Last year’s influenza season was severe enough that hospitals around the United States set up special evaluation areas beyond their emergency departments, at times spilling over to tents or other temporary structures in what otherwise would be parking lots. The scale and potential severity of the annual epidemic can be difficult to convey to our patients, who sometimes say “just the flu” to refer to an illness responsible for more than 170 pediatric deaths in the United States this past year.¹ The Centers for Disease Control and Prevention (CDC) recently updated its 5-year estimates of influenza-related deaths in the United States; influenza mortality ranges from about 12,000 deaths in a mild season (such as 2011-2012) to 56,000 in a more severe season (eg, 2012-2013).²

Although influenza cannot be completely prevented, the following strategies can help reduce the risk for the illness and limit its severity if contracted.

Prevention

Strategy 1: Vaccinate against influenza

While the efficacy of vaccines varies from year to year, vaccination remains the core of influenza prevention efforts. In this decade, vaccine effectiveness has ranged from 19% to 60%.³ However, models suggest that even when the vaccine is only 20% effective, vaccinating 140 million people (the average number of doses delivered annually in the United States over the past 5 seasons) prevents 21 million infections, 130,000 hospitalizations, and more than 61,000 deaths.⁴ In a case-control study, Flannery et al found that vaccination was 65% effective in preventing laboratory-confirmed influenza-associated death in children over 4 seasons (July 2010 through June 2014).⁵

Deciding who should be vaccinated is simpler than in prior years: Rather than targeting people who are at higher risk (those ages 65 and older, or those with comorbidities), the current CDC recommendation is to vaccinate nearly everyone ages 6 months or older, with limited exceptions.^6,7 (See Table 1⁸).

Formulations. Many types of influenza vaccine are approved for use in the United States; these differ in the number of strains included (3 or 4), the amount of antigen present for each strain, the presence of an adjuvant, the growth medium used for the virus, and the route of administration (see Table 2⁹). The relative merits of each type are a matter of some debate. There is ongoing research into the comparative efficacy of vaccines comprised of egg- vs cell-based cultures, as well as studies comparing high-dose or adjuvant vaccines to standard-dose inactivated vaccines.

Previously, the CDC has recommended preferential use (or avoidance) of some vaccine types, based on their efficacy. For the 2018-2019 flu season, however, the CDC has rescinded its recommendation against vaccine containing live attenuated virus (LAIV; FluMist brand) and expresses no preference for any vaccine formulation for patients of appropriate age and health status.¹⁰ The American Academy of Pediatrics (AAP), however, is recommends that LAIV be used only if patients and their families decline injectable vaccines.¹¹

Timing. Influenza vaccines are now distributed as early as July to some locations, raising concerns about waning immunity from early vaccination (July/August) if the influenza season does not peak until February or March.^8,12,13 Currently, the CDC recommends balancing the possible benefit of delayed vaccination against the risks of missed opportunities to vaccinate, a possible early season, and logistical problems related to vaccinating the same number of people in a smaller time interval. Offering vaccination by the end of October, if possible, is recommended in order for immunity to develop by mid-November.⁸ Note: Children ages 6 months to 8 years will need to receive their initial vaccination in 2 half-doses administered at least 28 days apart; completing their vaccination by the end of October would require starting the process weeks earlier.

[polldaddy:10124269]

Continue to: Strategy 2

Strategy 2: Make use of chemoprophylaxis

Preventive use of antiviral medication (chemoprophylaxis) may be a useful adjunct or alternative to vaccination in certain circumstances: if the patient is at high risk for complications, has been exposed to someone with influenza, has contraindications to vaccination, or received the vaccine within the past 2 weeks. The CDC also suggests that chemoprophylaxis be considered for those with immune deficiencies or who are otherwise immunosuppressed after exposure.¹⁴ Antivirals can also be used to control outbreaks in long-term care facilities; in these cases, the recommendedregimen is daily administration for at least 2 weeks, continuing until at least 7 days after the identification of the last case.¹⁴ Oseltamivir (Tamiflu) and zanamivir (Relenza) are the recommended prophylactic agents; a related intravenous medication, peramivir (Rapivab), is recommend for treatment only (see Table 3¹⁴).

Strategy 3: Prevent comorbidities and opportunistic infections

Morbidity associated with influenza often comes from secondary infection. Pneumonia is among the most common complications, so influenza season is a good time to ensure that patients are appropriately vaccinated against pneumococcus, as well. Pneumococcal conjugate vaccine (Prevnar or PCV13) is recommended for children younger than 2 years of age, to be administered in a series of 4 doses: at 2, 4, 6, and 12-15 months. Vaccination with PCV13 is also recommended for those ages 65 or older, to be followed at least one year later with pneumococcal polysaccharide vaccine (Pneumovax or PPSV23).¹⁵ Additional doses of PCV13, PPSV23, or both may be indicated, depending on health status.

Strategy 4: Encourage good hygiene

The availability of immunizations and anti­virals does not replace good hygiene. Frequent handwashing reduces the transmission of respiratory viruses, including influenza.¹⁶ Few studies have evaluated the use of alcohol-based hand sanitizers, but available evidence suggests they are effective in lowering viral transmission.¹⁶

Barriers, such as masks, gloves, and gowns, are helpful for health care workers.¹⁶ Surgical masks are often considered more comfortable to wear than N95 respirators. It may therefore be welcome news that when a 2009 randomized study assessed their use by hospital-based nurses, masks were non-inferior in protecting these health care workers against influenza.¹⁷

Presenteeism, the practice of going to work while sick, should be discouraged. People at risk for influenza may wish to avoid crowds during flu season; those with symptoms should be encouraged to stay home and limit contact with others.

Continue to: Treatment

Strategy 1: Make prompt use of antivirals

Despite available preventive measures, tens of millions of people in the United States develop influenza every year. Use of antiviral medication, begun early in the course of illness, can reduce the duration of symptoms and may reduce the risk for complications.

The neuraminidase inhibitor (NI) group of antivirals—oseltamivir, zanamivir, and peramivir—is effective against influenza types A and B and current resistance rates are low.

The adamantine family of antivirals, amantadine and rimantadine, treat type A only. Since the circulating influenza strains in the past several seasons have demonstrated resistance >99%, these medications are not currently recommended.¹⁴

NIs reduce the duration of influenza symptoms by 10% to 20%, shortening the illness by 6 to 24 hours.^18,19 In otherwise healthy patients, this benefit must be balanced against the increased risk for nausea and vomiting (oseltamivir), bronchospasm and sinusitis (zanamivir), and diarrhea (peramivir). In adults, NIs reduce the risk for lower respiratory tract complications and hospitalization. A 2015 meta-analysis by Dobson et al found a relative risk for hospitalization among those prescribed oseltamivir vs placebo of 37%.¹⁸

In the past, antivirals were used only in high-risk patients, such as children younger than 2 years, adults older than 65 years, and those with chronic health conditions.¹⁴ Now, antivirals are recommended for those who are at higher risk for complications (see Table 4), those with “severe, complicated, or progressive illness,” and hospitalized patients.¹⁴

Continue to: Antiviral treatment may have some value...

Antiviral treatment may have some value for hospitalized patients when started even 5 days after symptom onset. Treatment may be extended beyond the usual recommendations (5 days for oseltamivir or zanamivir) in immunosuppressed patients or the critically ill. Additionally, recent guidelines include consideration of antiviral treatment in outpatients who are at normal risk if treatment can be started within 48 hours of symptom onset.¹⁴

The CDC currently recommends use of oseltamivir rather than other antivirals for most hospitalized patients, based on the availability of data on its use in this setting.¹⁴ Intravenous peramivir is recommended for patients who cannot tolerate or absorb oral medication; inhaled zanamivir or IV peramivir are preferred for patients with end-stage renal disease who are not undergoing dialysis (see Table 3).¹⁴

Strategy 2: Exercise caution when it comes to supportive care

There are other medications that may offer symptom relief or prevent complications, especially when antivirals are contraindicated or unavailable.

Corticosteroids are recommended as part of the treatment of community-acquired pneumonia,²⁰ but their role in influenza is controversial. A 2016 Cochrane review²¹ found no randomized controlled trials on the topic. Although the balance of available data from observational studies indicated that use of corticosteroids was associated with increased mortality, the authors also noted that all the studies included in their meta-analysis were of “very low quality.” They concluded that “the use of steroids in influenza remains a clinical judgement call.”

Offering vaccination by the end of October, if possible, is recommended in order for immunity to develop by mid-November.

Statins may be associated with improved outcomes in influenza and pneumonia. Studies thus far have given contradictory results,^22,23 and a planned Cochrane review of the question has been withdrawn.²⁴

Continue to: Over-the-counter medications...

Over-the-counter medications, such as aspirin, acetaminophen, and ibuprofen are often used to manage the fever and myalgia associated with influenza. Patients should be cautioned against using the same ingredient in multiple different branded medications. Acetaminophen, for example, is not limited to Tylenol-branded products. To avoid Reye’s syndrome, children and teens with febrile illness, such as influenza, should not use aspirin.

CORRESPONDENCE
Jennifer L. Hamilton, MD, PhD, Drexel Family Medicine, 10 Shurs Lane, Suite 301, Philadelphia, PA 19127; [email protected].

Last year’s influenza season was severe enough that hospitals around the United States set up special evaluation areas beyond their emergency departments, at times spilling over to tents or other temporary structures in what otherwise would be parking lots. The scale and potential severity of the annual epidemic can be difficult to convey to our patients, who sometimes say “just the flu” to refer to an illness responsible for more than 170 pediatric deaths in the United States this past year.¹ The Centers for Disease Control and Prevention (CDC) recently updated its 5-year estimates of influenza-related deaths in the United States; influenza mortality ranges from about 12,000 deaths in a mild season (such as 2011-2012) to 56,000 in a more severe season (eg, 2012-2013).²

Although influenza cannot be completely prevented, the following strategies can help reduce the risk for the illness and limit its severity if contracted.

Prevention

Strategy 1: Vaccinate against influenza

While the efficacy of vaccines varies from year to year, vaccination remains the core of influenza prevention efforts. In this decade, vaccine effectiveness has ranged from 19% to 60%.³ However, models suggest that even when the vaccine is only 20% effective, vaccinating 140 million people (the average number of doses delivered annually in the United States over the past 5 seasons) prevents 21 million infections, 130,000 hospitalizations, and more than 61,000 deaths.⁴ In a case-control study, Flannery et al found that vaccination was 65% effective in preventing laboratory-confirmed influenza-associated death in children over 4 seasons (July 2010 through June 2014).⁵

Deciding who should be vaccinated is simpler than in prior years: Rather than targeting people who are at higher risk (those ages 65 and older, or those with comorbidities), the current CDC recommendation is to vaccinate nearly everyone ages 6 months or older, with limited exceptions.^6,7 (See Table 1⁸).

Formulations. Many types of influenza vaccine are approved for use in the United States; these differ in the number of strains included (3 or 4), the amount of antigen present for each strain, the presence of an adjuvant, the growth medium used for the virus, and the route of administration (see Table 2⁹). The relative merits of each type are a matter of some debate. There is ongoing research into the comparative efficacy of vaccines comprised of egg- vs cell-based cultures, as well as studies comparing high-dose or adjuvant vaccines to standard-dose inactivated vaccines.

Previously, the CDC has recommended preferential use (or avoidance) of some vaccine types, based on their efficacy. For the 2018-2019 flu season, however, the CDC has rescinded its recommendation against vaccine containing live attenuated virus (LAIV; FluMist brand) and expresses no preference for any vaccine formulation for patients of appropriate age and health status.¹⁰ The American Academy of Pediatrics (AAP), however, is recommends that LAIV be used only if patients and their families decline injectable vaccines.¹¹

Timing. Influenza vaccines are now distributed as early as July to some locations, raising concerns about waning immunity from early vaccination (July/August) if the influenza season does not peak until February or March.^8,12,13 Currently, the CDC recommends balancing the possible benefit of delayed vaccination against the risks of missed opportunities to vaccinate, a possible early season, and logistical problems related to vaccinating the same number of people in a smaller time interval. Offering vaccination by the end of October, if possible, is recommended in order for immunity to develop by mid-November.⁸ Note: Children ages 6 months to 8 years will need to receive their initial vaccination in 2 half-doses administered at least 28 days apart; completing their vaccination by the end of October would require starting the process weeks earlier.

[polldaddy:10124269]

Continue to: Strategy 2

Strategy 2: Make use of chemoprophylaxis

Preventive use of antiviral medication (chemoprophylaxis) may be a useful adjunct or alternative to vaccination in certain circumstances: if the patient is at high risk for complications, has been exposed to someone with influenza, has contraindications to vaccination, or received the vaccine within the past 2 weeks. The CDC also suggests that chemoprophylaxis be considered for those with immune deficiencies or who are otherwise immunosuppressed after exposure.¹⁴ Antivirals can also be used to control outbreaks in long-term care facilities; in these cases, the recommendedregimen is daily administration for at least 2 weeks, continuing until at least 7 days after the identification of the last case.¹⁴ Oseltamivir (Tamiflu) and zanamivir (Relenza) are the recommended prophylactic agents; a related intravenous medication, peramivir (Rapivab), is recommend for treatment only (see Table 3¹⁴).

Strategy 3: Prevent comorbidities and opportunistic infections

Morbidity associated with influenza often comes from secondary infection. Pneumonia is among the most common complications, so influenza season is a good time to ensure that patients are appropriately vaccinated against pneumococcus, as well. Pneumococcal conjugate vaccine (Prevnar or PCV13) is recommended for children younger than 2 years of age, to be administered in a series of 4 doses: at 2, 4, 6, and 12-15 months. Vaccination with PCV13 is also recommended for those ages 65 or older, to be followed at least one year later with pneumococcal polysaccharide vaccine (Pneumovax or PPSV23).¹⁵ Additional doses of PCV13, PPSV23, or both may be indicated, depending on health status.

Strategy 4: Encourage good hygiene

The availability of immunizations and anti­virals does not replace good hygiene. Frequent handwashing reduces the transmission of respiratory viruses, including influenza.¹⁶ Few studies have evaluated the use of alcohol-based hand sanitizers, but available evidence suggests they are effective in lowering viral transmission.¹⁶

Barriers, such as masks, gloves, and gowns, are helpful for health care workers.¹⁶ Surgical masks are often considered more comfortable to wear than N95 respirators. It may therefore be welcome news that when a 2009 randomized study assessed their use by hospital-based nurses, masks were non-inferior in protecting these health care workers against influenza.¹⁷

Presenteeism, the practice of going to work while sick, should be discouraged. People at risk for influenza may wish to avoid crowds during flu season; those with symptoms should be encouraged to stay home and limit contact with others.

Continue to: Treatment

Strategy 1: Make prompt use of antivirals

Despite available preventive measures, tens of millions of people in the United States develop influenza every year. Use of antiviral medication, begun early in the course of illness, can reduce the duration of symptoms and may reduce the risk for complications.

The neuraminidase inhibitor (NI) group of antivirals—oseltamivir, zanamivir, and peramivir—is effective against influenza types A and B and current resistance rates are low.

The adamantine family of antivirals, amantadine and rimantadine, treat type A only. Since the circulating influenza strains in the past several seasons have demonstrated resistance >99%, these medications are not currently recommended.¹⁴

NIs reduce the duration of influenza symptoms by 10% to 20%, shortening the illness by 6 to 24 hours.^18,19 In otherwise healthy patients, this benefit must be balanced against the increased risk for nausea and vomiting (oseltamivir), bronchospasm and sinusitis (zanamivir), and diarrhea (peramivir). In adults, NIs reduce the risk for lower respiratory tract complications and hospitalization. A 2015 meta-analysis by Dobson et al found a relative risk for hospitalization among those prescribed oseltamivir vs placebo of 37%.¹⁸

In the past, antivirals were used only in high-risk patients, such as children younger than 2 years, adults older than 65 years, and those with chronic health conditions.¹⁴ Now, antivirals are recommended for those who are at higher risk for complications (see Table 4), those with “severe, complicated, or progressive illness,” and hospitalized patients.¹⁴

Continue to: Antiviral treatment may have some value...

Antiviral treatment may have some value for hospitalized patients when started even 5 days after symptom onset. Treatment may be extended beyond the usual recommendations (5 days for oseltamivir or zanamivir) in immunosuppressed patients or the critically ill. Additionally, recent guidelines include consideration of antiviral treatment in outpatients who are at normal risk if treatment can be started within 48 hours of symptom onset.¹⁴

The CDC currently recommends use of oseltamivir rather than other antivirals for most hospitalized patients, based on the availability of data on its use in this setting.¹⁴ Intravenous peramivir is recommended for patients who cannot tolerate or absorb oral medication; inhaled zanamivir or IV peramivir are preferred for patients with end-stage renal disease who are not undergoing dialysis (see Table 3).¹⁴

Strategy 2: Exercise caution when it comes to supportive care

There are other medications that may offer symptom relief or prevent complications, especially when antivirals are contraindicated or unavailable.

Corticosteroids are recommended as part of the treatment of community-acquired pneumonia,²⁰ but their role in influenza is controversial. A 2016 Cochrane review²¹ found no randomized controlled trials on the topic. Although the balance of available data from observational studies indicated that use of corticosteroids was associated with increased mortality, the authors also noted that all the studies included in their meta-analysis were of “very low quality.” They concluded that “the use of steroids in influenza remains a clinical judgement call.”

Offering vaccination by the end of October, if possible, is recommended in order for immunity to develop by mid-November.

Statins may be associated with improved outcomes in influenza and pneumonia. Studies thus far have given contradictory results,^22,23 and a planned Cochrane review of the question has been withdrawn.²⁴

Continue to: Over-the-counter medications...

Over-the-counter medications, such as aspirin, acetaminophen, and ibuprofen are often used to manage the fever and myalgia associated with influenza. Patients should be cautioned against using the same ingredient in multiple different branded medications. Acetaminophen, for example, is not limited to Tylenol-branded products. To avoid Reye’s syndrome, children and teens with febrile illness, such as influenza, should not use aspirin.

CORRESPONDENCE
Jennifer L. Hamilton, MD, PhD, Drexel Family Medicine, 10 Shurs Lane, Suite 301, Philadelphia, PA 19127; [email protected].

Last year’s influenza season was severe enough that hospitals around the United States set up special evaluation areas beyond their emergency departments, at times spilling over to tents or other temporary structures in what otherwise would be parking lots. The scale and potential severity of the annual epidemic can be difficult to convey to our patients, who sometimes say “just the flu” to refer to an illness responsible for more than 170 pediatric deaths in the United States this past year.¹ The Centers for Disease Control and Prevention (CDC) recently updated its 5-year estimates of influenza-related deaths in the United States; influenza mortality ranges from about 12,000 deaths in a mild season (such as 2011-2012) to 56,000 in a more severe season (eg, 2012-2013).²

Although influenza cannot be completely prevented, the following strategies can help reduce the risk for the illness and limit its severity if contracted.

Prevention

Strategy 1: Vaccinate against influenza

While the efficacy of vaccines varies from year to year, vaccination remains the core of influenza prevention efforts. In this decade, vaccine effectiveness has ranged from 19% to 60%.³ However, models suggest that even when the vaccine is only 20% effective, vaccinating 140 million people (the average number of doses delivered annually in the United States over the past 5 seasons) prevents 21 million infections, 130,000 hospitalizations, and more than 61,000 deaths.⁴ In a case-control study, Flannery et al found that vaccination was 65% effective in preventing laboratory-confirmed influenza-associated death in children over 4 seasons (July 2010 through June 2014).⁵

Deciding who should be vaccinated is simpler than in prior years: Rather than targeting people who are at higher risk (those ages 65 and older, or those with comorbidities), the current CDC recommendation is to vaccinate nearly everyone ages 6 months or older, with limited exceptions.^6,7 (See Table 1⁸).

Formulations. Many types of influenza vaccine are approved for use in the United States; these differ in the number of strains included (3 or 4), the amount of antigen present for each strain, the presence of an adjuvant, the growth medium used for the virus, and the route of administration (see Table 2⁹). The relative merits of each type are a matter of some debate. There is ongoing research into the comparative efficacy of vaccines comprised of egg- vs cell-based cultures, as well as studies comparing high-dose or adjuvant vaccines to standard-dose inactivated vaccines.

Previously, the CDC has recommended preferential use (or avoidance) of some vaccine types, based on their efficacy. For the 2018-2019 flu season, however, the CDC has rescinded its recommendation against vaccine containing live attenuated virus (LAIV; FluMist brand) and expresses no preference for any vaccine formulation for patients of appropriate age and health status.¹⁰ The American Academy of Pediatrics (AAP), however, is recommends that LAIV be used only if patients and their families decline injectable vaccines.¹¹

Timing. Influenza vaccines are now distributed as early as July to some locations, raising concerns about waning immunity from early vaccination (July/August) if the influenza season does not peak until February or March.^8,12,13 Currently, the CDC recommends balancing the possible benefit of delayed vaccination against the risks of missed opportunities to vaccinate, a possible early season, and logistical problems related to vaccinating the same number of people in a smaller time interval. Offering vaccination by the end of October, if possible, is recommended in order for immunity to develop by mid-November.⁸ Note: Children ages 6 months to 8 years will need to receive their initial vaccination in 2 half-doses administered at least 28 days apart; completing their vaccination by the end of October would require starting the process weeks earlier.

[polldaddy:10124269]

Continue to: Strategy 2

Strategy 2: Make use of chemoprophylaxis

Preventive use of antiviral medication (chemoprophylaxis) may be a useful adjunct or alternative to vaccination in certain circumstances: if the patient is at high risk for complications, has been exposed to someone with influenza, has contraindications to vaccination, or received the vaccine within the past 2 weeks. The CDC also suggests that chemoprophylaxis be considered for those with immune deficiencies or who are otherwise immunosuppressed after exposure.¹⁴ Antivirals can also be used to control outbreaks in long-term care facilities; in these cases, the recommendedregimen is daily administration for at least 2 weeks, continuing until at least 7 days after the identification of the last case.¹⁴ Oseltamivir (Tamiflu) and zanamivir (Relenza) are the recommended prophylactic agents; a related intravenous medication, peramivir (Rapivab), is recommend for treatment only (see Table 3¹⁴).

Strategy 3: Prevent comorbidities and opportunistic infections

Morbidity associated with influenza often comes from secondary infection. Pneumonia is among the most common complications, so influenza season is a good time to ensure that patients are appropriately vaccinated against pneumococcus, as well. Pneumococcal conjugate vaccine (Prevnar or PCV13) is recommended for children younger than 2 years of age, to be administered in a series of 4 doses: at 2, 4, 6, and 12-15 months. Vaccination with PCV13 is also recommended for those ages 65 or older, to be followed at least one year later with pneumococcal polysaccharide vaccine (Pneumovax or PPSV23).¹⁵ Additional doses of PCV13, PPSV23, or both may be indicated, depending on health status.

Strategy 4: Encourage good hygiene

The availability of immunizations and anti­virals does not replace good hygiene. Frequent handwashing reduces the transmission of respiratory viruses, including influenza.¹⁶ Few studies have evaluated the use of alcohol-based hand sanitizers, but available evidence suggests they are effective in lowering viral transmission.¹⁶

Barriers, such as masks, gloves, and gowns, are helpful for health care workers.¹⁶ Surgical masks are often considered more comfortable to wear than N95 respirators. It may therefore be welcome news that when a 2009 randomized study assessed their use by hospital-based nurses, masks were non-inferior in protecting these health care workers against influenza.¹⁷

Presenteeism, the practice of going to work while sick, should be discouraged. People at risk for influenza may wish to avoid crowds during flu season; those with symptoms should be encouraged to stay home and limit contact with others.

Continue to: Treatment

Strategy 1: Make prompt use of antivirals

Despite available preventive measures, tens of millions of people in the United States develop influenza every year. Use of antiviral medication, begun early in the course of illness, can reduce the duration of symptoms and may reduce the risk for complications.

The neuraminidase inhibitor (NI) group of antivirals—oseltamivir, zanamivir, and peramivir—is effective against influenza types A and B and current resistance rates are low.

The adamantine family of antivirals, amantadine and rimantadine, treat type A only. Since the circulating influenza strains in the past several seasons have demonstrated resistance >99%, these medications are not currently recommended.¹⁴

NIs reduce the duration of influenza symptoms by 10% to 20%, shortening the illness by 6 to 24 hours.^18,19 In otherwise healthy patients, this benefit must be balanced against the increased risk for nausea and vomiting (oseltamivir), bronchospasm and sinusitis (zanamivir), and diarrhea (peramivir). In adults, NIs reduce the risk for lower respiratory tract complications and hospitalization. A 2015 meta-analysis by Dobson et al found a relative risk for hospitalization among those prescribed oseltamivir vs placebo of 37%.¹⁸

In the past, antivirals were used only in high-risk patients, such as children younger than 2 years, adults older than 65 years, and those with chronic health conditions.¹⁴ Now, antivirals are recommended for those who are at higher risk for complications (see Table 4), those with “severe, complicated, or progressive illness,” and hospitalized patients.¹⁴

Continue to: Antiviral treatment may have some value...

Antiviral treatment may have some value for hospitalized patients when started even 5 days after symptom onset. Treatment may be extended beyond the usual recommendations (5 days for oseltamivir or zanamivir) in immunosuppressed patients or the critically ill. Additionally, recent guidelines include consideration of antiviral treatment in outpatients who are at normal risk if treatment can be started within 48 hours of symptom onset.¹⁴

The CDC currently recommends use of oseltamivir rather than other antivirals for most hospitalized patients, based on the availability of data on its use in this setting.¹⁴ Intravenous peramivir is recommended for patients who cannot tolerate or absorb oral medication; inhaled zanamivir or IV peramivir are preferred for patients with end-stage renal disease who are not undergoing dialysis (see Table 3).¹⁴

Strategy 2: Exercise caution when it comes to supportive care

There are other medications that may offer symptom relief or prevent complications, especially when antivirals are contraindicated or unavailable.

