the patient is immunocompromised or is a man who has sex with men, the risk for anogenital malignancy due to human papillomavirus (HPV) is higher, and GWs, which can be coinfected with oncogenic HPV types, should be treated more aggressively. If the patient is still getting new lesions, use of only a destructive method such as cryotherapy will likely lead to suboptimal results.

Any patients with GWs in the anal region but particularly those in high-risk groups such as men who have sex with men and human immunodeficiency virus–infected patients should have an anoscopy to evaluate for lesions on the anal mucosa and in the rectum.

What are your go-to treatments?

Prior treatments need to be taken into account; make sure to understand any side effects and how he/she applied the prior treatment before eliminating it as a viable option. Treatment usually depends on the number of lesions, surface area, anatomic locations involved, and size of the lesions. I start with a 2-pronged approach—a debulking therapy and a patient-applied topical therapy—which allows me to physically remove some of the lesions, typically the larger ones, and then have the patient apply a topical medication at home that will treat the smaller lesions as well as help to clear or decrease the burden of HPV virus on the skin. I use cryotherapy as a debulking agent, but curettage or podophyllin 25% also can be used in the office. I use imiquimod cream 5% as a first-line topical agent at the recommended dose of 3 times weekly; however, if after the first 2 weeks the patient has little response or too much irritation, I titrate the dose so that the patient has mild inflammation on the skin. The dose ultimately can range from daily to once weekly. Some patients who can only tolerate imiquimod once or twice weekly may require zinc oxide paste for the inguinal folds and scrotum to protect from irritation. Alternate topical medications for GWs include sinecatechins ointment 15% or cidofovir ointment 2%.

How do you keep patients compliant?

Start the visit with open communication about the disease, where it came from, what the risks are if it is not treated, and how we can best treat it to make sure we minimize those risks. I explain all of the treatment options as well as our role in treating these lesions and minimizing the risk for disease progression.

What do you do if they refuse treatment?

Most patients with GWs are motivated to be treated. If pain is a concern, such as with cryotherapy, I recommend topical treatments.

What patient resources do you recommend?

The American Academy of Dermatology (https://www.aad.org/public/diseases/contagious-skin-diseases/genital-warts), Harvard Medical School patient education center (Boston, Massachusetts)(http://www.patienteducationcenter.org/articles/genital-warts/), and American Family Physician (http://www.aafp.org/afp/2004/1215/p2345.html) provide patient materials that I recommend.

What does your patient need to know?

When a patient presents with a history of genital warts (GWs), find out when and where the lesions started; where the lesions are currently located; what new lesions have developed; what treatments have been administered (eg, physician applied, prescription) and which one(s) worked; what side effects to treatments have been experienced and at what dose; does a partner(s) have similar lesions; is there a history of other sexually transmitted diseases or genital cancer; is he/she immunocompromised (eg, human immunodeficiency virus, transplant, medications); and what is his/her sexual orientation.

Once all of the information has been gathered and the entire anogenital region has been examined, a treatment plan can be formulated. If the patient is immunocompromised or is a man who has sex with men, the risk for anogenital malignancy due to human papillomavirus (HPV) is higher, and GWs, which can be coinfected with oncogenic HPV types, should be treated more aggressively. If the patient is still getting new lesions, use of only a destructive method such as cryotherapy will likely lead to suboptimal results.

Any patients with GWs in the anal region but particularly those in high-risk groups such as men who have sex with men and human immunodeficiency virus–infected patients should have an anoscopy to evaluate for lesions on the anal mucosa and in the rectum.

What are your go-to treatments?

Prior treatments need to be taken into account; make sure to understand any side effects and how he/she applied the prior treatment before eliminating it as a viable option. Treatment usually depends on the number of lesions, surface area, anatomic locations involved, and size of the lesions. I start with a 2-pronged approach—a debulking therapy and a patient-applied topical therapy—which allows me to physically remove some of the lesions, typically the larger ones, and then have the patient apply a topical medication at home that will treat the smaller lesions as well as help to clear or decrease the burden of HPV virus on the skin. I use cryotherapy as a debulking agent, but curettage or podophyllin 25% also can be used in the office. I use imiquimod cream 5% as a first-line topical agent at the recommended dose of 3 times weekly; however, if after the first 2 weeks the patient has little response or too much irritation, I titrate the dose so that the patient has mild inflammation on the skin. The dose ultimately can range from daily to once weekly. Some patients who can only tolerate imiquimod once or twice weekly may require zinc oxide paste for the inguinal folds and scrotum to protect from irritation. Alternate topical medications for GWs include sinecatechins ointment 15% or cidofovir ointment 2%.