Corticosteroids are recommended as part of the treatment of community-acquired pneumonia,²⁰ but their role in influenza is controversial. A 2016 Cochrane review²¹ found no randomized controlled trials on the topic. Although the balance of available data from observational studies indicated that use of corticosteroids was associated with increased mortality, the authors also noted that all the studies included in their meta-analysis were of “very low quality.” They concluded that “the use of steroids in influenza remains a clinical judgement call.”

Offering vaccination by the end of October, if possible, is recommended in order for immunity to develop by mid-November.

Statins may be associated with improved outcomes in influenza and pneumonia. Studies thus far have given contradictory results,^22,23 and a planned Cochrane review of the question has been withdrawn.²⁴

Continue to: Over-the-counter medications...

Over-the-counter medications, such as aspirin, acetaminophen, and ibuprofen are often used to manage the fever and myalgia associated with influenza. Patients should be cautioned against using the same ingredient in multiple different branded medications. Acetaminophen, for example, is not limited to Tylenol-branded products. To avoid Reye’s syndrome, children and teens with febrile illness, such as influenza, should not use aspirin.

CORRESPONDENCE
Jennifer L. Hamilton, MD, PhD, Drexel Family Medicine, 10 Shurs Lane, Suite 301, Philadelphia, PA 19127; [email protected].

Multiple payment systems impede universal HPV screening access 

Unless the issue of multiple systems of payment and access (that is, multiple insurance companies and providers) can be resolved in the United States, I do not believe there will be an advancement across the board for human papillomavirus (HPV) screening. In my opinion, we need to work toward access to health care for all and a single-payer system.

C.L. Conrad-Forrest, MD
Davis, California

Dr. Barbieri responds

I agree with Dr. Conrad-Forrest that improving cervical cancer screening would be advanced by interoperable electronic medical records and health systems that are designed to manage population health. I predict that a large integrated health system will be the first to adopt the use of high-risk HPV testing to screen for cervical cancer in the United States.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Multiple payment systems impede universal HPV screening access 

Unless the issue of multiple systems of payment and access (that is, multiple insurance companies and providers) can be resolved in the United States, I do not believe there will be an advancement across the board for human papillomavirus (HPV) screening. In my opinion, we need to work toward access to health care for all and a single-payer system.

C.L. Conrad-Forrest, MD
Davis, California

Dr. Barbieri responds

I agree with Dr. Conrad-Forrest that improving cervical cancer screening would be advanced by interoperable electronic medical records and health systems that are designed to manage population health. I predict that a large integrated health system will be the first to adopt the use of high-risk HPV testing to screen for cervical cancer in the United States.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Multiple payment systems impede universal HPV screening access 

Unless the issue of multiple systems of payment and access (that is, multiple insurance companies and providers) can be resolved in the United States, I do not believe there will be an advancement across the board for human papillomavirus (HPV) screening. In my opinion, we need to work toward access to health care for all and a single-payer system.

C.L. Conrad-Forrest, MD
Davis, California

Dr. Barbieri responds

I agree with Dr. Conrad-Forrest that improving cervical cancer screening would be advanced by interoperable electronic medical records and health systems that are designed to manage population health. I predict that a large integrated health system will be the first to adopt the use of high-risk HPV testing to screen for cervical cancer in the United States.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Patients with overweight and obesity are at increased risk of multiple morbidities, including cardiovascular disease, stroke, type 2 diabetes (T2D), osteoarthritis, obstructive sleep apnea (OSA), and all-cause mortality.¹ Even modest weight loss—5% to 10%—can lead to a clinically relevant reduction in this risk of disease.^2,3 The American Academy of Family Physicians recognizes obesity as a disease, and recommends screening of all adults for obesity and referral for those with body mass index (BMI)* ≥30 to intensive, multicomponent behavioral interventions.^4,5

For some patients, diet, exercise, and behavioral modifications are sufficient; for the great majority, however, weight loss achieved by lifestyle modification is counteracted by metabolic adaptations that promote weight regain.⁶ For patients with obesity who are unable to achieve or maintain sufficient weight loss to improve health outcomes with lifestyle modification alone, options include pharmacotherapy, devices, endoscopic bariatric therapies, and bariatric surgery.

Bariatric surgery is the most effective of these treatments, due to its association with significant and sustained weight loss, reduction in obesity-related comorbidities, and improved quality of life.^1,7 Furthermore, compared with usual care, bariatric surgery is associated with a reduced number of cardiovascular deaths, a lower incidence of cardiovascular events in adults with obesity, and a long-term reduction in overall mortality.^8-10

What are the options? Who is a candidate?

The 3 most common bariatric procedures in the United States are sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), and laparoscopic adjustable gastric band (LAGB).¹¹ SG and RYGB are performed more often than the LAGB, consequent to greater efficacy and fewer complications.¹² Weight loss is maximal at 1 to 2 years, and is estimated to be 15% of total body weight for LAGB; 25% for SG; and 35% for RYGB.^13,14

Weight loss is estimated to be 15% of total body weight for the laparoscopic adjustable gastric band, 25% for sleeve gastrectomy, and 35% for Roux-en-Y gastric bypass.

Not all patients are candidates for bariatric surgery. Contraindications include chronic obstructive pulmonary disease or respiratory dysfunction, poor cardiac reserve, nonadherence to medical treatment, and severe psychological disorders.¹⁵ Because some patients have difficulty maintaining weight loss following bariatric surgery and, on average, patients regain at least some weight, patients must understand that long-term lifestyle changes and follow-up are critical to the success of bariatric surgery.¹⁶

When should bariatric surgery be considered?

American Heart Association/American College of Cardiology/The Obesity Society guidelines¹⁶ conceptualize 2 indications for bariatric surgery:

• adults with BMI ≥40
• adults with BMI ≥35 who have obesity-related comorbid conditions and are motivated to lose weight but have not responded to behavioral treatment, with or without pharmacotherapy, to achieve sufficient weight loss for target health goals.

American Association of Clinical Endocrinologists guidelines¹⁷ conceptualize 3 indications for bariatric surgery:

• adults with BMI ≥40
• adults with BMI ≥35 with 1 or more severe obesity-related complications
• adults with BMI 30-34.9 with diabetes or metabolic syndrome (evidence for this recommendation is limited).

Continue to: The 3 illustrative vignettes presented...

The 3 illustrative vignettes presented in this article offer examples of patients with obesity who could benefit from bariatric surgery. Each has been unable to achieve or maintain sufficient weight loss to improve health outcomes with nonsurgical interventions alone.

CASE 1

Sleep apnea persists despite weight loss

Robin W, a 50-year-old woman with class-II obesity (5’8”; 250 lb; BMI, 38 ), OSA requiring continuous positive airway pressure (CPAP), hyperlipidemia, hypertension, and iron-deficiency anemia secondary to menorrhagia, and taking an iron supplement, presents for weight management. She has lost 50 lb, reducing her BMI from 45.6 with behavioral modifications and pharmacotherapy, but she has been unsuccessful at achieving further weight loss despite a reduced-calorie diet and at least 30 minutes of physical activity most days.

Long-term lifestyle changes and follow-up are critical to the success of bariatric surgery.

Ms. W is frustrated that she has reached a weight plateau; she is motivated to lose more weight. Her goal is to improve her weight-related comorbid conditions and reduce her medication requirement. Despite the initial weight loss, she continues to require CPAP therapy for OSA and remains on 3 medications for hypertension. She does not have cardiac or respiratory disease, psychiatric diagnoses, or a history of gastroesophageal reflux disease (GERD).

Is bariatric surgery a reasonable option for Ms. W? If so, which procedure would you recommend?

Good option for Ms. W: Sleeve gastrectomy

It is reasonable to consider bariatric surgery—in particular, SG—for this patient with class-II obesity and multiple weight-related comorbid conditions because she has been unable to achieve further weight loss with more conservative measures.

Continue to: How does the procedure work?

How does the procedure work? SG removes a large portion of the stomach along the greater curvature, reducing the organ to approximately 15% to 25% of its original size.¹⁸ The procedure leaves the pyloric valve intact and does not involve removal or bypass of the intestines.

How appealing and successful is it? The majority of patients who undergo SG experience significant weight loss; studies report approximately 25% total body weight loss after 1 to 2 years.¹⁴ Furthermore, most patients with T2D experience resolution of, or improvement in, disease markers.¹⁹ Because SG leaves the pylorus intact, there are fewer restrictions on what a patient can eat after surgery, compared with RYGB. With further weight loss, Ms. W may experience improvement in, or resolution of, hypertension, hyperlipidemia, and OSA.

The SG procedure itself is simpler than some other bariatric procedures and presents less risk of malabsorption because the intestines are left intact. Patients who undergo SG report feeling less hungry because the fundus of the stomach, which secretes ghrelin (the so-called hunger hormone), is removed.^18,20

What are special considerations, including candidacy? Patients with GERD are not ideal candidates for this procedure because exacerbation of the disease is a potential associated adverse event. SG is a reasonable surgical option for Ms. W because the procedure is less likely to exacerbate her nutritional deficiency (iron-deficiency anemia), compared to RYGB, and she does not have a history of GERD.

What are the complications? Complications of SG occur at a lower rate than they do with RYGB, which is associated with a greater risk of nutritional deficiency.¹⁸ Common early complications of SG include leaking, bleeding, stenosis, GERD, and vomiting due to excessive eating. Late complications include stomach expansion by 12 months, leading to decreased restriction.¹⁵ Unlike RYGB and LAGB, SG is not reversible.

Continue to: CASE 2

CASE 2

Severe obesity, polypharmacy for type 2 diabetes

Anne P, a 42-year-old woman with class-III obesity (5’6”; 290 lb; BMI, 46.8 kg/m²), presents to discuss bariatric surgery. Comorbidities include T2D, for which she takes metformin, a glucagon-like peptide-1 (GLP-1) receptor agonist, and a sodium–glucose cotransporter-2 (SGLT-2) inhibitor; GERD; hypertension, for which she takes an angiotensin-converting enzyme inhibitor and a calcium-channel blocker; hyperlipidemia, for which she takes a statin; and osteoarthritis.

Roux-en-Y gastric bypass is effective for weight loss because patients eat smaller portions and cannot absorb all they eat.

Ms. P lost 30 pounds—reducing her BMI from 51.6—when the sulfonylurea and thiazolidinedione she was taking were switched to the GLP-1 receptor agonist and the SGLT2 inhibitor. She also made behavioral modifications, including 30 minutes a day of physical activity and a reduced-calorie meal plan under the guidance of a dietitian.

However, Ms. P has been unable to lose more weight or reduce her hemoglobin A_1c (HbA_1c) level below 8%. Her goal is to avoid the need to take insulin (which several members of her family take), lower her HbA_1c level, and decrease her medication requirement.

Ms. P does not have cardiac or respiratory disease or psychiatric diagnoses. Which surgical intervention would you recommend for her?

Good option for Ms. P: Roux-en-Y gastric bypass

RYGB is a reasonable option for a patient with class-III obesity and multiple comorbidities, including poorly controlled T2D and GERD, who has failed conservative measures but wants to lose more weight, reduce her HbA_1c, reduce her medication requirement, and avoid the need for insulin.

Continue to: How does the procedure work?

How does the procedure work? RYGB constructs a small pouch from the proximal portion of the stomach and attaches it directly to the jejunum, thus bypassing part of the stomach and duodenum. The procedure is effective for weight loss because it is both restrictive and malabsorptive: patients not only eat smaller portions, but cannot absorb all they eat. Other mechanisms attributed to RYGB that are hypothesized to promote weight loss include²¹:

• alteration of endogenous gut hormones, which promotes postprandial satiety
• increased levels of bile acids, which promotes alteration of the gut microbiome
• intestinal hypertrophy.

How successful is it? RYGB is associated with significant total body weight loss of approximately 35% at 2 years.⁹ The procedure has been shown to produce superior outcomes in reducing comorbid disease compared to other bariatric procedures or medical therapy alone. Of the procedures discussed in this article, RYGB is associated with the greatest reduction in triglycerides, HbA_1c, and use of diabetes medications, including insulin.²²

What are special considerations, including candidacy? For patients with mild or moderate T2D (calculated using the Individualized Metabolic Surgery Score [http://riskcalc.org/Metabolic_Surgery_Score/], which categorizes patients by number of diabetes medications, insulin use, duration of diabetes before surgery, and HbA_1c), RYGB is recommended over SG because it leads to greater long-term remission of T2D.

RYGB is associated with a lower rate of GERD than SG and can even alleviate GERD in patients who have the disease. Furthermore, for patients with limited pancreatic beta cell reserve, RYBG and SG have similarly low efficacy for T2D remission; SG is therefore recommended over RYGB in this specific circumstance, given its slightly lower risk profile.²³

What are the complications? Patients who undergo any bariatric surgical procedure require long-term follow-up and vitamin supplementation, but those who undergo RYGB require stricter dietary adherence after the procedure; lifelong vitamin (D, B₁₂, folic acid, and thiamine), iron, and calcium supplementation; and long-term follow-up to reduce the risk and severity of complications and to monitor for nutritional deficiencies.⁷ As such, patients who have shown poor adherence to medical treatment are not good candidates for the procedure.

Continue to: Early complications include...

Early complications include leak, stricture, obstruction, and failure of the staple partition of the upper stomach. Late complications include nutritional deficiencies, as noted, and ulceration of the anastomosis. Dumping syndrome (overly rapid transit of food from the stomach into the small intestine) can develop early or late; early dumping leads to osmotic diarrhea and abdominal cramping, and late dumping leads to reactive hypoglycemia.¹⁵

Most patients with T2D who undergo sleeve gastrectomy see resolution of, or improvement in, markers of diabetes.

Technically, RYGB is a reversible procedure, although generally it is reversed only in extreme circumstances.

CASE 3

Fatty liver disease, hesitation to undergo surgery

Walt Z, a 35 year-old-man with class-II obesity (5’10”; 265 lb; BMI, 38 kg/m²), T2D, and hepatic steatosis, presents for weight management. He has been able to lose modest weight over the years with behavioral modifications, but has been unsuccessful in maintaining that loss. He requests referral to a bariatric surgeon but is concerned about the permanence and invasiveness of most bariatric procedures.

Which surgical intervention would you recommend for this patient?

Good option for Mr. Z: Laparoscopic adjustable gastric band

Given that Mr. Z is a candidate for a surgical intervention but does not want a permanent or invasive procedure, LAGB is a reasonable option.

Continue to: How does the procedure work?

How does the procedure work? LAGB is a reversible procedure in which an inflatable band is placed around the fundus of the stomach to create a small pouch. The band can be adjusted to regulate food intake by adding or removing saline through a subcutaneous access port.

How appealing and successful is it? LAGB results in approximately 15% total body weight loss at 2 years.¹³ Because the procedure is purely restrictive, it carries a reduced risk of nutritional deficiency associated more commonly with malabsorptive procedures.

What are special considerations, including candidacy? As noted, Mr. Z expressed concern about the permanence and invasiveness of most bariatric procedures, and therefore wants to undergo a reversible procedure; LAGB can be a reasonable option for such a patient. Patients who want a reversible or minimally invasive procedure should also be made aware that endoscopic bariatric therapies and other devices are being developed to fill the treatment gap in the management of obesity.

What are the complications? Although LAGB is the least invasive procedure discussed here, it is associated with the highest rate of complications—most commonly, complications associated with the band itself (eg, nausea, vomiting, obstruction, band erosion or migration, esophageal dysmotility leading to acid reflux) and failure to lose weight.⁷ LAGB also requires more postoperative visits than other procedures, to optimize band tightness. A high number of bands are removed eventually because of complications or inadequate weight loss, or both.^13,24

Shared decision-making and dialogue are essential to overcome obstacles

Despite the known benefits of bariatric surgery, including greater reduction in the risk and severity of obesity-related comorbid conditions than seen with other interventions and a long-term reduction in overall mortality when compared with usual care, fewer than 1% of eligible patients undergo a weight-loss procedure.²⁵ Likely, this is due to:

• limited patient knowledge of the health benefits of surgery
• limited provider comfort recommending surgery
• inadequate insurance coverage, which might, in part, be due to a lack of prospective studies comparing various bariatric procedures.¹⁸

Continue to: Ultimately, the decision whether to undergo a bariatric procedure...

Ultimately, the decision whether to undergo a bariatric procedure, and which one(s) to consider, should be the product of a thorough conversation between patient and provider.

CORRESPONDENCE
Sarah R. Barenbaum, MD, Department of Internal Medicine, New York–Presbyterian Hospital/Weill Cornell Medical College, 530 East 70th Street, M-507, New York, NY 10021; [email protected]

Patients with overweight and obesity are at increased risk of multiple morbidities, including cardiovascular disease, stroke, type 2 diabetes (T2D), osteoarthritis, obstructive sleep apnea (OSA), and all-cause mortality.¹ Even modest weight loss—5% to 10%—can lead to a clinically relevant reduction in this risk of disease.^2,3 The American Academy of Family Physicians recognizes obesity as a disease, and recommends screening of all adults for obesity and referral for those with body mass index (BMI)* ≥30 to intensive, multicomponent behavioral interventions.^4,5

For some patients, diet, exercise, and behavioral modifications are sufficient; for the great majority, however, weight loss achieved by lifestyle modification is counteracted by metabolic adaptations that promote weight regain.⁶ For patients with obesity who are unable to achieve or maintain sufficient weight loss to improve health outcomes with lifestyle modification alone, options include pharmacotherapy, devices, endoscopic bariatric therapies, and bariatric surgery.

Bariatric surgery is the most effective of these treatments, due to its association with significant and sustained weight loss, reduction in obesity-related comorbidities, and improved quality of life.^1,7 Furthermore, compared with usual care, bariatric surgery is associated with a reduced number of cardiovascular deaths, a lower incidence of cardiovascular events in adults with obesity, and a long-term reduction in overall mortality.^8-10

What are the options? Who is a candidate?

The 3 most common bariatric procedures in the United States are sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), and laparoscopic adjustable gastric band (LAGB).¹¹ SG and RYGB are performed more often than the LAGB, consequent to greater efficacy and fewer complications.¹² Weight loss is maximal at 1 to 2 years, and is estimated to be 15% of total body weight for LAGB; 25% for SG; and 35% for RYGB.^13,14

Weight loss is estimated to be 15% of total body weight for the laparoscopic adjustable gastric band, 25% for sleeve gastrectomy, and 35% for Roux-en-Y gastric bypass.

Not all patients are candidates for bariatric surgery. Contraindications include chronic obstructive pulmonary disease or respiratory dysfunction, poor cardiac reserve, nonadherence to medical treatment, and severe psychological disorders.¹⁵ Because some patients have difficulty maintaining weight loss following bariatric surgery and, on average, patients regain at least some weight, patients must understand that long-term lifestyle changes and follow-up are critical to the success of bariatric surgery.¹⁶

When should bariatric surgery be considered?

American Heart Association/American College of Cardiology/The Obesity Society guidelines¹⁶ conceptualize 2 indications for bariatric surgery:

• adults with BMI ≥40
• adults with BMI ≥35 who have obesity-related comorbid conditions and are motivated to lose weight but have not responded to behavioral treatment, with or without pharmacotherapy, to achieve sufficient weight loss for target health goals.

American Association of Clinical Endocrinologists guidelines¹⁷ conceptualize 3 indications for bariatric surgery:

• adults with BMI ≥40
• adults with BMI ≥35 with 1 or more severe obesity-related complications
• adults with BMI 30-34.9 with diabetes or metabolic syndrome (evidence for this recommendation is limited).

Continue to: The 3 illustrative vignettes presented...

The 3 illustrative vignettes presented in this article offer examples of patients with obesity who could benefit from bariatric surgery. Each has been unable to achieve or maintain sufficient weight loss to improve health outcomes with nonsurgical interventions alone.

CASE 1

Sleep apnea persists despite weight loss

Robin W, a 50-year-old woman with class-II obesity (5’8”; 250 lb; BMI, 38 ), OSA requiring continuous positive airway pressure (CPAP), hyperlipidemia, hypertension, and iron-deficiency anemia secondary to menorrhagia, and taking an iron supplement, presents for weight management. She has lost 50 lb, reducing her BMI from 45.6 with behavioral modifications and pharmacotherapy, but she has been unsuccessful at achieving further weight loss despite a reduced-calorie diet and at least 30 minutes of physical activity most days.

Long-term lifestyle changes and follow-up are critical to the success of bariatric surgery.

Ms. W is frustrated that she has reached a weight plateau; she is motivated to lose more weight. Her goal is to improve her weight-related comorbid conditions and reduce her medication requirement. Despite the initial weight loss, she continues to require CPAP therapy for OSA and remains on 3 medications for hypertension. She does not have cardiac or respiratory disease, psychiatric diagnoses, or a history of gastroesophageal reflux disease (GERD).

Is bariatric surgery a reasonable option for Ms. W? If so, which procedure would you recommend?

Good option for Ms. W: Sleeve gastrectomy

It is reasonable to consider bariatric surgery—in particular, SG—for this patient with class-II obesity and multiple weight-related comorbid conditions because she has been unable to achieve further weight loss with more conservative measures.

Continue to: How does the procedure work?

How does the procedure work? SG removes a large portion of the stomach along the greater curvature, reducing the organ to approximately 15% to 25% of its original size.¹⁸ The procedure leaves the pyloric valve intact and does not involve removal or bypass of the intestines.

How appealing and successful is it? The majority of patients who undergo SG experience significant weight loss; studies report approximately 25% total body weight loss after 1 to 2 years.¹⁴ Furthermore, most patients with T2D experience resolution of, or improvement in, disease markers.¹⁹ Because SG leaves the pylorus intact, there are fewer restrictions on what a patient can eat after surgery, compared with RYGB. With further weight loss, Ms. W may experience improvement in, or resolution of, hypertension, hyperlipidemia, and OSA.

The SG procedure itself is simpler than some other bariatric procedures and presents less risk of malabsorption because the intestines are left intact. Patients who undergo SG report feeling less hungry because the fundus of the stomach, which secretes ghrelin (the so-called hunger hormone), is removed.^18,20

What are special considerations, including candidacy? Patients with GERD are not ideal candidates for this procedure because exacerbation of the disease is a potential associated adverse event. SG is a reasonable surgical option for Ms. W because the procedure is less likely to exacerbate her nutritional deficiency (iron-deficiency anemia), compared to RYGB, and she does not have a history of GERD.

What are the complications? Complications of SG occur at a lower rate than they do with RYGB, which is associated with a greater risk of nutritional deficiency.¹⁸ Common early complications of SG include leaking, bleeding, stenosis, GERD, and vomiting due to excessive eating. Late complications include stomach expansion by 12 months, leading to decreased restriction.¹⁵ Unlike RYGB and LAGB, SG is not reversible.

Continue to: CASE 2

CASE 2

Severe obesity, polypharmacy for type 2 diabetes

Anne P, a 42-year-old woman with class-III obesity (5’6”; 290 lb; BMI, 46.8 kg/m²), presents to discuss bariatric surgery. Comorbidities include T2D, for which she takes metformin, a glucagon-like peptide-1 (GLP-1) receptor agonist, and a sodium–glucose cotransporter-2 (SGLT-2) inhibitor; GERD; hypertension, for which she takes an angiotensin-converting enzyme inhibitor and a calcium-channel blocker; hyperlipidemia, for which she takes a statin; and osteoarthritis.

Roux-en-Y gastric bypass is effective for weight loss because patients eat smaller portions and cannot absorb all they eat.

Ms. P lost 30 pounds—reducing her BMI from 51.6—when the sulfonylurea and thiazolidinedione she was taking were switched to the GLP-1 receptor agonist and the SGLT2 inhibitor. She also made behavioral modifications, including 30 minutes a day of physical activity and a reduced-calorie meal plan under the guidance of a dietitian.

However, Ms. P has been unable to lose more weight or reduce her hemoglobin A_1c (HbA_1c) level below 8%. Her goal is to avoid the need to take insulin (which several members of her family take), lower her HbA_1c level, and decrease her medication requirement.

Ms. P does not have cardiac or respiratory disease or psychiatric diagnoses. Which surgical intervention would you recommend for her?

Good option for Ms. P: Roux-en-Y gastric bypass

RYGB is a reasonable option for a patient with class-III obesity and multiple comorbidities, including poorly controlled T2D and GERD, who has failed conservative measures but wants to lose more weight, reduce her HbA_1c, reduce her medication requirement, and avoid the need for insulin.

Continue to: How does the procedure work?

How does the procedure work? RYGB constructs a small pouch from the proximal portion of the stomach and attaches it directly to the jejunum, thus bypassing part of the stomach and duodenum. The procedure is effective for weight loss because it is both restrictive and malabsorptive: patients not only eat smaller portions, but cannot absorb all they eat. Other mechanisms attributed to RYGB that are hypothesized to promote weight loss include²¹:

• alteration of endogenous gut hormones, which promotes postprandial satiety
• increased levels of bile acids, which promotes alteration of the gut microbiome
• intestinal hypertrophy.

How successful is it? RYGB is associated with significant total body weight loss of approximately 35% at 2 years.⁹ The procedure has been shown to produce superior outcomes in reducing comorbid disease compared to other bariatric procedures or medical therapy alone. Of the procedures discussed in this article, RYGB is associated with the greatest reduction in triglycerides, HbA_1c, and use of diabetes medications, including insulin.²²

What are special considerations, including candidacy? For patients with mild or moderate T2D (calculated using the Individualized Metabolic Surgery Score [http://riskcalc.org/Metabolic_Surgery_Score/], which categorizes patients by number of diabetes medications, insulin use, duration of diabetes before surgery, and HbA_1c), RYGB is recommended over SG because it leads to greater long-term remission of T2D.

RYGB is associated with a lower rate of GERD than SG and can even alleviate GERD in patients who have the disease. Furthermore, for patients with limited pancreatic beta cell reserve, RYBG and SG have similarly low efficacy for T2D remission; SG is therefore recommended over RYGB in this specific circumstance, given its slightly lower risk profile.²³

What are the complications? Patients who undergo any bariatric surgical procedure require long-term follow-up and vitamin supplementation, but those who undergo RYGB require stricter dietary adherence after the procedure; lifelong vitamin (D, B₁₂, folic acid, and thiamine), iron, and calcium supplementation; and long-term follow-up to reduce the risk and severity of complications and to monitor for nutritional deficiencies.⁷ As such, patients who have shown poor adherence to medical treatment are not good candidates for the procedure.

Continue to: Early complications include...

Early complications include leak, stricture, obstruction, and failure of the staple partition of the upper stomach. Late complications include nutritional deficiencies, as noted, and ulceration of the anastomosis. Dumping syndrome (overly rapid transit of food from the stomach into the small intestine) can develop early or late; early dumping leads to osmotic diarrhea and abdominal cramping, and late dumping leads to reactive hypoglycemia.¹⁵

Most patients with T2D who undergo sleeve gastrectomy see resolution of, or improvement in, markers of diabetes.

Technically, RYGB is a reversible procedure, although generally it is reversed only in extreme circumstances.

CASE 3

Fatty liver disease, hesitation to undergo surgery

Walt Z, a 35 year-old-man with class-II obesity (5’10”; 265 lb; BMI, 38 kg/m²), T2D, and hepatic steatosis, presents for weight management. He has been able to lose modest weight over the years with behavioral modifications, but has been unsuccessful in maintaining that loss. He requests referral to a bariatric surgeon but is concerned about the permanence and invasiveness of most bariatric procedures.

Which surgical intervention would you recommend for this patient?

Good option for Mr. Z: Laparoscopic adjustable gastric band

Given that Mr. Z is a candidate for a surgical intervention but does not want a permanent or invasive procedure, LAGB is a reasonable option.

Continue to: How does the procedure work?

How does the procedure work? LAGB is a reversible procedure in which an inflatable band is placed around the fundus of the stomach to create a small pouch. The band can be adjusted to regulate food intake by adding or removing saline through a subcutaneous access port.

How appealing and successful is it? LAGB results in approximately 15% total body weight loss at 2 years.¹³ Because the procedure is purely restrictive, it carries a reduced risk of nutritional deficiency associated more commonly with malabsorptive procedures.

What are special considerations, including candidacy? As noted, Mr. Z expressed concern about the permanence and invasiveness of most bariatric procedures, and therefore wants to undergo a reversible procedure; LAGB can be a reasonable option for such a patient. Patients who want a reversible or minimally invasive procedure should also be made aware that endoscopic bariatric therapies and other devices are being developed to fill the treatment gap in the management of obesity.

What are the complications? Although LAGB is the least invasive procedure discussed here, it is associated with the highest rate of complications—most commonly, complications associated with the band itself (eg, nausea, vomiting, obstruction, band erosion or migration, esophageal dysmotility leading to acid reflux) and failure to lose weight.⁷ LAGB also requires more postoperative visits than other procedures, to optimize band tightness. A high number of bands are removed eventually because of complications or inadequate weight loss, or both.^13,24

Shared decision-making and dialogue are essential to overcome obstacles

Despite the known benefits of bariatric surgery, including greater reduction in the risk and severity of obesity-related comorbid conditions than seen with other interventions and a long-term reduction in overall mortality when compared with usual care, fewer than 1% of eligible patients undergo a weight-loss procedure.²⁵ Likely, this is due to:

• limited patient knowledge of the health benefits of surgery
• limited provider comfort recommending surgery
• inadequate insurance coverage, which might, in part, be due to a lack of prospective studies comparing various bariatric procedures.¹⁸

Continue to: Ultimately, the decision whether to undergo a bariatric procedure...

Ultimately, the decision whether to undergo a bariatric procedure, and which one(s) to consider, should be the product of a thorough conversation between patient and provider.

CORRESPONDENCE
Sarah R. Barenbaum, MD, Department of Internal Medicine, New York–Presbyterian Hospital/Weill Cornell Medical College, 530 East 70th Street, M-507, New York, NY 10021; [email protected]

Patients with overweight and obesity are at increased risk of multiple morbidities, including cardiovascular disease, stroke, type 2 diabetes (T2D), osteoarthritis, obstructive sleep apnea (OSA), and all-cause mortality.¹ Even modest weight loss—5% to 10%—can lead to a clinically relevant reduction in this risk of disease.^2,3 The American Academy of Family Physicians recognizes obesity as a disease, and recommends screening of all adults for obesity and referral for those with body mass index (BMI)* ≥30 to intensive, multicomponent behavioral interventions.^4,5

For some patients, diet, exercise, and behavioral modifications are sufficient; for the great majority, however, weight loss achieved by lifestyle modification is counteracted by metabolic adaptations that promote weight regain.⁶ For patients with obesity who are unable to achieve or maintain sufficient weight loss to improve health outcomes with lifestyle modification alone, options include pharmacotherapy, devices, endoscopic bariatric therapies, and bariatric surgery.

Bariatric surgery is the most effective of these treatments, due to its association with significant and sustained weight loss, reduction in obesity-related comorbidities, and improved quality of life.^1,7 Furthermore, compared with usual care, bariatric surgery is associated with a reduced number of cardiovascular deaths, a lower incidence of cardiovascular events in adults with obesity, and a long-term reduction in overall mortality.^8-10

What are the options? Who is a candidate?

The 3 most common bariatric procedures in the United States are sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), and laparoscopic adjustable gastric band (LAGB).¹¹ SG and RYGB are performed more often than the LAGB, consequent to greater efficacy and fewer complications.¹² Weight loss is maximal at 1 to 2 years, and is estimated to be 15% of total body weight for LAGB; 25% for SG; and 35% for RYGB.^13,14

Weight loss is estimated to be 15% of total body weight for the laparoscopic adjustable gastric band, 25% for sleeve gastrectomy, and 35% for Roux-en-Y gastric bypass.

Not all patients are candidates for bariatric surgery. Contraindications include chronic obstructive pulmonary disease or respiratory dysfunction, poor cardiac reserve, nonadherence to medical treatment, and severe psychological disorders.¹⁵ Because some patients have difficulty maintaining weight loss following bariatric surgery and, on average, patients regain at least some weight, patients must understand that long-term lifestyle changes and follow-up are critical to the success of bariatric surgery.¹⁶

When should bariatric surgery be considered?

American Heart Association/American College of Cardiology/The Obesity Society guidelines¹⁶ conceptualize 2 indications for bariatric surgery:

• adults with BMI ≥40
• adults with BMI ≥35 who have obesity-related comorbid conditions and are motivated to lose weight but have not responded to behavioral treatment, with or without pharmacotherapy, to achieve sufficient weight loss for target health goals.

American Association of Clinical Endocrinologists guidelines¹⁷ conceptualize 3 indications for bariatric surgery:

• adults with BMI ≥40
• adults with BMI ≥35 with 1 or more severe obesity-related complications
• adults with BMI 30-34.9 with diabetes or metabolic syndrome (evidence for this recommendation is limited).

Continue to: The 3 illustrative vignettes presented...

The 3 illustrative vignettes presented in this article offer examples of patients with obesity who could benefit from bariatric surgery. Each has been unable to achieve or maintain sufficient weight loss to improve health outcomes with nonsurgical interventions alone.

CASE 1

Sleep apnea persists despite weight loss

Robin W, a 50-year-old woman with class-II obesity (5’8”; 250 lb; BMI, 38 ), OSA requiring continuous positive airway pressure (CPAP), hyperlipidemia, hypertension, and iron-deficiency anemia secondary to menorrhagia, and taking an iron supplement, presents for weight management. She has lost 50 lb, reducing her BMI from 45.6 with behavioral modifications and pharmacotherapy, but she has been unsuccessful at achieving further weight loss despite a reduced-calorie diet and at least 30 minutes of physical activity most days.

Long-term lifestyle changes and follow-up are critical to the success of bariatric surgery.

Ms. W is frustrated that she has reached a weight plateau; she is motivated to lose more weight. Her goal is to improve her weight-related comorbid conditions and reduce her medication requirement. Despite the initial weight loss, she continues to require CPAP therapy for OSA and remains on 3 medications for hypertension. She does not have cardiac or respiratory disease, psychiatric diagnoses, or a history of gastroesophageal reflux disease (GERD).

Is bariatric surgery a reasonable option for Ms. W? If so, which procedure would you recommend?

Good option for Ms. W: Sleeve gastrectomy

It is reasonable to consider bariatric surgery—in particular, SG—for this patient with class-II obesity and multiple weight-related comorbid conditions because she has been unable to achieve further weight loss with more conservative measures.

Continue to: How does the procedure work?

How does the procedure work? SG removes a large portion of the stomach along the greater curvature, reducing the organ to approximately 15% to 25% of its original size.¹⁸ The procedure leaves the pyloric valve intact and does not involve removal or bypass of the intestines.

How appealing and successful is it? The majority of patients who undergo SG experience significant weight loss; studies report approximately 25% total body weight loss after 1 to 2 years.¹⁴ Furthermore, most patients with T2D experience resolution of, or improvement in, disease markers.¹⁹ Because SG leaves the pylorus intact, there are fewer restrictions on what a patient can eat after surgery, compared with RYGB. With further weight loss, Ms. W may experience improvement in, or resolution of, hypertension, hyperlipidemia, and OSA.

The SG procedure itself is simpler than some other bariatric procedures and presents less risk of malabsorption because the intestines are left intact. Patients who undergo SG report feeling less hungry because the fundus of the stomach, which secretes ghrelin (the so-called hunger hormone), is removed.^18,20

What are special considerations, including candidacy? Patients with GERD are not ideal candidates for this procedure because exacerbation of the disease is a potential associated adverse event. SG is a reasonable surgical option for Ms. W because the procedure is less likely to exacerbate her nutritional deficiency (iron-deficiency anemia), compared to RYGB, and she does not have a history of GERD.

What are the complications? Complications of SG occur at a lower rate than they do with RYGB, which is associated with a greater risk of nutritional deficiency.¹⁸ Common early complications of SG include leaking, bleeding, stenosis, GERD, and vomiting due to excessive eating. Late complications include stomach expansion by 12 months, leading to decreased restriction.¹⁵ Unlike RYGB and LAGB, SG is not reversible.

Continue to: CASE 2

CASE 2

Severe obesity, polypharmacy for type 2 diabetes

Anne P, a 42-year-old woman with class-III obesity (5’6”; 290 lb; BMI, 46.8 kg/m²), presents to discuss bariatric surgery. Comorbidities include T2D, for which she takes metformin, a glucagon-like peptide-1 (GLP-1) receptor agonist, and a sodium–glucose cotransporter-2 (SGLT-2) inhibitor; GERD; hypertension, for which she takes an angiotensin-converting enzyme inhibitor and a calcium-channel blocker; hyperlipidemia, for which she takes a statin; and osteoarthritis.

Roux-en-Y gastric bypass is effective for weight loss because patients eat smaller portions and cannot absorb all they eat.

Ms. P lost 30 pounds—reducing her BMI from 51.6—when the sulfonylurea and thiazolidinedione she was taking were switched to the GLP-1 receptor agonist and the SGLT2 inhibitor. She also made behavioral modifications, including 30 minutes a day of physical activity and a reduced-calorie meal plan under the guidance of a dietitian.

However, Ms. P has been unable to lose more weight or reduce her hemoglobin A_1c (HbA_1c) level below 8%. Her goal is to avoid the need to take insulin (which several members of her family take), lower her HbA_1c level, and decrease her medication requirement.

Ms. P does not have cardiac or respiratory disease or psychiatric diagnoses. Which surgical intervention would you recommend for her?

Good option for Ms. P: Roux-en-Y gastric bypass

RYGB is a reasonable option for a patient with class-III obesity and multiple comorbidities, including poorly controlled T2D and GERD, who has failed conservative measures but wants to lose more weight, reduce her HbA_1c, reduce her medication requirement, and avoid the need for insulin.

Continue to: How does the procedure work?

How does the procedure work? RYGB constructs a small pouch from the proximal portion of the stomach and attaches it directly to the jejunum, thus bypassing part of the stomach and duodenum. The procedure is effective for weight loss because it is both restrictive and malabsorptive: patients not only eat smaller portions, but cannot absorb all they eat. Other mechanisms attributed to RYGB that are hypothesized to promote weight loss include²¹:

• alteration of endogenous gut hormones, which promotes postprandial satiety
• increased levels of bile acids, which promotes alteration of the gut microbiome
• intestinal hypertrophy.

How successful is it? RYGB is associated with significant total body weight loss of approximately 35% at 2 years.⁹ The procedure has been shown to produce superior outcomes in reducing comorbid disease compared to other bariatric procedures or medical therapy alone. Of the procedures discussed in this article, RYGB is associated with the greatest reduction in triglycerides, HbA_1c, and use of diabetes medications, including insulin.²²

What are special considerations, including candidacy? For patients with mild or moderate T2D (calculated using the Individualized Metabolic Surgery Score [http://riskcalc.org/Metabolic_Surgery_Score/], which categorizes patients by number of diabetes medications, insulin use, duration of diabetes before surgery, and HbA_1c), RYGB is recommended over SG because it leads to greater long-term remission of T2D.

RYGB is associated with a lower rate of GERD than SG and can even alleviate GERD in patients who have the disease. Furthermore, for patients with limited pancreatic beta cell reserve, RYBG and SG have similarly low efficacy for T2D remission; SG is therefore recommended over RYGB in this specific circumstance, given its slightly lower risk profile.²³

What are the complications? Patients who undergo any bariatric surgical procedure require long-term follow-up and vitamin supplementation, but those who undergo RYGB require stricter dietary adherence after the procedure; lifelong vitamin (D, B₁₂, folic acid, and thiamine), iron, and calcium supplementation; and long-term follow-up to reduce the risk and severity of complications and to monitor for nutritional deficiencies.⁷ As such, patients who have shown poor adherence to medical treatment are not good candidates for the procedure.

Continue to: Early complications include...

Early complications include leak, stricture, obstruction, and failure of the staple partition of the upper stomach. Late complications include nutritional deficiencies, as noted, and ulceration of the anastomosis. Dumping syndrome (overly rapid transit of food from the stomach into the small intestine) can develop early or late; early dumping leads to osmotic diarrhea and abdominal cramping, and late dumping leads to reactive hypoglycemia.¹⁵

Most patients with T2D who undergo sleeve gastrectomy see resolution of, or improvement in, markers of diabetes.

Technically, RYGB is a reversible procedure, although generally it is reversed only in extreme circumstances.

CASE 3

Fatty liver disease, hesitation to undergo surgery

Walt Z, a 35 year-old-man with class-II obesity (5’10”; 265 lb; BMI, 38 kg/m²), T2D, and hepatic steatosis, presents for weight management. He has been able to lose modest weight over the years with behavioral modifications, but has been unsuccessful in maintaining that loss. He requests referral to a bariatric surgeon but is concerned about the permanence and invasiveness of most bariatric procedures.

Which surgical intervention would you recommend for this patient?

Good option for Mr. Z: Laparoscopic adjustable gastric band

Given that Mr. Z is a candidate for a surgical intervention but does not want a permanent or invasive procedure, LAGB is a reasonable option.

Continue to: How does the procedure work?

How does the procedure work? LAGB is a reversible procedure in which an inflatable band is placed around the fundus of the stomach to create a small pouch. The band can be adjusted to regulate food intake by adding or removing saline through a subcutaneous access port.

How appealing and successful is it? LAGB results in approximately 15% total body weight loss at 2 years.¹³ Because the procedure is purely restrictive, it carries a reduced risk of nutritional deficiency associated more commonly with malabsorptive procedures.

What are special considerations, including candidacy? As noted, Mr. Z expressed concern about the permanence and invasiveness of most bariatric procedures, and therefore wants to undergo a reversible procedure; LAGB can be a reasonable option for such a patient. Patients who want a reversible or minimally invasive procedure should also be made aware that endoscopic bariatric therapies and other devices are being developed to fill the treatment gap in the management of obesity.

What are the complications? Although LAGB is the least invasive procedure discussed here, it is associated with the highest rate of complications—most commonly, complications associated with the band itself (eg, nausea, vomiting, obstruction, band erosion or migration, esophageal dysmotility leading to acid reflux) and failure to lose weight.⁷ LAGB also requires more postoperative visits than other procedures, to optimize band tightness. A high number of bands are removed eventually because of complications or inadequate weight loss, or both.^13,24

Shared decision-making and dialogue are essential to overcome obstacles

Despite the known benefits of bariatric surgery, including greater reduction in the risk and severity of obesity-related comorbid conditions than seen with other interventions and a long-term reduction in overall mortality when compared with usual care, fewer than 1% of eligible patients undergo a weight-loss procedure.²⁵ Likely, this is due to:

• limited patient knowledge of the health benefits of surgery
• limited provider comfort recommending surgery
• inadequate insurance coverage, which might, in part, be due to a lack of prospective studies comparing various bariatric procedures.¹⁸

Continue to: Ultimately, the decision whether to undergo a bariatric procedure...

Ultimately, the decision whether to undergo a bariatric procedure, and which one(s) to consider, should be the product of a thorough conversation between patient and provider.

CORRESPONDENCE
Sarah R. Barenbaum, MD, Department of Internal Medicine, New York–Presbyterian Hospital/Weill Cornell Medical College, 530 East 70th Street, M-507, New York, NY 10021; [email protected]

Two researchers who made groundbreaking discoveries leading to the development of immune checkpoint therapy have jointly received the 2018 Nobel Prize in Physiology or Medicine.

James P. Allison, PhD, and Tasuku Honjo, MD, PhD, share the prize for their work in showing how strategies for “inhibiting the brakes” on T cells can be used in the treatment of cancer, the Nobel Assembly at Karolinska Institutet, Stockholm, said in a news release.

The discoveries of Dr. Allison and Dr. Honjo represent a landmark in the fight against cancer, according to the Nobel Assembly.

“This new form of immunotherapy unleashes a vigorous, and often durable, immune response directed against essentially any tumor already recognized by the immune system,” members of the Nobel Committee and Assembly said in a simultaneously published manuscript explaining the scientific background behind the discovery.

The “unprecedented” research activity in the immune checkpoint field demonstrates how influential the discoveries of Dr. Allison and Dr. Honjo have been, molecular genetics professor C. I. Edvard Smith, MD, PhD, and coauthors said in the manuscript.

Their findings have “conferred great benefit on mankind” and add a “new pillar” to existing cancer treatments, Dr. Smith and coauthors said in their report.

Dr. Allison was one of several scientists to observe that the cytotoxic T-lymphocyte antigen 4 (CTLA4) protein functions as a brake on T cells, the Nobel Assembly said in the press release. He developed an antibody that could bind to CTLA4 and block its function, and demonstrated its activity in experiments taking place near the end of 1994.

The “spectacular” results showed that, in mice, the antibodies could inhibit the brake and unlock antitumor T-cell activity, according to the release.

Studies of CTLA-4 blockade in humans from several research groups yielded promising results, and in 2010, a major breakthrough came, according to the Nobel Assembly, when it was reported that the CTLA4 blocker ipilimumab improved survival in patients with metastatic melanoma.

Dr. Honjo discovered the programmed cell death protein (PD-1) in 1992, a few years before Dr. Allison’s discovery, and explored its function in experiments carried out over many years at his laboratory at Kyoto University.

Dr. Honjo’s experiments showed that PD-1 functioned as a T-cell brake, but by a different mechanism than CTLA4, paving the way for studying PD-1 as a target of cancer treatment.

That led to a considerable amount of clinical development, including a key 2012 study showing that patients treated with the anti-PD-1 antibody nivolumab led to long-term remissions and possible cures in some patients, the assembly said in their press release.

Scientists have attempted to harness the immune system in the fight against cancer for more than 100 years, according to the assembly. “Until the seminal discoveries by the two laureates, progress into clinical development was modest. Checkpoint therapy has now revolutionized cancer treatment and has fundamentally changed the way we view how cancer can be managed.”

Two researchers who made groundbreaking discoveries leading to the development of immune checkpoint therapy have jointly received the 2018 Nobel Prize in Physiology or Medicine.

James P. Allison, PhD, and Tasuku Honjo, MD, PhD, share the prize for their work in showing how strategies for “inhibiting the brakes” on T cells can be used in the treatment of cancer, the Nobel Assembly at Karolinska Institutet, Stockholm, said in a news release.

The discoveries of Dr. Allison and Dr. Honjo represent a landmark in the fight against cancer, according to the Nobel Assembly.

“This new form of immunotherapy unleashes a vigorous, and often durable, immune response directed against essentially any tumor already recognized by the immune system,” members of the Nobel Committee and Assembly said in a simultaneously published manuscript explaining the scientific background behind the discovery.

The “unprecedented” research activity in the immune checkpoint field demonstrates how influential the discoveries of Dr. Allison and Dr. Honjo have been, molecular genetics professor C. I. Edvard Smith, MD, PhD, and coauthors said in the manuscript.

Their findings have “conferred great benefit on mankind” and add a “new pillar” to existing cancer treatments, Dr. Smith and coauthors said in their report.

Dr. Allison was one of several scientists to observe that the cytotoxic T-lymphocyte antigen 4 (CTLA4) protein functions as a brake on T cells, the Nobel Assembly said in the press release. He developed an antibody that could bind to CTLA4 and block its function, and demonstrated its activity in experiments taking place near the end of 1994.

The “spectacular” results showed that, in mice, the antibodies could inhibit the brake and unlock antitumor T-cell activity, according to the release.

Studies of CTLA-4 blockade in humans from several research groups yielded promising results, and in 2010, a major breakthrough came, according to the Nobel Assembly, when it was reported that the CTLA4 blocker ipilimumab improved survival in patients with metastatic melanoma.

Dr. Honjo discovered the programmed cell death protein (PD-1) in 1992, a few years before Dr. Allison’s discovery, and explored its function in experiments carried out over many years at his laboratory at Kyoto University.

Dr. Honjo’s experiments showed that PD-1 functioned as a T-cell brake, but by a different mechanism than CTLA4, paving the way for studying PD-1 as a target of cancer treatment.

That led to a considerable amount of clinical development, including a key 2012 study showing that patients treated with the anti-PD-1 antibody nivolumab led to long-term remissions and possible cures in some patients, the assembly said in their press release.

Scientists have attempted to harness the immune system in the fight against cancer for more than 100 years, according to the assembly. “Until the seminal discoveries by the two laureates, progress into clinical development was modest. Checkpoint therapy has now revolutionized cancer treatment and has fundamentally changed the way we view how cancer can be managed.”

Two researchers who made groundbreaking discoveries leading to the development of immune checkpoint therapy have jointly received the 2018 Nobel Prize in Physiology or Medicine.

James P. Allison, PhD, and Tasuku Honjo, MD, PhD, share the prize for their work in showing how strategies for “inhibiting the brakes” on T cells can be used in the treatment of cancer, the Nobel Assembly at Karolinska Institutet, Stockholm, said in a news release.

The discoveries of Dr. Allison and Dr. Honjo represent a landmark in the fight against cancer, according to the Nobel Assembly.

“This new form of immunotherapy unleashes a vigorous, and often durable, immune response directed against essentially any tumor already recognized by the immune system,” members of the Nobel Committee and Assembly said in a simultaneously published manuscript explaining the scientific background behind the discovery.

The “unprecedented” research activity in the immune checkpoint field demonstrates how influential the discoveries of Dr. Allison and Dr. Honjo have been, molecular genetics professor C. I. Edvard Smith, MD, PhD, and coauthors said in the manuscript.

Their findings have “conferred great benefit on mankind” and add a “new pillar” to existing cancer treatments, Dr. Smith and coauthors said in their report.

Dr. Allison was one of several scientists to observe that the cytotoxic T-lymphocyte antigen 4 (CTLA4) protein functions as a brake on T cells, the Nobel Assembly said in the press release. He developed an antibody that could bind to CTLA4 and block its function, and demonstrated its activity in experiments taking place near the end of 1994.

The “spectacular” results showed that, in mice, the antibodies could inhibit the brake and unlock antitumor T-cell activity, according to the release.

Studies of CTLA-4 blockade in humans from several research groups yielded promising results, and in 2010, a major breakthrough came, according to the Nobel Assembly, when it was reported that the CTLA4 blocker ipilimumab improved survival in patients with metastatic melanoma.

Dr. Honjo discovered the programmed cell death protein (PD-1) in 1992, a few years before Dr. Allison’s discovery, and explored its function in experiments carried out over many years at his laboratory at Kyoto University.

Dr. Honjo’s experiments showed that PD-1 functioned as a T-cell brake, but by a different mechanism than CTLA4, paving the way for studying PD-1 as a target of cancer treatment.

That led to a considerable amount of clinical development, including a key 2012 study showing that patients treated with the anti-PD-1 antibody nivolumab led to long-term remissions and possible cures in some patients, the assembly said in their press release.

Scientists have attempted to harness the immune system in the fight against cancer for more than 100 years, according to the assembly. “Until the seminal discoveries by the two laureates, progress into clinical development was modest. Checkpoint therapy has now revolutionized cancer treatment and has fundamentally changed the way we view how cancer can be managed.”

The textbook answer would have been straightforward: No additional chemotherapy. Focus on palliative care.

But Max (not his real name) was not a textbook case. He was a person, and he was terrified of dying.

When I met him in clinic, four lines of chemotherapy had not slowed the spread of his rare cancer that was already metastatic at the time of diagnosis. His skin was yellow. His hair had fallen out in clumps. His legs were swollen to the point that he couldn’t walk. He had trouble transferring from his wheelchair on his own.

All this was offset by the college hoodie he wore, a disarming display of his youth. I had to look at the chart to remind myself. He was only 19 years old.

“Will Dr. D give Max chemotherapy?” his mother asked me, referring to the attending oncologist who had been caring for her son since the beginning. “I think he needs it right away,” she said. She was holding back tears.

Protected by the fact that I was a visiting fellow in her clinic for the day, and I was just meeting Max, I deferred the decision to Dr. D.

Dr. D and I reviewed Max’s case outside the room, scrolling through his PET scans showing spread of cancer in his liver, lungs, and bones in only 2 short months. We recounted the multiple lines of chemotherapy and immunotherapy he had tried and that had failed him.

Palliative care? I offered. She agreed.