How do you keep patients compliant?

Start the visit with open communication about the disease, where it came from, what the risks are if it is not treated, and how we can best treat it to make sure we minimize those risks. I explain all of the treatment options as well as our role in treating these lesions and minimizing the risk for disease progression.

What do you do if they refuse treatment?

Most patients with GWs are motivated to be treated. If pain is a concern, such as with cryotherapy, I recommend topical treatments.

What patient resources do you recommend?

The American Academy of Dermatology (https://www.aad.org/public/diseases/contagious-skin-diseases/genital-warts), Harvard Medical School patient education center (Boston, Massachusetts)(http://www.patienteducationcenter.org/articles/genital-warts/), and American Family Physician (http://www.aafp.org/afp/2004/1215/p2345.html) provide patient materials that I recommend.

An established patient comes into your office with a painful new lesion on the hand. He thinks it may be a wart. You take a focused history of the lesion, do a physical examination, and confirm the diagnosis of verruca vulgaris. You discuss treatment options, risks, and the benefits of treatment, as well as the pathophysiology of warts. The decision is made to proceed that same day with cryosurgical destruction, which is performed. You feel that billing both an office visit with an appended modifier -25 and the benign destruction code 17110 is warranted, but your biller says only the procedure should be reported. Who is correct?

Modifier -25 use has come under increased scrutiny by insurers and regulators. There is a perception that this modifier is frequently used inappropriately or unnecessarily. In fact, the Office of Inspector General reported that 35% of claims using modifier -25 that Medicare allowed did not meet the requirements. The Office of Inspector General has recommended that the “[Centers for Medicare & Medicaid Services] should work with carriers to reduce the number of claims submitted using modifier -25” and “include modifier -25 reviews in their medical review strategies.”¹ Translation: More chart reviews and audits! In my discussions with insurer medical directors, they point to the single diagnosis modifier -25 as likely abused and feel that its use in this context is almost never appropriate. Their audits have been focused on this aspect of dermatologists’ coding. In addition, some private insurers have started to discount reimbursement for office visits billed with modifier -25 by 50% to account for the level of perceived overuse.²

The Current Procedural Terminology description of modifier -25 is relatively clear: Modifier -25 is used to facilitate billing of evaluation and management (E/M) services on the day of a procedure for which separate payment may be made.³ This modifier indicates that a significant, separately identifiable E/M service was performed by the same physician on the day of a procedure. To appropriately bill both the E/M service and the procedure, the physician must indicate that the patient’s condition required an E/M service “above and beyond the usual pre- and post-operative work of a procedure.”⁴ However, it is largely left up to the physician to decide what constitutes the significant, separately identifiable E/M service.

As dermatologists, we all report modifier -25 appropriately as part of our daily practice. Performance of a medically necessary procedure on the same day as an E/M service generally is done to facilitate a prompt diagnosis or streamline treatment of a complex condition. Providing distinct medically necessary services on the same date allows physicians to provide effective and efficient high-quality care, in many cases saving patients a return visit. The most common scenario for using modifier -25 involves multiple concerns and multiple diagnoses, some of which are not associated with a procedure(s) that is performed on the same date of service. With multiple diagnoses, it is straightforward to demonstrate the separate E/M service associated with the nonprocedure-related diagnosis code(s); however, with one diagnosis for both the office visit and the procedure, clear documentation of the separate and identifiable E/M service is critical and is dependent on understanding what is included in the global surgical package.

Insurer payment for procedures includes local or topical anesthesia, the surgical service/procedure itself, immediate postoperative care including dictating the operative note, meeting/discussing the patient’s procedure with family and other physicians, evaluating the patient in postanesthesia/recovery area, and writing orders for the patient. This group of services is called the global surgical package. For minor procedures (ie, those with either 0- or 10-day global periods), the surgical package also includes same-day E/M associated with the decision to perform surgery. An appropriate history and physical examination, as well as the discussion of differential diagnosis, treatment options, and risk and benefits of treatments, are all included in the payment of a minor procedure itself. Therefore, if an E/M service is performed on the same day as a minor procedure to decide whether to proceed with the minor surgical procedure, this E/M service cannot be separately reported. Moreover, the fact that the patient is new to the physician is not sufficient to allow reporting of an E/M service with such a minor procedure. For major procedures (ie, those with 90-day postoperative periods), the decision for surgery is excluded from the global surgical package.