But as we went back in together, it was harder. Max’s mother began to cry as Dr. D tried to broach the option. To her, palliative care meant death. That was not something she could swallow. Her questions turned back only to the next chemotherapy we would be giving.

I learned that Max’s father worked in a hospital. He knew how serious it was. “He calls me every day, crying,” my attending later told me solemnly. Begging her to do something. Pleading for more chemotherapy.

After some painful back and forth in the room, we didn’t come to a resolution. Dr. D would call them later, she said.

It was a busy clinic day, and we saw the rest of her patients.

“What are we going to do about Max?” I asked at the end of the day. I was writing the note in his chart. We still didn’t have a plan.

More chemotherapy, from any technical and data-based standpoint, was not the right choice. We had no evidence it would improve survival. We did have evidence that it could worsen the quality of life when time was limited. If we gave him more chemotherapy, it would be beyond guidelines, beyond evidence. We would be off the grid.

I thought about the conversations I’d been privy to about giving toxic therapies near the end of life. While a handful felt productive, others were uncomfortably strained. The latter involved a tension that manifests when the goals of the patient and the oncologist are misaligned. The words may be slightly different each time, but the theme is the same.

The oncologist says: “More chemotherapy is not going to work.”

The patient says: “But we don’t know. It’s better than doing nothing. Can’t we try?”

This can be excruciatingly challenging because both sides are correct. Both sides are logical, and yet they are talking past each other.

From the point of view of the person desperate to survive, anything is worth a try. Without trying some form of treatment, there’s a zero percent chance of surviving. Low odds of something working are still better than zero percent odds.

But it’s not an issue of logic. For people like Max’s parents, the questions come from a place of helplessness. The cognitive dissonance sets in because our job is to help and we struggle when we feel we cannot. We want to say yes. I wish we had a treatment to slow Max’s cancer, too. I wish more chemotherapy would help him.

What I’ve learned from these conversations is the importance of defining terms. Specifically, what do we mean when we say a treatment will or will not “work”? What are we trying to achieve? To prolong life by weeks? By months or years? To make your pain go away? To help you feel stronger? To allow you to spend time doing what you love?

The relevant question is not: Will this treatment work? It is: What are your goals, and will this treatment help you achieve them?

Defining terms in that way can mean the difference of a conversation where two sides are talking past one another to one that comes to a mutual understanding – even if the ultimate conclusion is painful for everyone.

Yet sometimes, even for the most skilled communicators, there may be compromise. There may be an agreement to trial Nth-line chemotherapy, even without evidence that it will achieve a person’s goals. It will require nuanced informed consent from both sides. And it will come from a place of compassion.

This is what I thought about as I signed chemotherapy orders for Max that evening. I felt for him, for his parents, and for his oncologist.

Because even though I suspected the treatment wouldn’t work the way they all hoped it would, I also wasn’t the one fielding daily phone calls from a father, begging his oncologist to do something, anything at all, to save his son’s life.
 

Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.

The textbook answer would have been straightforward: No additional chemotherapy. Focus on palliative care.

But Max (not his real name) was not a textbook case. He was a person, and he was terrified of dying.

When I met him in clinic, four lines of chemotherapy had not slowed the spread of his rare cancer that was already metastatic at the time of diagnosis. His skin was yellow. His hair had fallen out in clumps. His legs were swollen to the point that he couldn’t walk. He had trouble transferring from his wheelchair on his own.

All this was offset by the college hoodie he wore, a disarming display of his youth. I had to look at the chart to remind myself. He was only 19 years old.

“Will Dr. D give Max chemotherapy?” his mother asked me, referring to the attending oncologist who had been caring for her son since the beginning. “I think he needs it right away,” she said. She was holding back tears.

Protected by the fact that I was a visiting fellow in her clinic for the day, and I was just meeting Max, I deferred the decision to Dr. D.

Dr. D and I reviewed Max’s case outside the room, scrolling through his PET scans showing spread of cancer in his liver, lungs, and bones in only 2 short months. We recounted the multiple lines of chemotherapy and immunotherapy he had tried and that had failed him.

Palliative care? I offered. She agreed.

But as we went back in together, it was harder. Max’s mother began to cry as Dr. D tried to broach the option. To her, palliative care meant death. That was not something she could swallow. Her questions turned back only to the next chemotherapy we would be giving.

I learned that Max’s father worked in a hospital. He knew how serious it was. “He calls me every day, crying,” my attending later told me solemnly. Begging her to do something. Pleading for more chemotherapy.

After some painful back and forth in the room, we didn’t come to a resolution. Dr. D would call them later, she said.

It was a busy clinic day, and we saw the rest of her patients.

“What are we going to do about Max?” I asked at the end of the day. I was writing the note in his chart. We still didn’t have a plan.

More chemotherapy, from any technical and data-based standpoint, was not the right choice. We had no evidence it would improve survival. We did have evidence that it could worsen the quality of life when time was limited. If we gave him more chemotherapy, it would be beyond guidelines, beyond evidence. We would be off the grid.

I thought about the conversations I’d been privy to about giving toxic therapies near the end of life. While a handful felt productive, others were uncomfortably strained. The latter involved a tension that manifests when the goals of the patient and the oncologist are misaligned. The words may be slightly different each time, but the theme is the same.

The oncologist says: “More chemotherapy is not going to work.”

The patient says: “But we don’t know. It’s better than doing nothing. Can’t we try?”

This can be excruciatingly challenging because both sides are correct. Both sides are logical, and yet they are talking past each other.

From the point of view of the person desperate to survive, anything is worth a try. Without trying some form of treatment, there’s a zero percent chance of surviving. Low odds of something working are still better than zero percent odds.

But it’s not an issue of logic. For people like Max’s parents, the questions come from a place of helplessness. The cognitive dissonance sets in because our job is to help and we struggle when we feel we cannot. We want to say yes. I wish we had a treatment to slow Max’s cancer, too. I wish more chemotherapy would help him.

What I’ve learned from these conversations is the importance of defining terms. Specifically, what do we mean when we say a treatment will or will not “work”? What are we trying to achieve? To prolong life by weeks? By months or years? To make your pain go away? To help you feel stronger? To allow you to spend time doing what you love?

The relevant question is not: Will this treatment work? It is: What are your goals, and will this treatment help you achieve them?

Defining terms in that way can mean the difference of a conversation where two sides are talking past one another to one that comes to a mutual understanding – even if the ultimate conclusion is painful for everyone.

Yet sometimes, even for the most skilled communicators, there may be compromise. There may be an agreement to trial Nth-line chemotherapy, even without evidence that it will achieve a person’s goals. It will require nuanced informed consent from both sides. And it will come from a place of compassion.

This is what I thought about as I signed chemotherapy orders for Max that evening. I felt for him, for his parents, and for his oncologist.

Because even though I suspected the treatment wouldn’t work the way they all hoped it would, I also wasn’t the one fielding daily phone calls from a father, begging his oncologist to do something, anything at all, to save his son’s life.
 

Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.

The textbook answer would have been straightforward: No additional chemotherapy. Focus on palliative care.

But Max (not his real name) was not a textbook case. He was a person, and he was terrified of dying.

When I met him in clinic, four lines of chemotherapy had not slowed the spread of his rare cancer that was already metastatic at the time of diagnosis. His skin was yellow. His hair had fallen out in clumps. His legs were swollen to the point that he couldn’t walk. He had trouble transferring from his wheelchair on his own.

All this was offset by the college hoodie he wore, a disarming display of his youth. I had to look at the chart to remind myself. He was only 19 years old.

“Will Dr. D give Max chemotherapy?” his mother asked me, referring to the attending oncologist who had been caring for her son since the beginning. “I think he needs it right away,” she said. She was holding back tears.

Protected by the fact that I was a visiting fellow in her clinic for the day, and I was just meeting Max, I deferred the decision to Dr. D.

Dr. D and I reviewed Max’s case outside the room, scrolling through his PET scans showing spread of cancer in his liver, lungs, and bones in only 2 short months. We recounted the multiple lines of chemotherapy and immunotherapy he had tried and that had failed him.

Palliative care? I offered. She agreed.

But as we went back in together, it was harder. Max’s mother began to cry as Dr. D tried to broach the option. To her, palliative care meant death. That was not something she could swallow. Her questions turned back only to the next chemotherapy we would be giving.

I learned that Max’s father worked in a hospital. He knew how serious it was. “He calls me every day, crying,” my attending later told me solemnly. Begging her to do something. Pleading for more chemotherapy.

After some painful back and forth in the room, we didn’t come to a resolution. Dr. D would call them later, she said.

It was a busy clinic day, and we saw the rest of her patients.

“What are we going to do about Max?” I asked at the end of the day. I was writing the note in his chart. We still didn’t have a plan.

More chemotherapy, from any technical and data-based standpoint, was not the right choice. We had no evidence it would improve survival. We did have evidence that it could worsen the quality of life when time was limited. If we gave him more chemotherapy, it would be beyond guidelines, beyond evidence. We would be off the grid.

I thought about the conversations I’d been privy to about giving toxic therapies near the end of life. While a handful felt productive, others were uncomfortably strained. The latter involved a tension that manifests when the goals of the patient and the oncologist are misaligned. The words may be slightly different each time, but the theme is the same.

The oncologist says: “More chemotherapy is not going to work.”

The patient says: “But we don’t know. It’s better than doing nothing. Can’t we try?”

This can be excruciatingly challenging because both sides are correct. Both sides are logical, and yet they are talking past each other.

From the point of view of the person desperate to survive, anything is worth a try. Without trying some form of treatment, there’s a zero percent chance of surviving. Low odds of something working are still better than zero percent odds.

But it’s not an issue of logic. For people like Max’s parents, the questions come from a place of helplessness. The cognitive dissonance sets in because our job is to help and we struggle when we feel we cannot. We want to say yes. I wish we had a treatment to slow Max’s cancer, too. I wish more chemotherapy would help him.

What I’ve learned from these conversations is the importance of defining terms. Specifically, what do we mean when we say a treatment will or will not “work”? What are we trying to achieve? To prolong life by weeks? By months or years? To make your pain go away? To help you feel stronger? To allow you to spend time doing what you love?

The relevant question is not: Will this treatment work? It is: What are your goals, and will this treatment help you achieve them?

Defining terms in that way can mean the difference of a conversation where two sides are talking past one another to one that comes to a mutual understanding – even if the ultimate conclusion is painful for everyone.

Yet sometimes, even for the most skilled communicators, there may be compromise. There may be an agreement to trial Nth-line chemotherapy, even without evidence that it will achieve a person’s goals. It will require nuanced informed consent from both sides. And it will come from a place of compassion.

This is what I thought about as I signed chemotherapy orders for Max that evening. I felt for him, for his parents, and for his oncologist.

Because even though I suspected the treatment wouldn’t work the way they all hoped it would, I also wasn’t the one fielding daily phone calls from a father, begging his oncologist to do something, anything at all, to save his son’s life.
 

Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.

Hayden Bosworth, PhD, has advice on how to get on top of home BP monitoring and how it can be clinically relevant. Also today, opioid use in osteoarthritis may mean more activity-limiting pain, sulfasalazine is pinpointed as the reason for high triple-therapy discontinuation, and point-of-care test for respiratory viruses lowers antibiotic use.
Amazon Alexa
Apple Podcasts
Spotify

Hayden Bosworth, PhD, has advice on how to get on top of home BP monitoring and how it can be clinically relevant. Also today, opioid use in osteoarthritis may mean more activity-limiting pain, sulfasalazine is pinpointed as the reason for high triple-therapy discontinuation, and point-of-care test for respiratory viruses lowers antibiotic use.
Amazon Alexa
Apple Podcasts
Spotify

Hayden Bosworth, PhD, has advice on how to get on top of home BP monitoring and how it can be clinically relevant. Also today, opioid use in osteoarthritis may mean more activity-limiting pain, sulfasalazine is pinpointed as the reason for high triple-therapy discontinuation, and point-of-care test for respiratory viruses lowers antibiotic use.
Amazon Alexa
Apple Podcasts
Spotify

Peripheral neuropathy is the most common reason for an outpatient neurology visit in the United States and accounts for over $10 billion in healthcare spending each year.^1,2 When the disorder affects only small, thinly myelinated or unmyelinated nerve fibers, it is referred to as small fiber neuropathy, which commonly presents as numbness and burning pain in the feet.

This article details the manifestations and evaluation of small fiber neuropathy, with an eye toward diagnosing an underlying cause amenable to treatment. 

OLDER PATIENTS MOST AFFECTED

The epidemiology of small fiber neuropathy is not well established. It occurs more commonly in older patients, but data are mixed on prevalence by sex.^3–6 In a Dutch study,³ the overall prevalence was at least 53 cases per 100,000, with the highest rate in men over age 65.

CHARACTERISTIC SENSORY DISTURBANCES

Sensations vary in quality and time

Patients with small fiber neuropathy typically present with a symmetric length-dependent (“stocking-glove”) distribution of sensory changes, starting in the feet and gradually ascending up the legs and then to the hands.

Commonly reported neuropathic symptoms include various combinations of burning, numbness, tingling, itching, sunburn-like, and frostbite-like sensations. Nonneuropathic symptoms may include tightness, a vise-like squeezing of the feet, and the sensation of a sock rolled up at the end of the shoe. Cramps or spasms may also be reported but rarely occur in isolation.⁷

Symptoms are typically worse at the end of the day and while sitting or lying down at night. They can arise spontaneously but may also be triggered by something as minor as the touch of clothing or cool air against the skin. Bedsheet sensitivity of the feet is reported so often that it is used as an outcome measure in clinical trials. Symptoms can also be exacer­bated by extremes in ambient temperature and are especially worse in cold weather.

Random patterns suggest an immune cause

Symptoms may also have a non–length-dependent distribution that is asymmetric, patchy, intermittent, and migratory, and can involve the face, proximal limbs, and trunk. Symptoms may vary throughout the day, eg, starting with electric-shock sensations on one side of the face, followed by perineal numbness and then tingling in the arms lasting for a few minutes to several hours. While such patterns may be seen with diabetes and other common etiologies, they often suggest an underlying immune-mediated disorder such as Sjögren syndrome or sarcoidosis.^8–10 Although large fiber polyneuropathy may also be non–length-dependent, the deficits are usually fixed, with no migratory component.

Autonomic features may be prominent

Autonomic symptoms occur in nearly half of patients and can be as troublesome as neuropathic pain.³ Small nerve fibers mediate somatic and autonomic functions, an evolutionary link that may reflect visceral defense mechanisms responding to pain as a signal of danger.¹¹ This may help explain the multi­systemic nature of symptoms, which can include sweating abnormalities, bowel and bladder disturbances, dry eyes, dry mouth, gastrointestinal dysmotility, skin changes (eg, discoloration, loss of hair, shiny skin), sexual dysfunction, orthostatic hypotension, and palpitations. In some cases, isolated dysautonomia may be seen.

TARGETED EXAMINATION

History: Medications, alcohol, infections

When a patient presents with neuropathic pain in the feet, a detailed history should be obtained, including alcohol use, family history of neuropathy, and use of neurotoxic medications such as metronidazole, colchicine, and chemotherapeutic agents.

Human immunodeficiency virus (HIV) and hepatitis C infection are well known to be associated with small fiber neuropathy, so relevant risk factors (eg, blood transfusions, sexual history, intravenous drug use) should be asked about. Recent illnesses and vaccinations are another important line of questioning, as a small-fiber variant of Guillain-Barré syndrome has been described.¹²

Assess reflexes, strength, sensation

On physical examination, particular attention should be focused on searching for abnormalities indicating large nerve fiber involvement (eg, absent deep tendon reflexes, weakness of the toes). However, absent ankle deep tendon reflexes and reduced vibratory sense may also occur in healthy elderly people.

Similarly, proprioception, motor strength, balance, and vibratory sensation are functions of large myelinated nerve fibers, and thus remain unaffected in patients with only small fiber neuropathy.

Evidence of a systemic disorder should also be sought, as it may indicate an underlying etiology.

Although patients with either large or small fiber neuropathy may have subjective hyperesthesia or numbness of the distal lower extremities, the absence of significant abnormalities on neurologic examination should prompt consideration of small fiber neuropathy.

Electromyography worthwhile

Nerve conduction studies and needle electrode examination evaluate only large nerve fiber conditions. While electromyographic results are normal in patients with isolated small fiber neuropathy, the test can help evaluate subclinical large nerve fiber involvement and alternative diagnoses such as bilateral S1 radiculopathy. Nerve conduction studies may be less useful in patients over age 75, as they may lack sural sensory responses because of aging changes.¹³

Skin biopsy easy to do

Skin biopsy for evaluating intraepidermal nerve fiber density is one of the most widely used tests for small fiber neuropathy. This minimally invasive procedure can now be performed in a primary care office using readily available tools or prepackaged kits and analyzed by several commercial laboratories.

Reduced intraepidermal nerve fiber density on skin biopsy has been described in various other conditions such as fibromyalgia and chronic pain syndromes.^16,17 The clinical significance of these findings remains uncertain.

Quantitative sudomotor axon reflex testing

Quantitative sudomotor axon reflex testing (QSART) is a noninvasive autonomic study that assesses the volume of sweat produced by the limbs in response to acetylcholine. A measure of postganglionic sympathetic sudomotor nerve function, QSART has a sensitivity of up to 80% and can be used to diagnose small fiber neuropathy.¹⁸ In a series of 115 patients with sarcoidosis small fiber neuropathy,⁹ the QSART and skin biopsy findings were concordant in 17 cases and complementary in 29, allowing for confirmation of small fiber neuropathy in patients whose condition would have remained undiagnosed had only one test been performed. QSART can also be considered in cases where skin biopsy may be contraindicated (eg, patient use of anticoagulation).  Of note, the study may be affected by a number of external factors, including caffeine, tobacco, antihistamines, and tricyclic antidepressants; these should be held before testing.

Other diagnostic studies

Other tests may be helpful, as follows:

Tilt-table and cardiovagal testing may be useful for patients with orthostasis and palpitations.

Thermoregulatory sweat testing can be used to evaluate patients with abnormal patterns of sweating, eg, hyperhidrosis of the face and head.

INITIAL TESTING FOR AN UNDERLYING CAUSE

Glucose tolerance test for diabetes

Diabetes is the most common identifiable cause of small fiber neuropathy and accounts for about a third of all cases.⁵ Impaired glucose tolerance is also thought to be a risk factor and has been found in up to 50% of idiopathic cases, but the association is still being debated.²¹

While testing for hemoglobin A_1c is more convenient for the patient, especially because it does not require fasting, a 2-hour oral glucose tolerance test is more sensitive for detecting glucose dysmetabolism.²²

Lipid panel for metabolic syndrome

Small fiber neuropathy is associated with individual components of the metabolic syndrome, which include obesity, hyperglycemia, and dyslipidemia. Of these, dyslipidemia has emerged as the primary factor involved in the development of small fiber neuropathy, via an inflammatory pathway or oxidative stress mechanism.^23,24

Vitamin B₁₂ deficiency testing

Vitamin B₁₂ deficiency, a potentially correctable cause of small fiber neuropathy, may be underdiagnosed, especially as values obtained by blood testing may not reflect tissue uptake. Causes of vitamin B₁₂ deficiency include reduced intake, pernicious anemia, and medications that can affect absorption of vitamin B₁₂ (eg, proton pump inhibitors, histamine 2 receptor antagonists, metformin).

Testing should include:

• Complete blood cell count to evaluate for vitamin B₁₂-related macrocytic anemia and other hematologic abnormalities
• Serum vitamin B₁₂ level
• Methylmalonic acid or homocysteine level in patients with subclinical or mild vitamin B₁₂ deficiency, manifested as low to normal vitamin B₁₂ levels (< 400 pg/mL); methylmalonic acid and homocysteine require vitamin B₁₂ as a cofactor for enzymatic conversion, and either or both may be elevated in early vitamin B₁₂ deficiency.

Celiac antibody panel

Celiac disease, a T-cell mediated enteropathy characterized by gluten intolerance and a herpetiform-like rash, can be associated with small fiber neuropathy.²⁵ In some cases, neuropathy symptoms are preceded by the onset of gastrointestinal symptoms, or they may occur in isolation.²⁵

Sjögren syndrome accounts for nearly 10% of cases of small fiber neuropathy. Associated neuropathic symptoms are often non–length-dependent, can precede sicca symptoms for up to 6 years, and in some cases are the sole manifestation of the disease.¹⁰ Small fiber neuropathy may also be associated with vasculitis, systemic lupus erythematosus, and other connective tissue disorders. 

Testing should include:

• Erythrocyte sedimentation rate, C-reactive protein, and antinuclear antibodies: though these are nonspecific markers of inflammation, they may support an immune-mediated etiology if positive
• Extractable nuclear antigen panel: Sjögren syndrome A and B autoantibodies are the most important components in this setting^5,11
• The Schirmer test or salivary gland biopsy should be considered for seronegative patients with sicca or a suspected immune-mediated etiology, as the sensitivity of antibody testing ranges from only 10% to 55%.¹⁰

Thyroid function testing

Hypothyroidism, and less commonly hyperthyroidism, are associated with small fiber neuropathy.

Metabolic tests for liver and kidney disease

Renal insufficiency and liver impairment are well-known causes of small nerve fiber dysfunction. Testing should include:

• Comprehensive metabolic panel
• Gamma-glutamyltransferase if alcohol abuse is suspected, since heavy alcohol use is one of the most common causes of both large and small fiber neuropathy.

HIV and hepatitis C testing

For patients with relevant risk factors, HIV and hepatitis C testing should be part of the initial workup (and as second-tier testing for others). Patients who test positive for hepatitis C should undergo further testing for cryoglobulinemia, which can present with painful small fiber neuropathy.²⁶

Serum and urine immunoelectrophoresis

Paraproteinemia, with causes ranging from monoclonal gammopathy of uncertain significance to multiple myeloma, has been associated with small fiber neuropathy. An abnormal serum or urine immunoelectrophoresis test warrants further investigation and possibly referral to a hematology-oncology specialist.

SECOND-TIER TESTING

Less common treatable causes of small fiber neuropathy may also be evaluated.

Copper, vitamin B₁ (thiamine), or vitamin B₆ (pyridoxine) deficiency testing. Although vitamin B₆ toxicity may also result in neuropathy due to its toxic effect on the dorsal root ganglia, the mildly elevated vitamin B₆ levels often found in patients being evaluated for neuropathy are unlikely to be the primary cause of symptoms. Many laboratories require fasting samples for accurate vitamin B₆ levels.

Angiotensin-converting enzyme levels for sarcoidosis. Small fiber neuropathy is common in sarcoidosis, occurring in more than 30% of patients with systemic disease.²⁷ However, screening for sarcoidosis by measuring serum levels is often falsely positive and is not cost-effective. In a study of 195 patients with idiopathic small fiber neuropathy,¹¹ 44% had an elevated serum level, but no evidence of sarcoidosis was seen on further testing, which included computed tomography of the chest in 29 patients.¹² Thus, this test is best used for patients with evidence of systemic disease.

Amyloid testing for amyloidosis. Fat pad or bone marrow biopsy should be considered in the appropriate clinical setting.

Paraneoplastic autoantibody panel for occult cancer. Such testing may also be considered if clinically warranted. However, if a patient is found to have low positive titers of paraneoplastic antibodies and suspicion is low for an occult cancer (eg, no weight loss or early satiety), repeat confirmatory testing at another laboratory should be done before embarking on an extensive search for malignancy.

Ganglionic acetylcholine receptor antibody testing for autoimmune autonomic ganglionopathy. This should be ordered for patients with prominent autonomic dysfunction. The antibody test can be ordered separately or as part of an autoantibody panel. The antibody may indicate a primary immune-mediated process or a paraneoplastic disease.²⁸

Genetic mutation testing. Recent discoveries of gene mutations leading to peripheral nerve hyperexcitability of voltage-gated sodium channels have elucidated a hereditary cause of small fiber neuropathy in nearly 30% of cases that were once thought to be idiopathic.^29,30 Genetic testing for mutations in SCN9A and SCN10 (which code for the Nav1.7 and Nav1.8 sodium channels, respectively) is commercially available and may be considered for those with a family history of neuropathic pain in the feet or for young, otherwise healthy patients.

Fabry disease is an X-linked lysosomal disorder characterized by angiokeratomas, cardiac and renal impairment, and small fiber neuropathy. Treatment is now available, but screening is not cost-efficient and should only be pursued in patients with other symptoms of the disease.^31,32

OTHER POSSIBLE CAUSES

Guillain-Barré syndrome

A Guillain-Barré syndrome variant has been reported that is characterized by ascending limb paresthesias and cerebrospinal fluid albuminocytologic dissociation in the setting of preserved deep tendon reflexes and normal findings on EMG.¹² The clinical course is similar to that of typical Guillain-Barré syndrome, in that symptoms follow an upper respiratory or gastrointestinal tract infection, reach their nadir at 4 weeks, and then gradually improve. Some patients respond to intravenous immune globulin.

Vaccine-associated

Postvaccination small fiber neuropathy has also been reported. The nature of the association is unclear.³³

Parkinson disease

Small fiber neuropathy is associated with Parkinson disease. It is attributed to a number of proposed factors, including neurodegeneration that occurs parallel to central nervous system decline, as well as intestinal malabsorption with resultant vitamin deficiency.^34,35

Rapid glycemic lowering

Aggressive treatment of diabetes, defined as at least a 2-point reduction of serum hemoglobin A_1c level over 3 months, may result in acute small fiber neuropathy. It manifests as severe distal extremity pain and dysautonomia.

In a retrospective study,³⁶ 104 (10.9%) of 954 patients presenting to a tertiary diabetic clinic developed treatment-induced diabetic neuropathy with symptoms occurring within 8 weeks of rapid glycemic control. The severity of neuropathy correlated with the degree and rate of glycemic lowering. The condition was reversible in some cases.

For patients with an identified cause of neuropathy, targeted treatment offers the best chance of halting progression and possibly improving symptoms. Below are recommendations for addressing neuropathy associated with the common diagnoses.