Therefore, it is clear that the clinical scenario for verruca vulgaris treatment as described at the start of this article does not meet criteria for an office visit billed in addition to the destruction. The E/M services performed prior to the patient’s verruca vulgaris treatment are integral to and necessary for the decision to perform the procedure. Making and confirming the diagnosis of a condition or lesion prior to a procedure either by physical evaluation or by interpretation of a pathology report is part of the evaluation required to make the decision to proceed with a particular procedure.

There are clinical scenarios in which a physician can support additional E/M services beyond that of the procedure with just one diagnosis. If a patient presents with warts on the hand and face with resultant cryosurgical destruction done on the hand and a prescription for imiquimod to be used on the face to induce immunologic clearance of viral infection and decrease the risk of scarring, it is clear that a significant and separately identifiable E/M service exists. The evaluation of the facial warts and the prescription of medication and discussion of the risks, benefits, and therapeutic effects of that prescription is definitely distinct from the procedure. Similarly, if an evaluation of a patient with a rash results in only a diagnostic biopsy with no separate cognitive services other than the decision to perform the biopsy, an office visit charge in addition to the biopsy charge would not be warranted. However, if in addition to the biopsy the rash also is treated with topical or systemic steroids because of pruritus or a more extensive evaluation for systemic complications is required, an office visit charge is appropriate.

The frequent use of modifier -25 is a critical part of a high-quality and cost-effective dermatology practice. Same-day performance of E/M services and minor procedures allows for more rapid and efficient diagnosis and treatment of various conditions as well as minimizing unnecessary office visits. However, modifier -25 use, particularly in the context of the same diagnosis for the office visit and the procedure, is under intense insurer scrutiny. Careful and complete documentation of the additional E/M service provided, including the additional history, physical examination results, and treatment considerations above and beyond those typically required by the minor procedure, will reduce the likelihood of redeterminations from reviews and audits. Understanding Medicare guidelines and National Correct Coding Initiative recommendations will help keep the dermatologist out of hot water.⁵

An established patient comes into your office with a painful new lesion on the hand. He thinks it may be a wart. You take a focused history of the lesion, do a physical examination, and confirm the diagnosis of verruca vulgaris. You discuss treatment options, risks, and the benefits of treatment, as well as the pathophysiology of warts. The decision is made to proceed that same day with cryosurgical destruction, which is performed. You feel that billing both an office visit with an appended modifier -25 and the benign destruction code 17110 is warranted, but your biller says only the procedure should be reported. Who is correct?

Modifier -25 use has come under increased scrutiny by insurers and regulators. There is a perception that this modifier is frequently used inappropriately or unnecessarily. In fact, the Office of Inspector General reported that 35% of claims using modifier -25 that Medicare allowed did not meet the requirements. The Office of Inspector General has recommended that the “[Centers for Medicare & Medicaid Services] should work with carriers to reduce the number of claims submitted using modifier -25” and “include modifier -25 reviews in their medical review strategies.”¹ Translation: More chart reviews and audits! In my discussions with insurer medical directors, they point to the single diagnosis modifier -25 as likely abused and feel that its use in this context is almost never appropriate. Their audits have been focused on this aspect of dermatologists’ coding. In addition, some private insurers have started to discount reimbursement for office visits billed with modifier -25 by 50% to account for the level of perceived overuse.²

The Current Procedural Terminology description of modifier -25 is relatively clear: Modifier -25 is used to facilitate billing of evaluation and management (E/M) services on the day of a procedure for which separate payment may be made.³ This modifier indicates that a significant, separately identifiable E/M service was performed by the same physician on the day of a procedure. To appropriately bill both the E/M service and the procedure, the physician must indicate that the patient’s condition required an E/M service “above and beyond the usual pre- and post-operative work of a procedure.”⁴ However, it is largely left up to the physician to decide what constitutes the significant, separately identifiable E/M service.

As dermatologists, we all report modifier -25 appropriately as part of our daily practice. Performance of a medically necessary procedure on the same day as an E/M service generally is done to facilitate a prompt diagnosis or streamline treatment of a complex condition. Providing distinct medically necessary services on the same date allows physicians to provide effective and efficient high-quality care, in many cases saving patients a return visit. The most common scenario for using modifier -25 involves multiple concerns and multiple diagnoses, some of which are not associated with a procedure(s) that is performed on the same date of service. With multiple diagnoses, it is straightforward to demonstrate the separate E/M service associated with the nonprocedure-related diagnosis code(s); however, with one diagnosis for both the office visit and the procedure, clear documentation of the separate and identifiable E/M service is critical and is dependent on understanding what is included in the global surgical package.