Diabetes, impaired glucose tolerance, and metabolic syndrome. In addition to glycemic- and lipid-lowering therapies, lifestyle modifications with a specific focus on exercise and nutrition are integral to treating diabetes and related disorders.

In the Look AHEAD (Action for Health in Diabetes) study,³⁷ which evaluated the effects of intensive lifestyle intervention on neuropathy in 5,145 overweight patients with type 2 diabetes, patients in the intervention group had lower pain scores and better touch sensation in the toes compared with controls at 1 year. Differences correlated with the degree of weight loss and reduction of hemoglobin A_1c and lipid levels.

As running and walking may not be feasible for many patients owing to pain, stationary cycling, aqua therapy, and swimming are other options. A stationary recumbent bike may be useful for older patients with balance issues.

Vitamin B₁₂ deficiency. As reduced absorption rather than low dietary intake is the primary cause of vitamin B₁₂ deficiency for many patients, parenteral rather than oral supplementation may be best. A suggested regimen is subcutaneous or intramuscular methylcobalamin injection of 1,000 µg given daily for 1 week, then once weekly for 1 month, followed by a maintenance dose once a month for at least 6 to 12 months. Alternatively, a daily dose of vitamin B₁₂ 1,000 µg can be taken sublingually.

Sjögren syndrome. According to anecdotal case reports, intravenous immune globulin, corticosteroids, and other immunosuppressants help painful small fiber neuropathy and dysautonomia associated with Sjögren syndrome.¹⁰

Sarcoidosis. Sarcoidosis-associated small fiber neuropathy may also respond to intravenous immune globulin, as well as infliximab and combination therapy.⁹ Culver et al³⁸ found that cibinetide, an experimental erythropoetin agonist, resulted in improved corneal nerve fiber measures in patients with small fiber neuropathy associated with sarcoidosis.

Celiac disease. A gluten-free diet is the treatment for celiac disease and can help some patients.

GENERAL MANAGEMENT

For all patients, regardless of whether the cause of small fiber neuropathy has been identified, managing symptoms remains key, as pain and autonomic dysfunction can markedly impair quality of life. A multidisciplinary approach that incorporates pain medications, physical therapy, and lifestyle modifications is ideal. Integrative holistic treatments such as natural supplements, yoga, and other mind-body therapies may also help.

Pain control

Mexiletine, a voltage-gated sodium channel blocker used as an antiarrhythmic, may help refractory pain or hereditary small fiber neuropathy related to sodium channel dysfunction. However, it is not recommended for diabetic neuropathy.³⁹

Combination regimens that use drugs with different mechanisms of action can be effective. In one study, combined gabapentin and nortriptyline were more effective than either drug alone for neuropathic pain.⁴⁰

Inhaled cannabis reduced pain in patients with HIV and diabetic neuropathy in a number of studies. Side effects included euphoria, somnolence, and cognitive impairment.^41,42 The use of medical marijuana is not yet legal nationwide and may affect employability even in states in which it has been legalized.

Owing to the opioid epidemic and high addiction potential, opioids are no longer a preferred recommendation for chronic treatment of noncancer-related neuropathy. A population-based study of 2,892 patients with neuropathy found that those on chronic opioid therapy (≥ 90 days) had worse functional outcomes and higher rates of addiction and overdose than those on short-term therapy.⁴³ However, the opioid agonist tramadol was found to be effective in reducing neuropathic pain and may be a safer option for patients with chronic small fiber neuropathy.⁴⁴

Integrative, holistic therapies

PROGNOSIS

For many patients, small fiber neuropathy is a slowly progressive disorder that reaches a clinical plateau lasting for years, with progression to large fiber involvement reported in 13% to 36% of cases; over half of patients in one series either improved or remained stable over a period of 2 years.^5,57 Long-term studies are needed to fully understand the natural disease course. In the meantime, treating underlying disease and managing symptoms are imperative to patient care.

Peripheral neuropathy is the most common reason for an outpatient neurology visit in the United States and accounts for over $10 billion in healthcare spending each year.^1,2 When the disorder affects only small, thinly myelinated or unmyelinated nerve fibers, it is referred to as small fiber neuropathy, which commonly presents as numbness and burning pain in the feet.

This article details the manifestations and evaluation of small fiber neuropathy, with an eye toward diagnosing an underlying cause amenable to treatment. 

OLDER PATIENTS MOST AFFECTED

The epidemiology of small fiber neuropathy is not well established. It occurs more commonly in older patients, but data are mixed on prevalence by sex.^3–6 In a Dutch study,³ the overall prevalence was at least 53 cases per 100,000, with the highest rate in men over age 65.

CHARACTERISTIC SENSORY DISTURBANCES

Sensations vary in quality and time

Patients with small fiber neuropathy typically present with a symmetric length-dependent (“stocking-glove”) distribution of sensory changes, starting in the feet and gradually ascending up the legs and then to the hands.

Commonly reported neuropathic symptoms include various combinations of burning, numbness, tingling, itching, sunburn-like, and frostbite-like sensations. Nonneuropathic symptoms may include tightness, a vise-like squeezing of the feet, and the sensation of a sock rolled up at the end of the shoe. Cramps or spasms may also be reported but rarely occur in isolation.⁷

Symptoms are typically worse at the end of the day and while sitting or lying down at night. They can arise spontaneously but may also be triggered by something as minor as the touch of clothing or cool air against the skin. Bedsheet sensitivity of the feet is reported so often that it is used as an outcome measure in clinical trials. Symptoms can also be exacer­bated by extremes in ambient temperature and are especially worse in cold weather.

Random patterns suggest an immune cause

Symptoms may also have a non–length-dependent distribution that is asymmetric, patchy, intermittent, and migratory, and can involve the face, proximal limbs, and trunk. Symptoms may vary throughout the day, eg, starting with electric-shock sensations on one side of the face, followed by perineal numbness and then tingling in the arms lasting for a few minutes to several hours. While such patterns may be seen with diabetes and other common etiologies, they often suggest an underlying immune-mediated disorder such as Sjögren syndrome or sarcoidosis.^8–10 Although large fiber polyneuropathy may also be non–length-dependent, the deficits are usually fixed, with no migratory component.

Autonomic features may be prominent

Autonomic symptoms occur in nearly half of patients and can be as troublesome as neuropathic pain.³ Small nerve fibers mediate somatic and autonomic functions, an evolutionary link that may reflect visceral defense mechanisms responding to pain as a signal of danger.¹¹ This may help explain the multi­systemic nature of symptoms, which can include sweating abnormalities, bowel and bladder disturbances, dry eyes, dry mouth, gastrointestinal dysmotility, skin changes (eg, discoloration, loss of hair, shiny skin), sexual dysfunction, orthostatic hypotension, and palpitations. In some cases, isolated dysautonomia may be seen.

TARGETED EXAMINATION

History: Medications, alcohol, infections

When a patient presents with neuropathic pain in the feet, a detailed history should be obtained, including alcohol use, family history of neuropathy, and use of neurotoxic medications such as metronidazole, colchicine, and chemotherapeutic agents.

Human immunodeficiency virus (HIV) and hepatitis C infection are well known to be associated with small fiber neuropathy, so relevant risk factors (eg, blood transfusions, sexual history, intravenous drug use) should be asked about. Recent illnesses and vaccinations are another important line of questioning, as a small-fiber variant of Guillain-Barré syndrome has been described.¹²

Assess reflexes, strength, sensation

On physical examination, particular attention should be focused on searching for abnormalities indicating large nerve fiber involvement (eg, absent deep tendon reflexes, weakness of the toes). However, absent ankle deep tendon reflexes and reduced vibratory sense may also occur in healthy elderly people.

Similarly, proprioception, motor strength, balance, and vibratory sensation are functions of large myelinated nerve fibers, and thus remain unaffected in patients with only small fiber neuropathy.

Evidence of a systemic disorder should also be sought, as it may indicate an underlying etiology.

Although patients with either large or small fiber neuropathy may have subjective hyperesthesia or numbness of the distal lower extremities, the absence of significant abnormalities on neurologic examination should prompt consideration of small fiber neuropathy.

Electromyography worthwhile

Nerve conduction studies and needle electrode examination evaluate only large nerve fiber conditions. While electromyographic results are normal in patients with isolated small fiber neuropathy, the test can help evaluate subclinical large nerve fiber involvement and alternative diagnoses such as bilateral S1 radiculopathy. Nerve conduction studies may be less useful in patients over age 75, as they may lack sural sensory responses because of aging changes.¹³

Skin biopsy easy to do

Skin biopsy for evaluating intraepidermal nerve fiber density is one of the most widely used tests for small fiber neuropathy. This minimally invasive procedure can now be performed in a primary care office using readily available tools or prepackaged kits and analyzed by several commercial laboratories.

Reduced intraepidermal nerve fiber density on skin biopsy has been described in various other conditions such as fibromyalgia and chronic pain syndromes.^16,17 The clinical significance of these findings remains uncertain.

Quantitative sudomotor axon reflex testing

Quantitative sudomotor axon reflex testing (QSART) is a noninvasive autonomic study that assesses the volume of sweat produced by the limbs in response to acetylcholine. A measure of postganglionic sympathetic sudomotor nerve function, QSART has a sensitivity of up to 80% and can be used to diagnose small fiber neuropathy.¹⁸ In a series of 115 patients with sarcoidosis small fiber neuropathy,⁹ the QSART and skin biopsy findings were concordant in 17 cases and complementary in 29, allowing for confirmation of small fiber neuropathy in patients whose condition would have remained undiagnosed had only one test been performed. QSART can also be considered in cases where skin biopsy may be contraindicated (eg, patient use of anticoagulation).  Of note, the study may be affected by a number of external factors, including caffeine, tobacco, antihistamines, and tricyclic antidepressants; these should be held before testing.

Other diagnostic studies

Other tests may be helpful, as follows:

Tilt-table and cardiovagal testing may be useful for patients with orthostasis and palpitations.

Thermoregulatory sweat testing can be used to evaluate patients with abnormal patterns of sweating, eg, hyperhidrosis of the face and head.

INITIAL TESTING FOR AN UNDERLYING CAUSE

Glucose tolerance test for diabetes

Diabetes is the most common identifiable cause of small fiber neuropathy and accounts for about a third of all cases.⁵ Impaired glucose tolerance is also thought to be a risk factor and has been found in up to 50% of idiopathic cases, but the association is still being debated.²¹

While testing for hemoglobin A_1c is more convenient for the patient, especially because it does not require fasting, a 2-hour oral glucose tolerance test is more sensitive for detecting glucose dysmetabolism.²²

Lipid panel for metabolic syndrome

Small fiber neuropathy is associated with individual components of the metabolic syndrome, which include obesity, hyperglycemia, and dyslipidemia. Of these, dyslipidemia has emerged as the primary factor involved in the development of small fiber neuropathy, via an inflammatory pathway or oxidative stress mechanism.^23,24

Vitamin B₁₂ deficiency testing

Vitamin B₁₂ deficiency, a potentially correctable cause of small fiber neuropathy, may be underdiagnosed, especially as values obtained by blood testing may not reflect tissue uptake. Causes of vitamin B₁₂ deficiency include reduced intake, pernicious anemia, and medications that can affect absorption of vitamin B₁₂ (eg, proton pump inhibitors, histamine 2 receptor antagonists, metformin).

Testing should include:

• Complete blood cell count to evaluate for vitamin B₁₂-related macrocytic anemia and other hematologic abnormalities
• Serum vitamin B₁₂ level
• Methylmalonic acid or homocysteine level in patients with subclinical or mild vitamin B₁₂ deficiency, manifested as low to normal vitamin B₁₂ levels (< 400 pg/mL); methylmalonic acid and homocysteine require vitamin B₁₂ as a cofactor for enzymatic conversion, and either or both may be elevated in early vitamin B₁₂ deficiency.

Celiac antibody panel

Celiac disease, a T-cell mediated enteropathy characterized by gluten intolerance and a herpetiform-like rash, can be associated with small fiber neuropathy.²⁵ In some cases, neuropathy symptoms are preceded by the onset of gastrointestinal symptoms, or they may occur in isolation.²⁵

Sjögren syndrome accounts for nearly 10% of cases of small fiber neuropathy. Associated neuropathic symptoms are often non–length-dependent, can precede sicca symptoms for up to 6 years, and in some cases are the sole manifestation of the disease.¹⁰ Small fiber neuropathy may also be associated with vasculitis, systemic lupus erythematosus, and other connective tissue disorders. 

Testing should include:

• Erythrocyte sedimentation rate, C-reactive protein, and antinuclear antibodies: though these are nonspecific markers of inflammation, they may support an immune-mediated etiology if positive
• Extractable nuclear antigen panel: Sjögren syndrome A and B autoantibodies are the most important components in this setting^5,11
• The Schirmer test or salivary gland biopsy should be considered for seronegative patients with sicca or a suspected immune-mediated etiology, as the sensitivity of antibody testing ranges from only 10% to 55%.¹⁰

Thyroid function testing

Hypothyroidism, and less commonly hyperthyroidism, are associated with small fiber neuropathy.

Metabolic tests for liver and kidney disease

Renal insufficiency and liver impairment are well-known causes of small nerve fiber dysfunction. Testing should include:

• Comprehensive metabolic panel
• Gamma-glutamyltransferase if alcohol abuse is suspected, since heavy alcohol use is one of the most common causes of both large and small fiber neuropathy.

HIV and hepatitis C testing

For patients with relevant risk factors, HIV and hepatitis C testing should be part of the initial workup (and as second-tier testing for others). Patients who test positive for hepatitis C should undergo further testing for cryoglobulinemia, which can present with painful small fiber neuropathy.²⁶

Serum and urine immunoelectrophoresis

Paraproteinemia, with causes ranging from monoclonal gammopathy of uncertain significance to multiple myeloma, has been associated with small fiber neuropathy. An abnormal serum or urine immunoelectrophoresis test warrants further investigation and possibly referral to a hematology-oncology specialist.

SECOND-TIER TESTING

Less common treatable causes of small fiber neuropathy may also be evaluated.

Copper, vitamin B₁ (thiamine), or vitamin B₆ (pyridoxine) deficiency testing. Although vitamin B₆ toxicity may also result in neuropathy due to its toxic effect on the dorsal root ganglia, the mildly elevated vitamin B₆ levels often found in patients being evaluated for neuropathy are unlikely to be the primary cause of symptoms. Many laboratories require fasting samples for accurate vitamin B₆ levels.

Angiotensin-converting enzyme levels for sarcoidosis. Small fiber neuropathy is common in sarcoidosis, occurring in more than 30% of patients with systemic disease.²⁷ However, screening for sarcoidosis by measuring serum levels is often falsely positive and is not cost-effective. In a study of 195 patients with idiopathic small fiber neuropathy,¹¹ 44% had an elevated serum level, but no evidence of sarcoidosis was seen on further testing, which included computed tomography of the chest in 29 patients.¹² Thus, this test is best used for patients with evidence of systemic disease.

Amyloid testing for amyloidosis. Fat pad or bone marrow biopsy should be considered in the appropriate clinical setting.

Paraneoplastic autoantibody panel for occult cancer. Such testing may also be considered if clinically warranted. However, if a patient is found to have low positive titers of paraneoplastic antibodies and suspicion is low for an occult cancer (eg, no weight loss or early satiety), repeat confirmatory testing at another laboratory should be done before embarking on an extensive search for malignancy.

Ganglionic acetylcholine receptor antibody testing for autoimmune autonomic ganglionopathy. This should be ordered for patients with prominent autonomic dysfunction. The antibody test can be ordered separately or as part of an autoantibody panel. The antibody may indicate a primary immune-mediated process or a paraneoplastic disease.²⁸

Genetic mutation testing. Recent discoveries of gene mutations leading to peripheral nerve hyperexcitability of voltage-gated sodium channels have elucidated a hereditary cause of small fiber neuropathy in nearly 30% of cases that were once thought to be idiopathic.^29,30 Genetic testing for mutations in SCN9A and SCN10 (which code for the Nav1.7 and Nav1.8 sodium channels, respectively) is commercially available and may be considered for those with a family history of neuropathic pain in the feet or for young, otherwise healthy patients.

Fabry disease is an X-linked lysosomal disorder characterized by angiokeratomas, cardiac and renal impairment, and small fiber neuropathy. Treatment is now available, but screening is not cost-efficient and should only be pursued in patients with other symptoms of the disease.^31,32

OTHER POSSIBLE CAUSES

Guillain-Barré syndrome

A Guillain-Barré syndrome variant has been reported that is characterized by ascending limb paresthesias and cerebrospinal fluid albuminocytologic dissociation in the setting of preserved deep tendon reflexes and normal findings on EMG.¹² The clinical course is similar to that of typical Guillain-Barré syndrome, in that symptoms follow an upper respiratory or gastrointestinal tract infection, reach their nadir at 4 weeks, and then gradually improve. Some patients respond to intravenous immune globulin.

Vaccine-associated

Postvaccination small fiber neuropathy has also been reported. The nature of the association is unclear.³³

Parkinson disease

Small fiber neuropathy is associated with Parkinson disease. It is attributed to a number of proposed factors, including neurodegeneration that occurs parallel to central nervous system decline, as well as intestinal malabsorption with resultant vitamin deficiency.^34,35

Rapid glycemic lowering

Aggressive treatment of diabetes, defined as at least a 2-point reduction of serum hemoglobin A_1c level over 3 months, may result in acute small fiber neuropathy. It manifests as severe distal extremity pain and dysautonomia.

In a retrospective study,³⁶ 104 (10.9%) of 954 patients presenting to a tertiary diabetic clinic developed treatment-induced diabetic neuropathy with symptoms occurring within 8 weeks of rapid glycemic control. The severity of neuropathy correlated with the degree and rate of glycemic lowering. The condition was reversible in some cases.

For patients with an identified cause of neuropathy, targeted treatment offers the best chance of halting progression and possibly improving symptoms. Below are recommendations for addressing neuropathy associated with the common diagnoses.

Diabetes, impaired glucose tolerance, and metabolic syndrome. In addition to glycemic- and lipid-lowering therapies, lifestyle modifications with a specific focus on exercise and nutrition are integral to treating diabetes and related disorders.

In the Look AHEAD (Action for Health in Diabetes) study,³⁷ which evaluated the effects of intensive lifestyle intervention on neuropathy in 5,145 overweight patients with type 2 diabetes, patients in the intervention group had lower pain scores and better touch sensation in the toes compared with controls at 1 year. Differences correlated with the degree of weight loss and reduction of hemoglobin A_1c and lipid levels.

As running and walking may not be feasible for many patients owing to pain, stationary cycling, aqua therapy, and swimming are other options. A stationary recumbent bike may be useful for older patients with balance issues.

Vitamin B₁₂ deficiency. As reduced absorption rather than low dietary intake is the primary cause of vitamin B₁₂ deficiency for many patients, parenteral rather than oral supplementation may be best. A suggested regimen is subcutaneous or intramuscular methylcobalamin injection of 1,000 µg given daily for 1 week, then once weekly for 1 month, followed by a maintenance dose once a month for at least 6 to 12 months. Alternatively, a daily dose of vitamin B₁₂ 1,000 µg can be taken sublingually.

Sjögren syndrome. According to anecdotal case reports, intravenous immune globulin, corticosteroids, and other immunosuppressants help painful small fiber neuropathy and dysautonomia associated with Sjögren syndrome.¹⁰

Sarcoidosis. Sarcoidosis-associated small fiber neuropathy may also respond to intravenous immune globulin, as well as infliximab and combination therapy.⁹ Culver et al³⁸ found that cibinetide, an experimental erythropoetin agonist, resulted in improved corneal nerve fiber measures in patients with small fiber neuropathy associated with sarcoidosis.

Celiac disease. A gluten-free diet is the treatment for celiac disease and can help some patients.

GENERAL MANAGEMENT

For all patients, regardless of whether the cause of small fiber neuropathy has been identified, managing symptoms remains key, as pain and autonomic dysfunction can markedly impair quality of life. A multidisciplinary approach that incorporates pain medications, physical therapy, and lifestyle modifications is ideal. Integrative holistic treatments such as natural supplements, yoga, and other mind-body therapies may also help.

Pain control

Mexiletine, a voltage-gated sodium channel blocker used as an antiarrhythmic, may help refractory pain or hereditary small fiber neuropathy related to sodium channel dysfunction. However, it is not recommended for diabetic neuropathy.³⁹

Combination regimens that use drugs with different mechanisms of action can be effective. In one study, combined gabapentin and nortriptyline were more effective than either drug alone for neuropathic pain.⁴⁰

Inhaled cannabis reduced pain in patients with HIV and diabetic neuropathy in a number of studies. Side effects included euphoria, somnolence, and cognitive impairment.^41,42 The use of medical marijuana is not yet legal nationwide and may affect employability even in states in which it has been legalized.

Owing to the opioid epidemic and high addiction potential, opioids are no longer a preferred recommendation for chronic treatment of noncancer-related neuropathy. A population-based study of 2,892 patients with neuropathy found that those on chronic opioid therapy (≥ 90 days) had worse functional outcomes and higher rates of addiction and overdose than those on short-term therapy.⁴³ However, the opioid agonist tramadol was found to be effective in reducing neuropathic pain and may be a safer option for patients with chronic small fiber neuropathy.⁴⁴

Integrative, holistic therapies

PROGNOSIS

For many patients, small fiber neuropathy is a slowly progressive disorder that reaches a clinical plateau lasting for years, with progression to large fiber involvement reported in 13% to 36% of cases; over half of patients in one series either improved or remained stable over a period of 2 years.^5,57 Long-term studies are needed to fully understand the natural disease course. In the meantime, treating underlying disease and managing symptoms are imperative to patient care.

Peripheral neuropathy is the most common reason for an outpatient neurology visit in the United States and accounts for over $10 billion in healthcare spending each year.^1,2 When the disorder affects only small, thinly myelinated or unmyelinated nerve fibers, it is referred to as small fiber neuropathy, which commonly presents as numbness and burning pain in the feet.

This article details the manifestations and evaluation of small fiber neuropathy, with an eye toward diagnosing an underlying cause amenable to treatment. 

OLDER PATIENTS MOST AFFECTED

The epidemiology of small fiber neuropathy is not well established. It occurs more commonly in older patients, but data are mixed on prevalence by sex.^3–6 In a Dutch study,³ the overall prevalence was at least 53 cases per 100,000, with the highest rate in men over age 65.

CHARACTERISTIC SENSORY DISTURBANCES

Sensations vary in quality and time

Patients with small fiber neuropathy typically present with a symmetric length-dependent (“stocking-glove”) distribution of sensory changes, starting in the feet and gradually ascending up the legs and then to the hands.

Commonly reported neuropathic symptoms include various combinations of burning, numbness, tingling, itching, sunburn-like, and frostbite-like sensations. Nonneuropathic symptoms may include tightness, a vise-like squeezing of the feet, and the sensation of a sock rolled up at the end of the shoe. Cramps or spasms may also be reported but rarely occur in isolation.⁷

Symptoms are typically worse at the end of the day and while sitting or lying down at night. They can arise spontaneously but may also be triggered by something as minor as the touch of clothing or cool air against the skin. Bedsheet sensitivity of the feet is reported so often that it is used as an outcome measure in clinical trials. Symptoms can also be exacer­bated by extremes in ambient temperature and are especially worse in cold weather.

Random patterns suggest an immune cause

Symptoms may also have a non–length-dependent distribution that is asymmetric, patchy, intermittent, and migratory, and can involve the face, proximal limbs, and trunk. Symptoms may vary throughout the day, eg, starting with electric-shock sensations on one side of the face, followed by perineal numbness and then tingling in the arms lasting for a few minutes to several hours. While such patterns may be seen with diabetes and other common etiologies, they often suggest an underlying immune-mediated disorder such as Sjögren syndrome or sarcoidosis.^8–10 Although large fiber polyneuropathy may also be non–length-dependent, the deficits are usually fixed, with no migratory component.

Autonomic features may be prominent

Autonomic symptoms occur in nearly half of patients and can be as troublesome as neuropathic pain.³ Small nerve fibers mediate somatic and autonomic functions, an evolutionary link that may reflect visceral defense mechanisms responding to pain as a signal of danger.¹¹ This may help explain the multi­systemic nature of symptoms, which can include sweating abnormalities, bowel and bladder disturbances, dry eyes, dry mouth, gastrointestinal dysmotility, skin changes (eg, discoloration, loss of hair, shiny skin), sexual dysfunction, orthostatic hypotension, and palpitations. In some cases, isolated dysautonomia may be seen.

TARGETED EXAMINATION

History: Medications, alcohol, infections

When a patient presents with neuropathic pain in the feet, a detailed history should be obtained, including alcohol use, family history of neuropathy, and use of neurotoxic medications such as metronidazole, colchicine, and chemotherapeutic agents.

Human immunodeficiency virus (HIV) and hepatitis C infection are well known to be associated with small fiber neuropathy, so relevant risk factors (eg, blood transfusions, sexual history, intravenous drug use) should be asked about. Recent illnesses and vaccinations are another important line of questioning, as a small-fiber variant of Guillain-Barré syndrome has been described.¹²

Assess reflexes, strength, sensation

On physical examination, particular attention should be focused on searching for abnormalities indicating large nerve fiber involvement (eg, absent deep tendon reflexes, weakness of the toes). However, absent ankle deep tendon reflexes and reduced vibratory sense may also occur in healthy elderly people.

Similarly, proprioception, motor strength, balance, and vibratory sensation are functions of large myelinated nerve fibers, and thus remain unaffected in patients with only small fiber neuropathy.

Evidence of a systemic disorder should also be sought, as it may indicate an underlying etiology.

Although patients with either large or small fiber neuropathy may have subjective hyperesthesia or numbness of the distal lower extremities, the absence of significant abnormalities on neurologic examination should prompt consideration of small fiber neuropathy.