Insurer payment for procedures includes local or topical anesthesia, the surgical service/procedure itself, immediate postoperative care including dictating the operative note, meeting/discussing the patient’s procedure with family and other physicians, evaluating the patient in postanesthesia/recovery area, and writing orders for the patient. This group of services is called the global surgical package. For minor procedures (ie, those with either 0- or 10-day global periods), the surgical package also includes same-day E/M associated with the decision to perform surgery. An appropriate history and physical examination, as well as the discussion of differential diagnosis, treatment options, and risk and benefits of treatments, are all included in the payment of a minor procedure itself. Therefore, if an E/M service is performed on the same day as a minor procedure to decide whether to proceed with the minor surgical procedure, this E/M service cannot be separately reported. Moreover, the fact that the patient is new to the physician is not sufficient to allow reporting of an E/M service with such a minor procedure. For major procedures (ie, those with 90-day postoperative periods), the decision for surgery is excluded from the global surgical package.

Therefore, it is clear that the clinical scenario for verruca vulgaris treatment as described at the start of this article does not meet criteria for an office visit billed in addition to the destruction. The E/M services performed prior to the patient’s verruca vulgaris treatment are integral to and necessary for the decision to perform the procedure. Making and confirming the diagnosis of a condition or lesion prior to a procedure either by physical evaluation or by interpretation of a pathology report is part of the evaluation required to make the decision to proceed with a particular procedure.

There are clinical scenarios in which a physician can support additional E/M services beyond that of the procedure with just one diagnosis. If a patient presents with warts on the hand and face with resultant cryosurgical destruction done on the hand and a prescription for imiquimod to be used on the face to induce immunologic clearance of viral infection and decrease the risk of scarring, it is clear that a significant and separately identifiable E/M service exists. The evaluation of the facial warts and the prescription of medication and discussion of the risks, benefits, and therapeutic effects of that prescription is definitely distinct from the procedure. Similarly, if an evaluation of a patient with a rash results in only a diagnostic biopsy with no separate cognitive services other than the decision to perform the biopsy, an office visit charge in addition to the biopsy charge would not be warranted. However, if in addition to the biopsy the rash also is treated with topical or systemic steroids because of pruritus or a more extensive evaluation for systemic complications is required, an office visit charge is appropriate.

The frequent use of modifier -25 is a critical part of a high-quality and cost-effective dermatology practice. Same-day performance of E/M services and minor procedures allows for more rapid and efficient diagnosis and treatment of various conditions as well as minimizing unnecessary office visits. However, modifier -25 use, particularly in the context of the same diagnosis for the office visit and the procedure, is under intense insurer scrutiny. Careful and complete documentation of the additional E/M service provided, including the additional history, physical examination results, and treatment considerations above and beyond those typically required by the minor procedure, will reduce the likelihood of redeterminations from reviews and audits. Understanding Medicare guidelines and National Correct Coding Initiative recommendations will help keep the dermatologist out of hot water.⁵

An established patient comes into your office with a painful new lesion on the hand. He thinks it may be a wart. You take a focused history of the lesion, do a physical examination, and confirm the diagnosis of verruca vulgaris. You discuss treatment options, risks, and the benefits of treatment, as well as the pathophysiology of warts. The decision is made to proceed that same day with cryosurgical destruction, which is performed. You feel that billing both an office visit with an appended modifier -25 and the benign destruction code 17110 is warranted, but your biller says only the procedure should be reported. Who is correct?