Electromyography worthwhile

Nerve conduction studies and needle electrode examination evaluate only large nerve fiber conditions. While electromyographic results are normal in patients with isolated small fiber neuropathy, the test can help evaluate subclinical large nerve fiber involvement and alternative diagnoses such as bilateral S1 radiculopathy. Nerve conduction studies may be less useful in patients over age 75, as they may lack sural sensory responses because of aging changes.¹³

Skin biopsy easy to do

Skin biopsy for evaluating intraepidermal nerve fiber density is one of the most widely used tests for small fiber neuropathy. This minimally invasive procedure can now be performed in a primary care office using readily available tools or prepackaged kits and analyzed by several commercial laboratories.

Reduced intraepidermal nerve fiber density on skin biopsy has been described in various other conditions such as fibromyalgia and chronic pain syndromes.^16,17 The clinical significance of these findings remains uncertain.

Quantitative sudomotor axon reflex testing

Quantitative sudomotor axon reflex testing (QSART) is a noninvasive autonomic study that assesses the volume of sweat produced by the limbs in response to acetylcholine. A measure of postganglionic sympathetic sudomotor nerve function, QSART has a sensitivity of up to 80% and can be used to diagnose small fiber neuropathy.¹⁸ In a series of 115 patients with sarcoidosis small fiber neuropathy,⁹ the QSART and skin biopsy findings were concordant in 17 cases and complementary in 29, allowing for confirmation of small fiber neuropathy in patients whose condition would have remained undiagnosed had only one test been performed. QSART can also be considered in cases where skin biopsy may be contraindicated (eg, patient use of anticoagulation).  Of note, the study may be affected by a number of external factors, including caffeine, tobacco, antihistamines, and tricyclic antidepressants; these should be held before testing.

Other diagnostic studies

Other tests may be helpful, as follows:

Tilt-table and cardiovagal testing may be useful for patients with orthostasis and palpitations.

Thermoregulatory sweat testing can be used to evaluate patients with abnormal patterns of sweating, eg, hyperhidrosis of the face and head.

INITIAL TESTING FOR AN UNDERLYING CAUSE

Glucose tolerance test for diabetes

Diabetes is the most common identifiable cause of small fiber neuropathy and accounts for about a third of all cases.⁵ Impaired glucose tolerance is also thought to be a risk factor and has been found in up to 50% of idiopathic cases, but the association is still being debated.²¹

While testing for hemoglobin A_1c is more convenient for the patient, especially because it does not require fasting, a 2-hour oral glucose tolerance test is more sensitive for detecting glucose dysmetabolism.²²

Lipid panel for metabolic syndrome

Small fiber neuropathy is associated with individual components of the metabolic syndrome, which include obesity, hyperglycemia, and dyslipidemia. Of these, dyslipidemia has emerged as the primary factor involved in the development of small fiber neuropathy, via an inflammatory pathway or oxidative stress mechanism.^23,24

Vitamin B₁₂ deficiency testing

Vitamin B₁₂ deficiency, a potentially correctable cause of small fiber neuropathy, may be underdiagnosed, especially as values obtained by blood testing may not reflect tissue uptake. Causes of vitamin B₁₂ deficiency include reduced intake, pernicious anemia, and medications that can affect absorption of vitamin B₁₂ (eg, proton pump inhibitors, histamine 2 receptor antagonists, metformin).

Testing should include:

• Complete blood cell count to evaluate for vitamin B₁₂-related macrocytic anemia and other hematologic abnormalities
• Serum vitamin B₁₂ level
• Methylmalonic acid or homocysteine level in patients with subclinical or mild vitamin B₁₂ deficiency, manifested as low to normal vitamin B₁₂ levels (< 400 pg/mL); methylmalonic acid and homocysteine require vitamin B₁₂ as a cofactor for enzymatic conversion, and either or both may be elevated in early vitamin B₁₂ deficiency.

Celiac antibody panel

Celiac disease, a T-cell mediated enteropathy characterized by gluten intolerance and a herpetiform-like rash, can be associated with small fiber neuropathy.²⁵ In some cases, neuropathy symptoms are preceded by the onset of gastrointestinal symptoms, or they may occur in isolation.²⁵

Sjögren syndrome accounts for nearly 10% of cases of small fiber neuropathy. Associated neuropathic symptoms are often non–length-dependent, can precede sicca symptoms for up to 6 years, and in some cases are the sole manifestation of the disease.¹⁰ Small fiber neuropathy may also be associated with vasculitis, systemic lupus erythematosus, and other connective tissue disorders. 

Testing should include:

• Erythrocyte sedimentation rate, C-reactive protein, and antinuclear antibodies: though these are nonspecific markers of inflammation, they may support an immune-mediated etiology if positive
• Extractable nuclear antigen panel: Sjögren syndrome A and B autoantibodies are the most important components in this setting^5,11
• The Schirmer test or salivary gland biopsy should be considered for seronegative patients with sicca or a suspected immune-mediated etiology, as the sensitivity of antibody testing ranges from only 10% to 55%.¹⁰

Thyroid function testing

Hypothyroidism, and less commonly hyperthyroidism, are associated with small fiber neuropathy.

Metabolic tests for liver and kidney disease

Renal insufficiency and liver impairment are well-known causes of small nerve fiber dysfunction. Testing should include:

• Comprehensive metabolic panel
• Gamma-glutamyltransferase if alcohol abuse is suspected, since heavy alcohol use is one of the most common causes of both large and small fiber neuropathy.

HIV and hepatitis C testing

For patients with relevant risk factors, HIV and hepatitis C testing should be part of the initial workup (and as second-tier testing for others). Patients who test positive for hepatitis C should undergo further testing for cryoglobulinemia, which can present with painful small fiber neuropathy.²⁶

Serum and urine immunoelectrophoresis

Paraproteinemia, with causes ranging from monoclonal gammopathy of uncertain significance to multiple myeloma, has been associated with small fiber neuropathy. An abnormal serum or urine immunoelectrophoresis test warrants further investigation and possibly referral to a hematology-oncology specialist.

SECOND-TIER TESTING

Less common treatable causes of small fiber neuropathy may also be evaluated.

Copper, vitamin B₁ (thiamine), or vitamin B₆ (pyridoxine) deficiency testing. Although vitamin B₆ toxicity may also result in neuropathy due to its toxic effect on the dorsal root ganglia, the mildly elevated vitamin B₆ levels often found in patients being evaluated for neuropathy are unlikely to be the primary cause of symptoms. Many laboratories require fasting samples for accurate vitamin B₆ levels.

Angiotensin-converting enzyme levels for sarcoidosis. Small fiber neuropathy is common in sarcoidosis, occurring in more than 30% of patients with systemic disease.²⁷ However, screening for sarcoidosis by measuring serum levels is often falsely positive and is not cost-effective. In a study of 195 patients with idiopathic small fiber neuropathy,¹¹ 44% had an elevated serum level, but no evidence of sarcoidosis was seen on further testing, which included computed tomography of the chest in 29 patients.¹² Thus, this test is best used for patients with evidence of systemic disease.

Amyloid testing for amyloidosis. Fat pad or bone marrow biopsy should be considered in the appropriate clinical setting.

Paraneoplastic autoantibody panel for occult cancer. Such testing may also be considered if clinically warranted. However, if a patient is found to have low positive titers of paraneoplastic antibodies and suspicion is low for an occult cancer (eg, no weight loss or early satiety), repeat confirmatory testing at another laboratory should be done before embarking on an extensive search for malignancy.

Ganglionic acetylcholine receptor antibody testing for autoimmune autonomic ganglionopathy. This should be ordered for patients with prominent autonomic dysfunction. The antibody test can be ordered separately or as part of an autoantibody panel. The antibody may indicate a primary immune-mediated process or a paraneoplastic disease.²⁸

Genetic mutation testing. Recent discoveries of gene mutations leading to peripheral nerve hyperexcitability of voltage-gated sodium channels have elucidated a hereditary cause of small fiber neuropathy in nearly 30% of cases that were once thought to be idiopathic.^29,30 Genetic testing for mutations in SCN9A and SCN10 (which code for the Nav1.7 and Nav1.8 sodium channels, respectively) is commercially available and may be considered for those with a family history of neuropathic pain in the feet or for young, otherwise healthy patients.

Fabry disease is an X-linked lysosomal disorder characterized by angiokeratomas, cardiac and renal impairment, and small fiber neuropathy. Treatment is now available, but screening is not cost-efficient and should only be pursued in patients with other symptoms of the disease.^31,32

OTHER POSSIBLE CAUSES

Guillain-Barré syndrome

A Guillain-Barré syndrome variant has been reported that is characterized by ascending limb paresthesias and cerebrospinal fluid albuminocytologic dissociation in the setting of preserved deep tendon reflexes and normal findings on EMG.¹² The clinical course is similar to that of typical Guillain-Barré syndrome, in that symptoms follow an upper respiratory or gastrointestinal tract infection, reach their nadir at 4 weeks, and then gradually improve. Some patients respond to intravenous immune globulin.

Vaccine-associated

Postvaccination small fiber neuropathy has also been reported. The nature of the association is unclear.³³

Parkinson disease

Small fiber neuropathy is associated with Parkinson disease. It is attributed to a number of proposed factors, including neurodegeneration that occurs parallel to central nervous system decline, as well as intestinal malabsorption with resultant vitamin deficiency.^34,35

Rapid glycemic lowering

Aggressive treatment of diabetes, defined as at least a 2-point reduction of serum hemoglobin A_1c level over 3 months, may result in acute small fiber neuropathy. It manifests as severe distal extremity pain and dysautonomia.

In a retrospective study,³⁶ 104 (10.9%) of 954 patients presenting to a tertiary diabetic clinic developed treatment-induced diabetic neuropathy with symptoms occurring within 8 weeks of rapid glycemic control. The severity of neuropathy correlated with the degree and rate of glycemic lowering. The condition was reversible in some cases.

For patients with an identified cause of neuropathy, targeted treatment offers the best chance of halting progression and possibly improving symptoms. Below are recommendations for addressing neuropathy associated with the common diagnoses.

Diabetes, impaired glucose tolerance, and metabolic syndrome. In addition to glycemic- and lipid-lowering therapies, lifestyle modifications with a specific focus on exercise and nutrition are integral to treating diabetes and related disorders.

In the Look AHEAD (Action for Health in Diabetes) study,³⁷ which evaluated the effects of intensive lifestyle intervention on neuropathy in 5,145 overweight patients with type 2 diabetes, patients in the intervention group had lower pain scores and better touch sensation in the toes compared with controls at 1 year. Differences correlated with the degree of weight loss and reduction of hemoglobin A_1c and lipid levels.

As running and walking may not be feasible for many patients owing to pain, stationary cycling, aqua therapy, and swimming are other options. A stationary recumbent bike may be useful for older patients with balance issues.

Vitamin B₁₂ deficiency. As reduced absorption rather than low dietary intake is the primary cause of vitamin B₁₂ deficiency for many patients, parenteral rather than oral supplementation may be best. A suggested regimen is subcutaneous or intramuscular methylcobalamin injection of 1,000 µg given daily for 1 week, then once weekly for 1 month, followed by a maintenance dose once a month for at least 6 to 12 months. Alternatively, a daily dose of vitamin B₁₂ 1,000 µg can be taken sublingually.

Sjögren syndrome. According to anecdotal case reports, intravenous immune globulin, corticosteroids, and other immunosuppressants help painful small fiber neuropathy and dysautonomia associated with Sjögren syndrome.¹⁰

Sarcoidosis. Sarcoidosis-associated small fiber neuropathy may also respond to intravenous immune globulin, as well as infliximab and combination therapy.⁹ Culver et al³⁸ found that cibinetide, an experimental erythropoetin agonist, resulted in improved corneal nerve fiber measures in patients with small fiber neuropathy associated with sarcoidosis.

Celiac disease. A gluten-free diet is the treatment for celiac disease and can help some patients.

GENERAL MANAGEMENT

For all patients, regardless of whether the cause of small fiber neuropathy has been identified, managing symptoms remains key, as pain and autonomic dysfunction can markedly impair quality of life. A multidisciplinary approach that incorporates pain medications, physical therapy, and lifestyle modifications is ideal. Integrative holistic treatments such as natural supplements, yoga, and other mind-body therapies may also help.

Pain control

Mexiletine, a voltage-gated sodium channel blocker used as an antiarrhythmic, may help refractory pain or hereditary small fiber neuropathy related to sodium channel dysfunction. However, it is not recommended for diabetic neuropathy.³⁹

Combination regimens that use drugs with different mechanisms of action can be effective. In one study, combined gabapentin and nortriptyline were more effective than either drug alone for neuropathic pain.⁴⁰

Inhaled cannabis reduced pain in patients with HIV and diabetic neuropathy in a number of studies. Side effects included euphoria, somnolence, and cognitive impairment.^41,42 The use of medical marijuana is not yet legal nationwide and may affect employability even in states in which it has been legalized.

Owing to the opioid epidemic and high addiction potential, opioids are no longer a preferred recommendation for chronic treatment of noncancer-related neuropathy. A population-based study of 2,892 patients with neuropathy found that those on chronic opioid therapy (≥ 90 days) had worse functional outcomes and higher rates of addiction and overdose than those on short-term therapy.⁴³ However, the opioid agonist tramadol was found to be effective in reducing neuropathic pain and may be a safer option for patients with chronic small fiber neuropathy.⁴⁴

Integrative, holistic therapies

PROGNOSIS

For many patients, small fiber neuropathy is a slowly progressive disorder that reaches a clinical plateau lasting for years, with progression to large fiber involvement reported in 13% to 36% of cases; over half of patients in one series either improved or remained stable over a period of 2 years.^5,57 Long-term studies are needed to fully understand the natural disease course. In the meantime, treating underlying disease and managing symptoms are imperative to patient care.

Many breast cancer survivors and women at high risk of breast cancer suffer from genitourinary syndrome of menopause (GSM), a term that encompasses any urinary, genital, or sexual dysfunction related to a hypoestrogenic state. Although GSM is usually caused by postmenopausal estrogen loss, it can also be caused by cancer treatments such as chemotherapy, radiation, and systemic endocrine therapy (eg, tamoxifen, aromatase inhibitors). These treatments can substantially decrease systemic estrogen levels, causing GSM symptoms that can profoundly worsen quality of life.

Managing GSM in these women poses a dilemma because systemic estrogen-containing therapies can increase the risk of breast cancer, and nonhormonal vaginal lubricants and moisturizers provide only minimal benefit. Fortunately, there are hormonal options, including locally applied estrogen, intravaginal dehydroepiandrosterone (DHEA), and estrogen receptor agonists/antagonists (ospemifene and bazedoxifene).

Here, we review the clinical management of GSM in breast cancer survivors and women at high risk of breast cancer and the efficacy and safety of available treatments, including their impact on breast cancer risk.

DRYNESS, IRRITATION, ATROPHY

The term GSM describes vulvovaginal and genitourinary symptoms associated with estrogen loss after menopause. Common symptoms are vaginal dryness, dyspareunia, irritation of genital skin, and pruritus.

LOCAL ESTROGEN THERAPY

Systemic estrogen therapy is widely used and effective for GSM, but there are concerns that it could increase the risk of breast cancer. After the Women’s Health Initiative in 2002 showed higher rates of cardiovascular disease and breast cancer with systemic estrogen-progestin use,⁵ the use of this hormone therapy declined by approximately 80%.⁶ Since then, healthcare providers have turned to local (ie, vaginal) estrogen therapies to manage GSM. These therapies have several advantages over systemic hormone therapy:

• Lower risk of adverse effects on the breast and cardiovascular system
• Greater efficacy in treating GSM
• In general, no need for progesterone when low-dose local estrogen is given to a woman with a uterus.⁷

Is locally applied estrogen systemically absorbed?

Despite these advantages, concerns remain as to whether vaginal estrogen therapy has adverse consequences associated with systemic absorption, particularly from atrophic vaginal tissues.

Santen,⁸ in a 2015 review of 33 studies, concluded that systemic absorption from low-dose vaginal estrogen is minimal, which provides some rationale for using it to treat vulvovaginal atrophy in postmenopausal women. This finding also suggests that the US Food and Drug Administration (FDA) “black box” warning of possible toxicities with vaginal estrogen is likely overstated, given that serum estrogen levels remained within normal postmenopausal levels.

Nevertheless, many providers are apprehensive about prescribing vaginal estrogen in women with a history of breast cancer because the threshold for systemic estrogen levels associated with breast cancer recurrence has not been established.

ACOG statement. In 2016, a committee of the American College of Obstetricians and Gynecologists cited data showing that low-dose vaginal estrogens do not result in sustained serum estrogen levels exceeding the normal postmenopausal range, and that the use of vaginal estrogens does not increase the risk of cancer recurrence.⁹ However, they recommend caution with vaginal estrogen use, especially in women with a history of estrogen-dependent breast cancer, reserving it for patients with GSM symptoms nonresponsive to nonhormonal treatment and specifying that it be used in low doses.

Vaginal estrogen formulations

Several types of locally applied estrogens are available, each with different properties and affinity for estrogen receptors. These include conjugated estrogens, 17-beta estradiol, estradiol acetate, and estradiol hemihydrate. Three delivery systems are FDA-approved: creams, rings, and tablets (Table 2).

Vaginal creams. Two vaginal creams are available, one (Estrace) containing 17-beta estradiol and the other (Premarin) containing conjugated estrogens.

The FDA-approved dosage for 17-beta estradiol is 2 to 4 g/day for 1 or 2 weeks, then gradually reduced to half the dose for a similar time. Maintenance dosing is 1 g 1 to 3 times per week. However, the ACOG statement notes that the FDA-approved dosages are higher than those proven to be effective and currently used in clinical practice, eg, 0.5 g twice a week.⁹

The FDA-approved dosage of conjugated estrogen cream for moderate to severe dyspareunia is 0.5 g daily for 21 days, then off for 7 days, or 0.5 g twice a week.

Vaginal tablets. The vaginal tablet Vagifem and its generic equivalent Yuvafem contain 10 µg of estradiol hemihydrate. The FDA-approved dosage is 10 µg daily for 2 weeks, followed by 10 µg twice a week, inserted into the lower third of the vagina. This dosage is significantly lower than that of estrogen creams.

Vaginal insert. A newly approved vaginal insert (Imvexxy) contains estradiol 4 µg (the lowest dose of vaginal estradiol available) or 10 µg, in a coconut oil vehicle. Its indications are for moderate to severe dyspareunia due to menopause and atrophic vaginitis due to menopause. A study cited in its package insert (www.accessdata.fda.gov/drugsatfda_docs/label/2018/208564s000lbl.pdf) showed that, in patients who used this product, systemic absorption of estradiol remained within the postmenopausal range. Its effects on breast cancer have not yet been studied.

Vaginal rings. Two vaginal rings are marketed. One (Estring) contains 17-beta estradiol, and the other (Femring) contains estradiol acetate. Only the 17-beta estradiol ring delivers a low dose to vaginal tissues, releasing 7.5 µg/day for 90 days. The estradiol acetate ring releases 0.05 mg/day or 0.10 mg/day and is a systemic treatment meant to be used with a progestin, not for local therapy.

After menopause, as the ovaries stop making estrogen from androstenedione, some production continues in other tissues, with DHEA as the primary precursor of androgens that are ultimately converted to estrogen. This has led to the theory that the cause of GSM is not estrogen deficiency but androgen deficiency. Evidence reviewed by Labrie et al¹¹ shows that vulvovaginal atrophy is caused by decreased DHEA availability, which in turn causes sex steroid deficiency-related menopausal symptoms.¹¹ Thus, it is reasonable to conclude that menopausal symptoms can be relieved by giving DHEA.

This theory has been borne out in clinical trials, in which DHEA in a vaginal tablet formulation increased the maturation of vaginal cells and lowered vaginal pH, leading to relief of GSM symptoms.¹²

The only DHEA product FDA-approved for treating GSM-related symptoms is prasterone (Intrarosa), indicated for moderate to severe dyspareunia due to vulvovaginal atrophy. The recommended dosing is a single 6.5-mg intravaginal tablet (0.5% prasterone) inserted nightly at bedtime. Its efficacy for treating hypoactive sexual desire disorder in postmenopausal women is being investigated.

Breast cancer implications

Because DHEA is converted to estrogen by aromatization, healthcare providers might hesitate to use it in women who have a history of hormone-sensitive cancer. Data on the safety of intravaginal DHEA use in breast cancer survivors are limited. However, studies have found that prasterone has highly beneficial effects on dyspareunia, vaginal dryness, and objective signs of vulvovaginal atrophy without significant drug-related adverse effects.^12,13 In these studies, serum estrogen levels in women treated with DHEA were within the values observed in normal postmenopausal women. In addition, there are no aromatase enzymes in the endometrium, so even high doses of vaginal DHEA (in contrast to high doses of vaginal estrogen) will not stimulate the endometrium.

Clinically, this evidence indicates that DHEA exerts both estrogenic and androgenic activity in the vagina without increasing serum estrogen levels, making it a good alternative to topical estrogen therapy.

OSPEMIFENE: AN ESTROGEN RECEPTOR AGONIST/ANTAGONIST

Ospemifene (Osphena) is an estrogen receptor agonist/antagonist, a class of drugs previously called selective estrogen receptor modulators (SERMs). It is FDA-approved to treat moderate to severe dyspareunia secondary to vulvar and vaginal atrophy.

Ospemifene has unique estrogenic effects on the vaginal mucosa, having been shown to increase the number of epithelial cells, lower the vaginal pH, and decrease the percentage of parabasal cells seen on Papanicolaou smears after 12 weeks of use.¹⁴

Unlike tamoxifen, another drug of this class, ospemifene does not change the endometrial lining.¹⁴ Similarly, ospemifene acts as an estrogenic agonist in bone and, thus, has the potential for use in preventing and managing osteoporosis or for use in women at risk of fractures.

Breast cancer impact

In preclinical trials, ospemifene was found to have antiestrogenic effects on breast tissue, similar to those seen with tamoxifen.

In a model using human tumor grafts, ospemifene decreased tumor growth in mice implanted with estrogen receptor-positive breast cancer cells.¹⁵

In a mouse model using breast cancer cells that were biologically and histologically similar to those of humans, ospemifene had strong antiestrogenic effects on the breast tissue.¹⁶ The evidence suggests that ospemifene has a favorable effect on vulvar and vaginal atrophy.¹⁷

Ospemifene is FDA-approved to treat moderate to severe dyspareunia secondary to menopause. Recommended dosing is 60 mg/day orally with food.

Its antiestrogenic effects on breast tissue make it a promising option for women with a history of estrogen-receptor positive breast cancer. However, further study is needed to fully understand its effects on human breast tissue. According to the manufacturer’s package insert (www.osphena.com/files/pdf/osphena_prescribing_information.pdf), because the drug has not been adequately studied in women with breast cancer, it should not be used in women with known or suspected breast cancer or a history of breast cancer.

CONJUGATED ESTROGENS PLUS BAZEDOXIFENE

The combination of conjugated estrogens and bazedoxifene (Duavee) is a progesterone-free alternative for treating various menopausal symptoms. Bazedoxifene is another estrogen receptor agonist/antagonist, and it was added to counteract estrogen’s effects on the endometrium, thus replacing progesterone. This protective effect has been validated in clinical trials, which also found a favorable safety profile in breast tissue.^18,19

SMART trials. The efficacy of this combination was studied in a series of large phase 3 multicenter trials called the SMART (Selective Estrogens, Menopause, and Response to Therapy) trials.^20–23 Treated patients had markedly fewer vasomotor symptoms at 1 year, along with an increase in superficial cells and intermediate cells of the vaginal epithelium and a decrease in parabasal cells. They also had a substantial decrease in the incidence of dyspareunia.

Its effects on breast tissue were evaluated in the SMART-5 trial. Therapy had no net impact on breast density, suggesting that it has an estrogen-neutral effect on the breast.²³

These results suggest that combined conjugated estrogens and bazedoxifene could be a noteworthy treatment option for GSM in women with a history of estrogen receptor-positive breast cancer, particularly in those with vasomotor symptoms and bone loss. However, the combination has not been studied specifically in breast cancer survivors.

Dosage. The FDA-approved dosing is 20 mg/0.45 mg per day orally to treat vasomotor symptoms, GSM, and osteoporosis in postmenopausal women with a uterus.

LASER THERAPY AND RADIOFREQUENCY HEAT: AN OFF-LABEL OPTION

Low-dose radiofrequency thermal therapy, delivered by carbon dioxide laser or by radiofrequency heat, has been used with some success to treat urinary stress incontinence and vaginal laxity in postpartum women. It may be an option for GSM, although it is not FDA-approved for this indication, and the FDA has recently issued a warning about it.²⁴

Marketing literature promotes laser therapy as an effective option that stimulates vaginal connective tissue to produce new collagen, which then promotes improved blood flow and tissue regeneration for vaginal lubrication and elasticity.

A study comparing fractional carbon dioxide vaginal laser treatment and local estrogen therapy in postmenopausal women with vulvovaginal atrophy found that laser therapy was an effective treatment for vulvovaginal atrophy (dyspareunia, dryness, and burning), both alone and with local estrogen.²⁵

Despite the promising effects of laser therapy for treating vulvovaginal atrophy in GSM, studies have not determined its short-term or long-term safety profile. Furthermore, laser therapy does not improve impaired sexual function, ie, decreased libido, arousal, and sexual satisfaction. Another important consideration is that the cost of laser therapy in 2017 was estimated to be $2,000 to $3,000 per treatment, not covered by healthcare insurance.

Symptoms of GSM are common in breast cancer survivors, both pre- and postmenopausal, especially those treated with tamoxifen or an aromatase inhibitor. Estimates are that 60% of postmenopausal breast cancer survivors and 40% of premenopausal breast cancer survivors suffer from GSM.²⁶ Unfortunately, many women do not seek medical attention for their symptoms.

A variety of hormonal and nonhormonal options are available for these patients. We recommend an interdisciplinary approach to treatment, with the decision to use hormonal options made in collaboration with the patient’s oncologist and the patient herself, in an informed, shared decision-making process that takes into consideration the risks and possible benefits depending on the symptoms.

The first step in selecting a management plan for GSM symptoms in women with breast cancer is to conduct a thorough assessment to provide data for individualizing the care plan. The decision to use a hormonal option should be made in collaboration with a woman’s oncologist and should include an informed decision-making process during which the potential risks and benefits, including the breast cancer impact, are fully disclosed.

Alternatives to systemic estrogen

Vaginal estrogen is an effective and safe option to treat GSM in women with either estrogen receptor-negative or estrogen receptor-positive breast cancer. It often completely cures the symptoms without any noticeable increase in serum estrogen levels.

Vaginal DHEA therapy is a nonestrogen option shown to effectively treat GSM without increasing systemic levels of estrogen or testosterone. This profile makes vaginal DHEA therapy a particularly attractive treatment for symptoms of GSM in women at risk for breast cancer.

Use of an estrogen receptor agonist/antagonist in breast cancer survivors needs careful consideration. Ospemifene has antiestrogenic effects that make it a good option for women with bone loss and those at high risk for breast cancer, but it should not be used concurrently with tamoxifen or raloxifene. Additionally, ospemifene does not cause uterine hyperplasia, so it can be used in women with a uterus.

Although more study is needed, we do have options to improve the overall quality of life in breast cancer survivors with GSM.

Many breast cancer survivors and women at high risk of breast cancer suffer from genitourinary syndrome of menopause (GSM), a term that encompasses any urinary, genital, or sexual dysfunction related to a hypoestrogenic state. Although GSM is usually caused by postmenopausal estrogen loss, it can also be caused by cancer treatments such as chemotherapy, radiation, and systemic endocrine therapy (eg, tamoxifen, aromatase inhibitors). These treatments can substantially decrease systemic estrogen levels, causing GSM symptoms that can profoundly worsen quality of life.

Managing GSM in these women poses a dilemma because systemic estrogen-containing therapies can increase the risk of breast cancer, and nonhormonal vaginal lubricants and moisturizers provide only minimal benefit. Fortunately, there are hormonal options, including locally applied estrogen, intravaginal dehydroepiandrosterone (DHEA), and estrogen receptor agonists/antagonists (ospemifene and bazedoxifene).

Here, we review the clinical management of GSM in breast cancer survivors and women at high risk of breast cancer and the efficacy and safety of available treatments, including their impact on breast cancer risk.

DRYNESS, IRRITATION, ATROPHY

The term GSM describes vulvovaginal and genitourinary symptoms associated with estrogen loss after menopause. Common symptoms are vaginal dryness, dyspareunia, irritation of genital skin, and pruritus.

LOCAL ESTROGEN THERAPY

Systemic estrogen therapy is widely used and effective for GSM, but there are concerns that it could increase the risk of breast cancer. After the Women’s Health Initiative in 2002 showed higher rates of cardiovascular disease and breast cancer with systemic estrogen-progestin use,⁵ the use of this hormone therapy declined by approximately 80%.⁶ Since then, healthcare providers have turned to local (ie, vaginal) estrogen therapies to manage GSM. These therapies have several advantages over systemic hormone therapy:

• Lower risk of adverse effects on the breast and cardiovascular system
• Greater efficacy in treating GSM
• In general, no need for progesterone when low-dose local estrogen is given to a woman with a uterus.⁷

Is locally applied estrogen systemically absorbed?

Despite these advantages, concerns remain as to whether vaginal estrogen therapy has adverse consequences associated with systemic absorption, particularly from atrophic vaginal tissues.

Santen,⁸ in a 2015 review of 33 studies, concluded that systemic absorption from low-dose vaginal estrogen is minimal, which provides some rationale for using it to treat vulvovaginal atrophy in postmenopausal women. This finding also suggests that the US Food and Drug Administration (FDA) “black box” warning of possible toxicities with vaginal estrogen is likely overstated, given that serum estrogen levels remained within normal postmenopausal levels.

Nevertheless, many providers are apprehensive about prescribing vaginal estrogen in women with a history of breast cancer because the threshold for systemic estrogen levels associated with breast cancer recurrence has not been established.

ACOG statement. In 2016, a committee of the American College of Obstetricians and Gynecologists cited data showing that low-dose vaginal estrogens do not result in sustained serum estrogen levels exceeding the normal postmenopausal range, and that the use of vaginal estrogens does not increase the risk of cancer recurrence.⁹ However, they recommend caution with vaginal estrogen use, especially in women with a history of estrogen-dependent breast cancer, reserving it for patients with GSM symptoms nonresponsive to nonhormonal treatment and specifying that it be used in low doses.

Vaginal estrogen formulations

Several types of locally applied estrogens are available, each with different properties and affinity for estrogen receptors. These include conjugated estrogens, 17-beta estradiol, estradiol acetate, and estradiol hemihydrate. Three delivery systems are FDA-approved: creams, rings, and tablets (Table 2).

Vaginal creams. Two vaginal creams are available, one (Estrace) containing 17-beta estradiol and the other (Premarin) containing conjugated estrogens.

The FDA-approved dosage for 17-beta estradiol is 2 to 4 g/day for 1 or 2 weeks, then gradually reduced to half the dose for a similar time. Maintenance dosing is 1 g 1 to 3 times per week. However, the ACOG statement notes that the FDA-approved dosages are higher than those proven to be effective and currently used in clinical practice, eg, 0.5 g twice a week.⁹

The FDA-approved dosage of conjugated estrogen cream for moderate to severe dyspareunia is 0.5 g daily for 21 days, then off for 7 days, or 0.5 g twice a week.

Vaginal tablets. The vaginal tablet Vagifem and its generic equivalent Yuvafem contain 10 µg of estradiol hemihydrate. The FDA-approved dosage is 10 µg daily for 2 weeks, followed by 10 µg twice a week, inserted into the lower third of the vagina. This dosage is significantly lower than that of estrogen creams.

Vaginal insert. A newly approved vaginal insert (Imvexxy) contains estradiol 4 µg (the lowest dose of vaginal estradiol available) or 10 µg, in a coconut oil vehicle. Its indications are for moderate to severe dyspareunia due to menopause and atrophic vaginitis due to menopause. A study cited in its package insert (www.accessdata.fda.gov/drugsatfda_docs/label/2018/208564s000lbl.pdf) showed that, in patients who used this product, systemic absorption of estradiol remained within the postmenopausal range. Its effects on breast cancer have not yet been studied.

Vaginal rings. Two vaginal rings are marketed. One (Estring) contains 17-beta estradiol, and the other (Femring) contains estradiol acetate. Only the 17-beta estradiol ring delivers a low dose to vaginal tissues, releasing 7.5 µg/day for 90 days. The estradiol acetate ring releases 0.05 mg/day or 0.10 mg/day and is a systemic treatment meant to be used with a progestin, not for local therapy.

After menopause, as the ovaries stop making estrogen from androstenedione, some production continues in other tissues, with DHEA as the primary precursor of androgens that are ultimately converted to estrogen. This has led to the theory that the cause of GSM is not estrogen deficiency but androgen deficiency. Evidence reviewed by Labrie et al¹¹ shows that vulvovaginal atrophy is caused by decreased DHEA availability, which in turn causes sex steroid deficiency-related menopausal symptoms.¹¹ Thus, it is reasonable to conclude that menopausal symptoms can be relieved by giving DHEA.

This theory has been borne out in clinical trials, in which DHEA in a vaginal tablet formulation increased the maturation of vaginal cells and lowered vaginal pH, leading to relief of GSM symptoms.¹²

The only DHEA product FDA-approved for treating GSM-related symptoms is prasterone (Intrarosa), indicated for moderate to severe dyspareunia due to vulvovaginal atrophy. The recommended dosing is a single 6.5-mg intravaginal tablet (0.5% prasterone) inserted nightly at bedtime. Its efficacy for treating hypoactive sexual desire disorder in postmenopausal women is being investigated.

Breast cancer implications

Because DHEA is converted to estrogen by aromatization, healthcare providers might hesitate to use it in women who have a history of hormone-sensitive cancer. Data on the safety of intravaginal DHEA use in breast cancer survivors are limited. However, studies have found that prasterone has highly beneficial effects on dyspareunia, vaginal dryness, and objective signs of vulvovaginal atrophy without significant drug-related adverse effects.^12,13 In these studies, serum estrogen levels in women treated with DHEA were within the values observed in normal postmenopausal women. In addition, there are no aromatase enzymes in the endometrium, so even high doses of vaginal DHEA (in contrast to high doses of vaginal estrogen) will not stimulate the endometrium.

Clinically, this evidence indicates that DHEA exerts both estrogenic and androgenic activity in the vagina without increasing serum estrogen levels, making it a good alternative to topical estrogen therapy.

OSPEMIFENE: AN ESTROGEN RECEPTOR AGONIST/ANTAGONIST

Ospemifene (Osphena) is an estrogen receptor agonist/antagonist, a class of drugs previously called selective estrogen receptor modulators (SERMs). It is FDA-approved to treat moderate to severe dyspareunia secondary to vulvar and vaginal atrophy.

Ospemifene has unique estrogenic effects on the vaginal mucosa, having been shown to increase the number of epithelial cells, lower the vaginal pH, and decrease the percentage of parabasal cells seen on Papanicolaou smears after 12 weeks of use.¹⁴

Unlike tamoxifen, another drug of this class, ospemifene does not change the endometrial lining.¹⁴ Similarly, ospemifene acts as an estrogenic agonist in bone and, thus, has the potential for use in preventing and managing osteoporosis or for use in women at risk of fractures.

Breast cancer impact

In preclinical trials, ospemifene was found to have antiestrogenic effects on breast tissue, similar to those seen with tamoxifen.

In a model using human tumor grafts, ospemifene decreased tumor growth in mice implanted with estrogen receptor-positive breast cancer cells.¹⁵

In a mouse model using breast cancer cells that were biologically and histologically similar to those of humans, ospemifene had strong antiestrogenic effects on the breast tissue.¹⁶ The evidence suggests that ospemifene has a favorable effect on vulvar and vaginal atrophy.¹⁷

Ospemifene is FDA-approved to treat moderate to severe dyspareunia secondary to menopause. Recommended dosing is 60 mg/day orally with food.

Its antiestrogenic effects on breast tissue make it a promising option for women with a history of estrogen-receptor positive breast cancer. However, further study is needed to fully understand its effects on human breast tissue. According to the manufacturer’s package insert (www.osphena.com/files/pdf/osphena_prescribing_information.pdf), because the drug has not been adequately studied in women with breast cancer, it should not be used in women with known or suspected breast cancer or a history of breast cancer.

CONJUGATED ESTROGENS PLUS BAZEDOXIFENE

The combination of conjugated estrogens and bazedoxifene (Duavee) is a progesterone-free alternative for treating various menopausal symptoms. Bazedoxifene is another estrogen receptor agonist/antagonist, and it was added to counteract estrogen’s effects on the endometrium, thus replacing progesterone. This protective effect has been validated in clinical trials, which also found a favorable safety profile in breast tissue.^18,19

SMART trials. The efficacy of this combination was studied in a series of large phase 3 multicenter trials called the SMART (Selective Estrogens, Menopause, and Response to Therapy) trials.^20–23 Treated patients had markedly fewer vasomotor symptoms at 1 year, along with an increase in superficial cells and intermediate cells of the vaginal epithelium and a decrease in parabasal cells. They also had a substantial decrease in the incidence of dyspareunia.

Its effects on breast tissue were evaluated in the SMART-5 trial. Therapy had no net impact on breast density, suggesting that it has an estrogen-neutral effect on the breast.²³

These results suggest that combined conjugated estrogens and bazedoxifene could be a noteworthy treatment option for GSM in women with a history of estrogen receptor-positive breast cancer, particularly in those with vasomotor symptoms and bone loss. However, the combination has not been studied specifically in breast cancer survivors.

Dosage. The FDA-approved dosing is 20 mg/0.45 mg per day orally to treat vasomotor symptoms, GSM, and osteoporosis in postmenopausal women with a uterus.

LASER THERAPY AND RADIOFREQUENCY HEAT: AN OFF-LABEL OPTION

Low-dose radiofrequency thermal therapy, delivered by carbon dioxide laser or by radiofrequency heat, has been used with some success to treat urinary stress incontinence and vaginal laxity in postpartum women. It may be an option for GSM, although it is not FDA-approved for this indication, and the FDA has recently issued a warning about it.²⁴

Marketing literature promotes laser therapy as an effective option that stimulates vaginal connective tissue to produce new collagen, which then promotes improved blood flow and tissue regeneration for vaginal lubrication and elasticity.

A study comparing fractional carbon dioxide vaginal laser treatment and local estrogen therapy in postmenopausal women with vulvovaginal atrophy found that laser therapy was an effective treatment for vulvovaginal atrophy (dyspareunia, dryness, and burning), both alone and with local estrogen.²⁵

Despite the promising effects of laser therapy for treating vulvovaginal atrophy in GSM, studies have not determined its short-term or long-term safety profile. Furthermore, laser therapy does not improve impaired sexual function, ie, decreased libido, arousal, and sexual satisfaction. Another important consideration is that the cost of laser therapy in 2017 was estimated to be $2,000 to $3,000 per treatment, not covered by healthcare insurance.

Symptoms of GSM are common in breast cancer survivors, both pre- and postmenopausal, especially those treated with tamoxifen or an aromatase inhibitor. Estimates are that 60% of postmenopausal breast cancer survivors and 40% of premenopausal breast cancer survivors suffer from GSM.²⁶ Unfortunately, many women do not seek medical attention for their symptoms.

A variety of hormonal and nonhormonal options are available for these patients. We recommend an interdisciplinary approach to treatment, with the decision to use hormonal options made in collaboration with the patient’s oncologist and the patient herself, in an informed, shared decision-making process that takes into consideration the risks and possible benefits depending on the symptoms.

The first step in selecting a management plan for GSM symptoms in women with breast cancer is to conduct a thorough assessment to provide data for individualizing the care plan. The decision to use a hormonal option should be made in collaboration with a woman’s oncologist and should include an informed decision-making process during which the potential risks and benefits, including the breast cancer impact, are fully disclosed.

Alternatives to systemic estrogen

Vaginal estrogen is an effective and safe option to treat GSM in women with either estrogen receptor-negative or estrogen receptor-positive breast cancer. It often completely cures the symptoms without any noticeable increase in serum estrogen levels.

Vaginal DHEA therapy is a nonestrogen option shown to effectively treat GSM without increasing systemic levels of estrogen or testosterone. This profile makes vaginal DHEA therapy a particularly attractive treatment for symptoms of GSM in women at risk for breast cancer.

Use of an estrogen receptor agonist/antagonist in breast cancer survivors needs careful consideration. Ospemifene has antiestrogenic effects that make it a good option for women with bone loss and those at high risk for breast cancer, but it should not be used concurrently with tamoxifen or raloxifene. Additionally, ospemifene does not cause uterine hyperplasia, so it can be used in women with a uterus.

Although more study is needed, we do have options to improve the overall quality of life in breast cancer survivors with GSM.

Many breast cancer survivors and women at high risk of breast cancer suffer from genitourinary syndrome of menopause (GSM), a term that encompasses any urinary, genital, or sexual dysfunction related to a hypoestrogenic state. Although GSM is usually caused by postmenopausal estrogen loss, it can also be caused by cancer treatments such as chemotherapy, radiation, and systemic endocrine therapy (eg, tamoxifen, aromatase inhibitors). These treatments can substantially decrease systemic estrogen levels, causing GSM symptoms that can profoundly worsen quality of life.

Managing GSM in these women poses a dilemma because systemic estrogen-containing therapies can increase the risk of breast cancer, and nonhormonal vaginal lubricants and moisturizers provide only minimal benefit. Fortunately, there are hormonal options, including locally applied estrogen, intravaginal dehydroepiandrosterone (DHEA), and estrogen receptor agonists/antagonists (ospemifene and bazedoxifene).

Here, we review the clinical management of GSM in breast cancer survivors and women at high risk of breast cancer and the efficacy and safety of available treatments, including their impact on breast cancer risk.

DRYNESS, IRRITATION, ATROPHY

The term GSM describes vulvovaginal and genitourinary symptoms associated with estrogen loss after menopause. Common symptoms are vaginal dryness, dyspareunia, irritation of genital skin, and pruritus.

LOCAL ESTROGEN THERAPY

Systemic estrogen therapy is widely used and effective for GSM, but there are concerns that it could increase the risk of breast cancer. After the Women’s Health Initiative in 2002 showed higher rates of cardiovascular disease and breast cancer with systemic estrogen-progestin use,⁵ the use of this hormone therapy declined by approximately 80%.⁶ Since then, healthcare providers have turned to local (ie, vaginal) estrogen therapies to manage GSM. These therapies have several advantages over systemic hormone therapy:

• Lower risk of adverse effects on the breast and cardiovascular system
• Greater efficacy in treating GSM
• In general, no need for progesterone when low-dose local estrogen is given to a woman with a uterus.⁷

Is locally applied estrogen systemically absorbed?

Despite these advantages, concerns remain as to whether vaginal estrogen therapy has adverse consequences associated with systemic absorption, particularly from atrophic vaginal tissues.

Santen,⁸ in a 2015 review of 33 studies, concluded that systemic absorption from low-dose vaginal estrogen is minimal, which provides some rationale for using it to treat vulvovaginal atrophy in postmenopausal women. This finding also suggests that the US Food and Drug Administration (FDA) “black box” warning of possible toxicities with vaginal estrogen is likely overstated, given that serum estrogen levels remained within normal postmenopausal levels.

Nevertheless, many providers are apprehensive about prescribing vaginal estrogen in women with a history of breast cancer because the threshold for systemic estrogen levels associated with breast cancer recurrence has not been established.

ACOG statement. In 2016, a committee of the American College of Obstetricians and Gynecologists cited data showing that low-dose vaginal estrogens do not result in sustained serum estrogen levels exceeding the normal postmenopausal range, and that the use of vaginal estrogens does not increase the risk of cancer recurrence.⁹ However, they recommend caution with vaginal estrogen use, especially in women with a history of estrogen-dependent breast cancer, reserving it for patients with GSM symptoms nonresponsive to nonhormonal treatment and specifying that it be used in low doses.

Vaginal estrogen formulations

Several types of locally applied estrogens are available, each with different properties and affinity for estrogen receptors. These include conjugated estrogens, 17-beta estradiol, estradiol acetate, and estradiol hemihydrate. Three delivery systems are FDA-approved: creams, rings, and tablets (Table 2).

Vaginal creams. Two vaginal creams are available, one (Estrace) containing 17-beta estradiol and the other (Premarin) containing conjugated estrogens.

The FDA-approved dosage for 17-beta estradiol is 2 to 4 g/day for 1 or 2 weeks, then gradually reduced to half the dose for a similar time. Maintenance dosing is 1 g 1 to 3 times per week. However, the ACOG statement notes that the FDA-approved dosages are higher than those proven to be effective and currently used in clinical practice, eg, 0.5 g twice a week.⁹

The FDA-approved dosage of conjugated estrogen cream for moderate to severe dyspareunia is 0.5 g daily for 21 days, then off for 7 days, or 0.5 g twice a week.

Vaginal tablets. The vaginal tablet Vagifem and its generic equivalent Yuvafem contain 10 µg of estradiol hemihydrate. The FDA-approved dosage is 10 µg daily for 2 weeks, followed by 10 µg twice a week, inserted into the lower third of the vagina. This dosage is significantly lower than that of estrogen creams.

Vaginal insert. A newly approved vaginal insert (Imvexxy) contains estradiol 4 µg (the lowest dose of vaginal estradiol available) or 10 µg, in a coconut oil vehicle. Its indications are for moderate to severe dyspareunia due to menopause and atrophic vaginitis due to menopause. A study cited in its package insert (www.accessdata.fda.gov/drugsatfda_docs/label/2018/208564s000lbl.pdf) showed that, in patients who used this product, systemic absorption of estradiol remained within the postmenopausal range. Its effects on breast cancer have not yet been studied.

Vaginal rings. Two vaginal rings are marketed. One (Estring) contains 17-beta estradiol, and the other (Femring) contains estradiol acetate. Only the 17-beta estradiol ring delivers a low dose to vaginal tissues, releasing 7.5 µg/day for 90 days. The estradiol acetate ring releases 0.05 mg/day or 0.10 mg/day and is a systemic treatment meant to be used with a progestin, not for local therapy.

After menopause, as the ovaries stop making estrogen from androstenedione, some production continues in other tissues, with DHEA as the primary precursor of androgens that are ultimately converted to estrogen. This has led to the theory that the cause of GSM is not estrogen deficiency but androgen deficiency. Evidence reviewed by Labrie et al¹¹ shows that vulvovaginal atrophy is caused by decreased DHEA availability, which in turn causes sex steroid deficiency-related menopausal symptoms.¹¹ Thus, it is reasonable to conclude that menopausal symptoms can be relieved by giving DHEA.

This theory has been borne out in clinical trials, in which DHEA in a vaginal tablet formulation increased the maturation of vaginal cells and lowered vaginal pH, leading to relief of GSM symptoms.¹²

The only DHEA product FDA-approved for treating GSM-related symptoms is prasterone (Intrarosa), indicated for moderate to severe dyspareunia due to vulvovaginal atrophy. The recommended dosing is a single 6.5-mg intravaginal tablet (0.5% prasterone) inserted nightly at bedtime. Its efficacy for treating hypoactive sexual desire disorder in postmenopausal women is being investigated.

Breast cancer implications

Because DHEA is converted to estrogen by aromatization, healthcare providers might hesitate to use it in women who have a history of hormone-sensitive cancer. Data on the safety of intravaginal DHEA use in breast cancer survivors are limited. However, studies have found that prasterone has highly beneficial effects on dyspareunia, vaginal dryness, and objective signs of vulvovaginal atrophy without significant drug-related adverse effects.^12,13 In these studies, serum estrogen levels in women treated with DHEA were within the values observed in normal postmenopausal women. In addition, there are no aromatase enzymes in the endometrium, so even high doses of vaginal DHEA (in contrast to high doses of vaginal estrogen) will not stimulate the endometrium.

Clinically, this evidence indicates that DHEA exerts both estrogenic and androgenic activity in the vagina without increasing serum estrogen levels, making it a good alternative to topical estrogen therapy.

OSPEMIFENE: AN ESTROGEN RECEPTOR AGONIST/ANTAGONIST

Ospemifene (Osphena) is an estrogen receptor agonist/antagonist, a class of drugs previously called selective estrogen receptor modulators (SERMs). It is FDA-approved to treat moderate to severe dyspareunia secondary to vulvar and vaginal atrophy.

Ospemifene has unique estrogenic effects on the vaginal mucosa, having been shown to increase the number of epithelial cells, lower the vaginal pH, and decrease the percentage of parabasal cells seen on Papanicolaou smears after 12 weeks of use.¹⁴

Unlike tamoxifen, another drug of this class, ospemifene does not change the endometrial lining.¹⁴ Similarly, ospemifene acts as an estrogenic agonist in bone and, thus, has the potential for use in preventing and managing osteoporosis or for use in women at risk of fractures.

Breast cancer impact

In preclinical trials, ospemifene was found to have antiestrogenic effects on breast tissue, similar to those seen with tamoxifen.

In a model using human tumor grafts, ospemifene decreased tumor growth in mice implanted with estrogen receptor-positive breast cancer cells.¹⁵

In a mouse model using breast cancer cells that were biologically and histologically similar to those of humans, ospemifene had strong antiestrogenic effects on the breast tissue.¹⁶ The evidence suggests that ospemifene has a favorable effect on vulvar and vaginal atrophy.¹⁷

Ospemifene is FDA-approved to treat moderate to severe dyspareunia secondary to menopause. Recommended dosing is 60 mg/day orally with food.

Its antiestrogenic effects on breast tissue make it a promising option for women with a history of estrogen-receptor positive breast cancer. However, further study is needed to fully understand its effects on human breast tissue. According to the manufacturer’s package insert (www.osphena.com/files/pdf/osphena_prescribing_information.pdf), because the drug has not been adequately studied in women with breast cancer, it should not be used in women with known or suspected breast cancer or a history of breast cancer.

CONJUGATED ESTROGENS PLUS BAZEDOXIFENE

The combination of conjugated estrogens and bazedoxifene (Duavee) is a progesterone-free alternative for treating various menopausal symptoms. Bazedoxifene is another estrogen receptor agonist/antagonist, and it was added to counteract estrogen’s effects on the endometrium, thus replacing progesterone. This protective effect has been validated in clinical trials, which also found a favorable safety profile in breast tissue.^18,19

SMART trials. The efficacy of this combination was studied in a series of large phase 3 multicenter trials called the SMART (Selective Estrogens, Menopause, and Response to Therapy) trials.^20–23 Treated patients had markedly fewer vasomotor symptoms at 1 year, along with an increase in superficial cells and intermediate cells of the vaginal epithelium and a decrease in parabasal cells. They also had a substantial decrease in the incidence of dyspareunia.

Its effects on breast tissue were evaluated in the SMART-5 trial. Therapy had no net impact on breast density, suggesting that it has an estrogen-neutral effect on the breast.²³

These results suggest that combined conjugated estrogens and bazedoxifene could be a noteworthy treatment option for GSM in women with a history of estrogen receptor-positive breast cancer, particularly in those with vasomotor symptoms and bone loss. However, the combination has not been studied specifically in breast cancer survivors.

Dosage. The FDA-approved dosing is 20 mg/0.45 mg per day orally to treat vasomotor symptoms, GSM, and osteoporosis in postmenopausal women with a uterus.

LASER THERAPY AND RADIOFREQUENCY HEAT: AN OFF-LABEL OPTION

Low-dose radiofrequency thermal therapy, delivered by carbon dioxide laser or by radiofrequency heat, has been used with some success to treat urinary stress incontinence and vaginal laxity in postpartum women. It may be an option for GSM, although it is not FDA-approved for this indication, and the FDA has recently issued a warning about it.²⁴

Marketing literature promotes laser therapy as an effective option that stimulates vaginal connective tissue to produce new collagen, which then promotes improved blood flow and tissue regeneration for vaginal lubrication and elasticity.