Modifier -25 use has come under increased scrutiny by insurers and regulators. There is a perception that this modifier is frequently used inappropriately or unnecessarily. In fact, the Office of Inspector General reported that 35% of claims using modifier -25 that Medicare allowed did not meet the requirements. The Office of Inspector General has recommended that the “[Centers for Medicare & Medicaid Services] should work with carriers to reduce the number of claims submitted using modifier -25” and “include modifier -25 reviews in their medical review strategies.”¹ Translation: More chart reviews and audits! In my discussions with insurer medical directors, they point to the single diagnosis modifier -25 as likely abused and feel that its use in this context is almost never appropriate. Their audits have been focused on this aspect of dermatologists’ coding. In addition, some private insurers have started to discount reimbursement for office visits billed with modifier -25 by 50% to account for the level of perceived overuse.²

The Current Procedural Terminology description of modifier -25 is relatively clear: Modifier -25 is used to facilitate billing of evaluation and management (E/M) services on the day of a procedure for which separate payment may be made.³ This modifier indicates that a significant, separately identifiable E/M service was performed by the same physician on the day of a procedure. To appropriately bill both the E/M service and the procedure, the physician must indicate that the patient’s condition required an E/M service “above and beyond the usual pre- and post-operative work of a procedure.”⁴ However, it is largely left up to the physician to decide what constitutes the significant, separately identifiable E/M service.

As dermatologists, we all report modifier -25 appropriately as part of our daily practice. Performance of a medically necessary procedure on the same day as an E/M service generally is done to facilitate a prompt diagnosis or streamline treatment of a complex condition. Providing distinct medically necessary services on the same date allows physicians to provide effective and efficient high-quality care, in many cases saving patients a return visit. The most common scenario for using modifier -25 involves multiple concerns and multiple diagnoses, some of which are not associated with a procedure(s) that is performed on the same date of service. With multiple diagnoses, it is straightforward to demonstrate the separate E/M service associated with the nonprocedure-related diagnosis code(s); however, with one diagnosis for both the office visit and the procedure, clear documentation of the separate and identifiable E/M service is critical and is dependent on understanding what is included in the global surgical package.

Insurer payment for procedures includes local or topical anesthesia, the surgical service/procedure itself, immediate postoperative care including dictating the operative note, meeting/discussing the patient’s procedure with family and other physicians, evaluating the patient in postanesthesia/recovery area, and writing orders for the patient. This group of services is called the global surgical package. For minor procedures (ie, those with either 0- or 10-day global periods), the surgical package also includes same-day E/M associated with the decision to perform surgery. An appropriate history and physical examination, as well as the discussion of differential diagnosis, treatment options, and risk and benefits of treatments, are all included in the payment of a minor procedure itself. Therefore, if an E/M service is performed on the same day as a minor procedure to decide whether to proceed with the minor surgical procedure, this E/M service cannot be separately reported. Moreover, the fact that the patient is new to the physician is not sufficient to allow reporting of an E/M service with such a minor procedure. For major procedures (ie, those with 90-day postoperative periods), the decision for surgery is excluded from the global surgical package.

Therefore, it is clear that the clinical scenario for verruca vulgaris treatment as described at the start of this article does not meet criteria for an office visit billed in addition to the destruction. The E/M services performed prior to the patient’s verruca vulgaris treatment are integral to and necessary for the decision to perform the procedure. Making and confirming the diagnosis of a condition or lesion prior to a procedure either by physical evaluation or by interpretation of a pathology report is part of the evaluation required to make the decision to proceed with a particular procedure.

There are clinical scenarios in which a physician can support additional E/M services beyond that of the procedure with just one diagnosis. If a patient presents with warts on the hand and face with resultant cryosurgical destruction done on the hand and a prescription for imiquimod to be used on the face to induce immunologic clearance of viral infection and decrease the risk of scarring, it is clear that a significant and separately identifiable E/M service exists. The evaluation of the facial warts and the prescription of medication and discussion of the risks, benefits, and therapeutic effects of that prescription is definitely distinct from the procedure. Similarly, if an evaluation of a patient with a rash results in only a diagnostic biopsy with no separate cognitive services other than the decision to perform the biopsy, an office visit charge in addition to the biopsy charge would not be warranted. However, if in addition to the biopsy the rash also is treated with topical or systemic steroids because of pruritus or a more extensive evaluation for systemic complications is required, an office visit charge is appropriate.

The frequent use of modifier -25 is a critical part of a high-quality and cost-effective dermatology practice. Same-day performance of E/M services and minor procedures allows for more rapid and efficient diagnosis and treatment of various conditions as well as minimizing unnecessary office visits. However, modifier -25 use, particularly in the context of the same diagnosis for the office visit and the procedure, is under intense insurer scrutiny. Careful and complete documentation of the additional E/M service provided, including the additional history, physical examination results, and treatment considerations above and beyond those typically required by the minor procedure, will reduce the likelihood of redeterminations from reviews and audits. Understanding Medicare guidelines and National Correct Coding Initiative recommendations will help keep the dermatologist out of hot water.⁵