A study comparing fractional carbon dioxide vaginal laser treatment and local estrogen therapy in postmenopausal women with vulvovaginal atrophy found that laser therapy was an effective treatment for vulvovaginal atrophy (dyspareunia, dryness, and burning), both alone and with local estrogen.²⁵

Despite the promising effects of laser therapy for treating vulvovaginal atrophy in GSM, studies have not determined its short-term or long-term safety profile. Furthermore, laser therapy does not improve impaired sexual function, ie, decreased libido, arousal, and sexual satisfaction. Another important consideration is that the cost of laser therapy in 2017 was estimated to be $2,000 to $3,000 per treatment, not covered by healthcare insurance.

Symptoms of GSM are common in breast cancer survivors, both pre- and postmenopausal, especially those treated with tamoxifen or an aromatase inhibitor. Estimates are that 60% of postmenopausal breast cancer survivors and 40% of premenopausal breast cancer survivors suffer from GSM.²⁶ Unfortunately, many women do not seek medical attention for their symptoms.

A variety of hormonal and nonhormonal options are available for these patients. We recommend an interdisciplinary approach to treatment, with the decision to use hormonal options made in collaboration with the patient’s oncologist and the patient herself, in an informed, shared decision-making process that takes into consideration the risks and possible benefits depending on the symptoms.

The first step in selecting a management plan for GSM symptoms in women with breast cancer is to conduct a thorough assessment to provide data for individualizing the care plan. The decision to use a hormonal option should be made in collaboration with a woman’s oncologist and should include an informed decision-making process during which the potential risks and benefits, including the breast cancer impact, are fully disclosed.

Alternatives to systemic estrogen

Vaginal estrogen is an effective and safe option to treat GSM in women with either estrogen receptor-negative or estrogen receptor-positive breast cancer. It often completely cures the symptoms without any noticeable increase in serum estrogen levels.

Vaginal DHEA therapy is a nonestrogen option shown to effectively treat GSM without increasing systemic levels of estrogen or testosterone. This profile makes vaginal DHEA therapy a particularly attractive treatment for symptoms of GSM in women at risk for breast cancer.

Use of an estrogen receptor agonist/antagonist in breast cancer survivors needs careful consideration. Ospemifene has antiestrogenic effects that make it a good option for women with bone loss and those at high risk for breast cancer, but it should not be used concurrently with tamoxifen or raloxifene. Additionally, ospemifene does not cause uterine hyperplasia, so it can be used in women with a uterus.

Although more study is needed, we do have options to improve the overall quality of life in breast cancer survivors with GSM.

Bicuspid aortic valve may initially be asymptomatic, but it is associated with progressive valvular and aortic abnormalities that can lead to chronic heart failure and sudden death. Regular monitoring is required with an eye toward surgery when indicated.

See related editorial

This article reviews inheritance patterns and conditions associated with bicuspid aortic valve. We discuss diagnosis, management, and monitoring, and offer surgical recommendations. Special guidance for dental procedures, pregnancy, and athletes is also provided.

A YOUNG MAN WITH PALPITATIONS AND A MURMUR

A 34-year-old man presented to an outpatient clinic with occasional palpitations over the past several months. He reported that he had been diagnosed with a murmur as a child but had received no further testing.

Physical examination at this time revealed a faint systolic crescendo-decrescendo murmur along the right sternal border without radiation to the carotid arteries or to the apex. Transthoracic echocardiography (TTE) showed a bicuspid aortic valve with fusion of the right and left coronary cusps, with no aortic valve stenosis or insufficiency. There was mild dilation of the aortic root, but the mid-ascending aorta could not be evaluated because of limited acoustic windows.

Is further diagnostic testing needed, and if so, what? May he participate in exertional physical activity? Does his newborn son need evaluation?

ABNORMALITIES OCCUR DURING EMBRYOGENESIS

Bicuspid aortic valve develops because of abnormal valvulogenesis. Adjacent cusps fail to separate from each other, resulting in only 2 cusps, with 1 usually larger than the other. Morphology varies according to which commissures are fused.¹

Bicuspid aortic valve is associated with abnormalities in the coronary artery anatomy in about 2% of patients, including anomalous origins of the coronary arteries and upwardly displaced coronary ostia.² Such features need to be considered before surgical intervention.

Bicuspid aortic valve can be found in 1% to 2% of the general population, with a male-to-female predominance of 3:1.^1,3,4 It is one of the most common congenital cardiac malformations and is the leading congenital cause of aortic valve stenosis.^1,3 However, routine screening of newborns for the condition is not recommended, and most cases are diagnosed incidentally.

GENETIC FACTORS PROMINENT

Bicuspid aortic valve is thought to be primarily inherited in an autosomal-dominant pattern, but there is evidence of genetic heterogeneity, and the pattern may be variable.^5,6

No single gene responsible for bicuspid aortic valve has been identified. The condition may occur as a component of different pleiotropic genetic syndromes such as Loeys-Dietz, DiGeorge, and Marfan syndromes,^7,8 as well as in patients with Turner syndrome and Williams syndrome.^8–11 It also commonly coexists with other congenital heart diseases, including ventricular septal defect, isolated aortic arch obstruction, and patent ductus arteriosus.⁹

Studies have found a 15% rate of familial clustering.^6,12 In a study of 142 patients with bicuspid aortic valve, 20% of first-degree relatives had some cardiac abnormality found by screening, of whom 68% had bicuspid aortic valve. Of these, 71% were newly detected abnormalities.¹³

CHARACTERISTIC CLICK AND MURMUR

Physical examination findings of a functionally normal bicuspid aortic valve include a systolic ejection click followed by an early peaking systolic murmur at the apex or left lower sternal border. With progression of aortic stenosis, the ejection murmur has a harsher sound, with later peaking, and the S2 sound diminishes or becomes inaudible.¹⁴ If aortic regurgitation is present, a diastolic decrescendo murmur is heard best at the left lower sternal border.

DISEASE PROGRESSION

Although bicuspid aortic valve is typically asymp­tomatic at first, it is commonly associated with progressive valvulopathy and thoracic aortic disease.^1,3,4,15 It can lead to chronic heart failure and increase the risk of acute aortic syndromes and sudden cardiac death.¹⁵

Michelena et al¹⁶ studied 212 cases of asymp­tomatic bicuspid aortic valve. Although the survival rate 20 years after diagnosis was the same as for an age-matched cohort in the general population, the frequency of adverse cardiovascular events and surgical interventions was higher.

Aortic stenosis progresses rapidly

Aortic stenosis associated with a bicuspid aortic valve tends to affect younger patients and progress more rapidly than when associated with a tricuspid valve.¹⁷

In a study of 542 patients with congenital bicuspid aortic valve undergoing aortic valve replacement,³ 75% had isolated aortic stenosis, 10% had aortic stenosis with some degree of aortic insufficiency, and 13% had isolated aortic insufficiency. Given the tendency of aortic stenosis to progress rapidly, early surgery is often pursued.^17,18

Aneurysmal disease is common

The thoracic aorta is at increased risk of aneurysmal disease, coarctation, and dissection in patients with a bicuspid aortic valve.^1,6,15

Michelena et al¹⁶ reported that in patients without an aneurysm at the time of bicuspid aortic valve diagnosis, the 25-year risk of aneurysm formation was approximately 26%. In patients with an aneurysm at the time of diagnosis, the 15-year risk of aortic surgery after the diagnosis of aneurysm was about 46% and the risk of aortic dissection after aneurysm diagnosis was 7%.¹⁵ Compared with the general population, the age-adjusted relative risk of aortic aneurysm in patients with bicuspid aortic valve was 86.2, and that of aortic dissection was 8.4. Although the absolute incidence of dissection is low in these patients, it is markedly higher than in the general population, particularly in older patients (age > 50) and those with an aneurysm at the time of diagnosis.¹⁵

The risk of infective endocarditis

Patients with bicuspid aortic valve are highly prone to infective endocarditis for reasons that remain poorly understood. The pathogens in most cases are staphylococci or viridans streptococci.¹⁹ Patients with infective endocarditis typically require emergency surgery. Complications including valvular abscess, myocardial abscess, and overt heart failure are common.¹⁹

Lamas and Eykyn²⁰ studied 408 cases of native valve endocarditis; in 12.3%, the patient had a bicuspid aortic valve. In this subset, all were male, the mean age was 39 at diagnosis, 82% needed surgery, and the death rate was 14%.

Patients with bicuspid aortic valve do not routinely need antibiotics before dental and surgical procedures, but if they have had endocarditis in the past, they need antibiotics to prevent a recurrence.²¹

REGULAR MONITORING NEEDED

Because complications may be life-threatening, early detection of progressive disease by regular screening is critical. Echocardiographic evaluation of valvular function, ventricular dimensions and function, and diameter of the aortic root and ascending aorta should be performed in every patient with bicuspid aortic valve. If initial imaging is normal and there is no aortic dilation, imaging should be repeated every 5 to 10 years. If any abnormality is found, repeat imaging is needed every year.²²

Magnetic resonance imaging (MRI) or computed tomographic (CT) angiography may be required to better assess the aorta for patients requiring a surgical intervention, or when aortic dimensions are not clearly visualized on TTE. MRI has 2 advantages over CT angiography: it poses no radiation risk, and it provides more information on left ventricular function and dimensions, in addition to valve assessment.^23,24

No published study has compared MRI or CT angiography and transesophageal echocardiography (TEE), but in a study of 174 patients with dilated aortic root, combined TTE and TEE detected aortic valve morphology accurately in 98% of cases. As TEE is more invasive, it is not recommended for regular surveillance (Figures 1 and 2).²⁵

FAMILY SCREENING RECOMMENDED

Close relatives should be evaluated for aortic valve and thoracic aortic disease.^12,13,23,26

The American College of Cardiology (ACC) and the American Heart Association (AHA), backed by radiologic and cardiovascular associations, concur in recommending echocardiographic screening and routine screening of the thoracic aorta for aortic root dilation in first-degree relatives (ie, siblings, parents, and children) of patients with bicuspid aortic valve (class I recommendation).^22,27,28

A comprehensive physical examination is recommended for family members in addition to TTE, with careful assessment of the aortic valve in short and long axes, and of the aortic root.¹⁴ If the aorta cannot be adequately evaluated with TTE, further assessment should be pursued with CT angiography or MRI.

EXERCISE RESTRICTIONS

The 2015 ACC/AHA guidelines for competitive athletes with cardiovascular abnormalities recommend annual screening with TTE or MRI angiography for athletes with bicuspid aortic valve and coexisting dilation of the ascending aorta (aortic diameter 40–42 mm in men and 36–39 mm in women) (class I recommendation, level of evidence C).²⁹

Athletes with a bicuspid aortic valve and a normal aortic root and ascending aorta may participate in all competitive activities.²⁹ However, those with a dilated aorta should avoid strenuous activities because of the increased risk of rupture.³⁰ The ACC/AHA recommendations²⁹ depend on the diameter of the ascending aorta and the nature of the sport:

• For an aortic diameter 40 to 42 mm in men or 36 to 39 mm in women, and no features of connective tissue disease or familial thoracic ascending aortic syndrome, low- and moderate-intensity sports with a low likelihood of significant body contact may be considered; consider avoiding intense weight training (class IIb, level of evidence C)
• For an aortic diameter 43 to 45 mm, low-intensity sports with a low likelihood of body contact may be considered (class IIb, level of evidence C)
• For an aortic diameter greater than 43 mm in men or greater than 40 mm in women, sports involving body collision should be avoided (class III, level of evidence C)
• For an aortic diameter greater than 45 mm, sports activities should be avoided (class III, level of evidence C).

PREGNANCY CONSIDERATIONS

Bicuspid aortic valve is associated with aortic dissection, mainly in the third trimester.³¹ Patients should ideally undergo echocardiographic screening before conception. The 2010 ACC/AHA guidelines for managing thoracic aortic disease recommend monthly or bimonthly echocardiography until delivery in pregnant women with a dilated thoracic aorta.²²

Patients with bicuspid aortic valve and aortic root enlargement of more than 40 mm should have preconception counseling about surgery for aortic root replacement before becoming pregnant. If the diagnosis of enlarged aortic root is made during pregnancy, echocardiographic surveillance at 4- to 6-week intervals is indicated.³²

SURGICAL MANAGEMENT

In the past, beta-blockers and angiotensin-converting enzyme inhibitors were recommended to minimize shear stress, with the goal of slowing progression of aortic dilation. However, evidence to support their use is inadequate.^33,34

The only definitive treatment is surgery, with various procedures that lower the risk of death or dissection.^24,35

The dimensions of the aortic root or ascending aorta should be examined vigilantly, according to the 2014 ACC/AHA guidelines²⁷:

• Repairing the aortic sinuses or replacing the ascending aorta is indicated if the diameter of the aortic sinuses or ascending aorta is greater than 5.5 cm (class I, level of evidence B)
• Repairing the aortic sinuses or replacing the ascending aorta is reasonable if the diameter of the aortic sinuses or ascending aorta is greater than 5.0 cm and the patient has a risk factor for dissection such as a family history of aortic dissection or an increase in diameter of 0.5 cm or greater per year (class IIa, level of evidence C)
• Replacement of the ascending aorta is reasonable if the diameter of the ascending aorta is greater than 4.5 cm and the patient is undergoing aortic valve surgery for severe aortic stenosis or regurgitation.

Valve repair or replacement

Aortic valve repair or replacement is sometimes done separately from aortic root repair.

The value of aortic valve repair is debatable, but a series of 728 patients at Cleveland Clinic showed a very low mortality rate (0.41%) and an annual reoperation rate of 2.6% during up to 15 years of follow-up.³⁶

Aortic valve replacement is usually considered for patients with severe valve dysfunction, abnormal left ventricular dimensions, or symptoms. It is important to determine if the patient is a good surgical candidate and to refer early for surgical evaluation to avoid the higher risk of death associated with emergency surgery.³⁶

Transcatheter aortic valve replacement has been studied in patients deemed to be at too high a risk for surgical replacement. Short- and intermediate-term outcomes have been good in these patients, but long-term data are lacking.³⁷

Surveillance after surgery

The type of operation determines postoperative surveillance.

After isolated aortic valve repair or replacement, patients should continue with surveillance at least annually to monitor for progressive aortopathy, as they remain at increased risk of dissection or rupture after isolated valve surgery, especially if they had aortic insufficiency preoperatively.³⁸

After definitive surgery with replacement or repair of the ascending aorta, no clear recommendations have been established for continued surveillance. However, it is reasonable to image these patients with either MRI or CT angiography 3 to 5 years after their surgery to monitor for anastomotic complications.

CASE QUESTIONS ANSWERED

Our patient should undergo repeat TTE in 1 year. He should also undergo CT angiography of the ascending aorta if it is not seen by TTE. He can participate in low-intensity sports but should avoid intense weight training. His parents, siblings, and children should be screened for bicuspid aortic valve or associated aortopathies.

Bicuspid aortic valve may initially be asymptomatic, but it is associated with progressive valvular and aortic abnormalities that can lead to chronic heart failure and sudden death. Regular monitoring is required with an eye toward surgery when indicated.

See related editorial

This article reviews inheritance patterns and conditions associated with bicuspid aortic valve. We discuss diagnosis, management, and monitoring, and offer surgical recommendations. Special guidance for dental procedures, pregnancy, and athletes is also provided.

A YOUNG MAN WITH PALPITATIONS AND A MURMUR

A 34-year-old man presented to an outpatient clinic with occasional palpitations over the past several months. He reported that he had been diagnosed with a murmur as a child but had received no further testing.

Physical examination at this time revealed a faint systolic crescendo-decrescendo murmur along the right sternal border without radiation to the carotid arteries or to the apex. Transthoracic echocardiography (TTE) showed a bicuspid aortic valve with fusion of the right and left coronary cusps, with no aortic valve stenosis or insufficiency. There was mild dilation of the aortic root, but the mid-ascending aorta could not be evaluated because of limited acoustic windows.

Is further diagnostic testing needed, and if so, what? May he participate in exertional physical activity? Does his newborn son need evaluation?

ABNORMALITIES OCCUR DURING EMBRYOGENESIS

Bicuspid aortic valve develops because of abnormal valvulogenesis. Adjacent cusps fail to separate from each other, resulting in only 2 cusps, with 1 usually larger than the other. Morphology varies according to which commissures are fused.¹

Bicuspid aortic valve is associated with abnormalities in the coronary artery anatomy in about 2% of patients, including anomalous origins of the coronary arteries and upwardly displaced coronary ostia.² Such features need to be considered before surgical intervention.

Bicuspid aortic valve can be found in 1% to 2% of the general population, with a male-to-female predominance of 3:1.^1,3,4 It is one of the most common congenital cardiac malformations and is the leading congenital cause of aortic valve stenosis.^1,3 However, routine screening of newborns for the condition is not recommended, and most cases are diagnosed incidentally.

GENETIC FACTORS PROMINENT

Bicuspid aortic valve is thought to be primarily inherited in an autosomal-dominant pattern, but there is evidence of genetic heterogeneity, and the pattern may be variable.^5,6

No single gene responsible for bicuspid aortic valve has been identified. The condition may occur as a component of different pleiotropic genetic syndromes such as Loeys-Dietz, DiGeorge, and Marfan syndromes,^7,8 as well as in patients with Turner syndrome and Williams syndrome.^8–11 It also commonly coexists with other congenital heart diseases, including ventricular septal defect, isolated aortic arch obstruction, and patent ductus arteriosus.⁹

Studies have found a 15% rate of familial clustering.^6,12 In a study of 142 patients with bicuspid aortic valve, 20% of first-degree relatives had some cardiac abnormality found by screening, of whom 68% had bicuspid aortic valve. Of these, 71% were newly detected abnormalities.¹³

CHARACTERISTIC CLICK AND MURMUR

Physical examination findings of a functionally normal bicuspid aortic valve include a systolic ejection click followed by an early peaking systolic murmur at the apex or left lower sternal border. With progression of aortic stenosis, the ejection murmur has a harsher sound, with later peaking, and the S2 sound diminishes or becomes inaudible.¹⁴ If aortic regurgitation is present, a diastolic decrescendo murmur is heard best at the left lower sternal border.

DISEASE PROGRESSION

Although bicuspid aortic valve is typically asymp­tomatic at first, it is commonly associated with progressive valvulopathy and thoracic aortic disease.^1,3,4,15 It can lead to chronic heart failure and increase the risk of acute aortic syndromes and sudden cardiac death.¹⁵

Michelena et al¹⁶ studied 212 cases of asymp­tomatic bicuspid aortic valve. Although the survival rate 20 years after diagnosis was the same as for an age-matched cohort in the general population, the frequency of adverse cardiovascular events and surgical interventions was higher.

Aortic stenosis progresses rapidly

Aortic stenosis associated with a bicuspid aortic valve tends to affect younger patients and progress more rapidly than when associated with a tricuspid valve.¹⁷

In a study of 542 patients with congenital bicuspid aortic valve undergoing aortic valve replacement,³ 75% had isolated aortic stenosis, 10% had aortic stenosis with some degree of aortic insufficiency, and 13% had isolated aortic insufficiency. Given the tendency of aortic stenosis to progress rapidly, early surgery is often pursued.^17,18

Aneurysmal disease is common

The thoracic aorta is at increased risk of aneurysmal disease, coarctation, and dissection in patients with a bicuspid aortic valve.^1,6,15

Michelena et al¹⁶ reported that in patients without an aneurysm at the time of bicuspid aortic valve diagnosis, the 25-year risk of aneurysm formation was approximately 26%. In patients with an aneurysm at the time of diagnosis, the 15-year risk of aortic surgery after the diagnosis of aneurysm was about 46% and the risk of aortic dissection after aneurysm diagnosis was 7%.¹⁵ Compared with the general population, the age-adjusted relative risk of aortic aneurysm in patients with bicuspid aortic valve was 86.2, and that of aortic dissection was 8.4. Although the absolute incidence of dissection is low in these patients, it is markedly higher than in the general population, particularly in older patients (age > 50) and those with an aneurysm at the time of diagnosis.¹⁵

The risk of infective endocarditis

Patients with bicuspid aortic valve are highly prone to infective endocarditis for reasons that remain poorly understood. The pathogens in most cases are staphylococci or viridans streptococci.¹⁹ Patients with infective endocarditis typically require emergency surgery. Complications including valvular abscess, myocardial abscess, and overt heart failure are common.¹⁹

Lamas and Eykyn²⁰ studied 408 cases of native valve endocarditis; in 12.3%, the patient had a bicuspid aortic valve. In this subset, all were male, the mean age was 39 at diagnosis, 82% needed surgery, and the death rate was 14%.

Patients with bicuspid aortic valve do not routinely need antibiotics before dental and surgical procedures, but if they have had endocarditis in the past, they need antibiotics to prevent a recurrence.²¹

REGULAR MONITORING NEEDED

Because complications may be life-threatening, early detection of progressive disease by regular screening is critical. Echocardiographic evaluation of valvular function, ventricular dimensions and function, and diameter of the aortic root and ascending aorta should be performed in every patient with bicuspid aortic valve. If initial imaging is normal and there is no aortic dilation, imaging should be repeated every 5 to 10 years. If any abnormality is found, repeat imaging is needed every year.²²

Magnetic resonance imaging (MRI) or computed tomographic (CT) angiography may be required to better assess the aorta for patients requiring a surgical intervention, or when aortic dimensions are not clearly visualized on TTE. MRI has 2 advantages over CT angiography: it poses no radiation risk, and it provides more information on left ventricular function and dimensions, in addition to valve assessment.^23,24

No published study has compared MRI or CT angiography and transesophageal echocardiography (TEE), but in a study of 174 patients with dilated aortic root, combined TTE and TEE detected aortic valve morphology accurately in 98% of cases. As TEE is more invasive, it is not recommended for regular surveillance (Figures 1 and 2).²⁵

FAMILY SCREENING RECOMMENDED

Close relatives should be evaluated for aortic valve and thoracic aortic disease.^12,13,23,26

The American College of Cardiology (ACC) and the American Heart Association (AHA), backed by radiologic and cardiovascular associations, concur in recommending echocardiographic screening and routine screening of the thoracic aorta for aortic root dilation in first-degree relatives (ie, siblings, parents, and children) of patients with bicuspid aortic valve (class I recommendation).^22,27,28

A comprehensive physical examination is recommended for family members in addition to TTE, with careful assessment of the aortic valve in short and long axes, and of the aortic root.¹⁴ If the aorta cannot be adequately evaluated with TTE, further assessment should be pursued with CT angiography or MRI.

EXERCISE RESTRICTIONS

The 2015 ACC/AHA guidelines for competitive athletes with cardiovascular abnormalities recommend annual screening with TTE or MRI angiography for athletes with bicuspid aortic valve and coexisting dilation of the ascending aorta (aortic diameter 40–42 mm in men and 36–39 mm in women) (class I recommendation, level of evidence C).²⁹

Athletes with a bicuspid aortic valve and a normal aortic root and ascending aorta may participate in all competitive activities.²⁹ However, those with a dilated aorta should avoid strenuous activities because of the increased risk of rupture.³⁰ The ACC/AHA recommendations²⁹ depend on the diameter of the ascending aorta and the nature of the sport:

• For an aortic diameter 40 to 42 mm in men or 36 to 39 mm in women, and no features of connective tissue disease or familial thoracic ascending aortic syndrome, low- and moderate-intensity sports with a low likelihood of significant body contact may be considered; consider avoiding intense weight training (class IIb, level of evidence C)
• For an aortic diameter 43 to 45 mm, low-intensity sports with a low likelihood of body contact may be considered (class IIb, level of evidence C)
• For an aortic diameter greater than 43 mm in men or greater than 40 mm in women, sports involving body collision should be avoided (class III, level of evidence C)
• For an aortic diameter greater than 45 mm, sports activities should be avoided (class III, level of evidence C).

PREGNANCY CONSIDERATIONS

Bicuspid aortic valve is associated with aortic dissection, mainly in the third trimester.³¹ Patients should ideally undergo echocardiographic screening before conception. The 2010 ACC/AHA guidelines for managing thoracic aortic disease recommend monthly or bimonthly echocardiography until delivery in pregnant women with a dilated thoracic aorta.²²

Patients with bicuspid aortic valve and aortic root enlargement of more than 40 mm should have preconception counseling about surgery for aortic root replacement before becoming pregnant. If the diagnosis of enlarged aortic root is made during pregnancy, echocardiographic surveillance at 4- to 6-week intervals is indicated.³²

SURGICAL MANAGEMENT

In the past, beta-blockers and angiotensin-converting enzyme inhibitors were recommended to minimize shear stress, with the goal of slowing progression of aortic dilation. However, evidence to support their use is inadequate.^33,34

The only definitive treatment is surgery, with various procedures that lower the risk of death or dissection.^24,35

The dimensions of the aortic root or ascending aorta should be examined vigilantly, according to the 2014 ACC/AHA guidelines²⁷:

• Repairing the aortic sinuses or replacing the ascending aorta is indicated if the diameter of the aortic sinuses or ascending aorta is greater than 5.5 cm (class I, level of evidence B)
• Repairing the aortic sinuses or replacing the ascending aorta is reasonable if the diameter of the aortic sinuses or ascending aorta is greater than 5.0 cm and the patient has a risk factor for dissection such as a family history of aortic dissection or an increase in diameter of 0.5 cm or greater per year (class IIa, level of evidence C)
• Replacement of the ascending aorta is reasonable if the diameter of the ascending aorta is greater than 4.5 cm and the patient is undergoing aortic valve surgery for severe aortic stenosis or regurgitation.

Valve repair or replacement

Aortic valve repair or replacement is sometimes done separately from aortic root repair.

The value of aortic valve repair is debatable, but a series of 728 patients at Cleveland Clinic showed a very low mortality rate (0.41%) and an annual reoperation rate of 2.6% during up to 15 years of follow-up.³⁶

Aortic valve replacement is usually considered for patients with severe valve dysfunction, abnormal left ventricular dimensions, or symptoms. It is important to determine if the patient is a good surgical candidate and to refer early for surgical evaluation to avoid the higher risk of death associated with emergency surgery.³⁶

Transcatheter aortic valve replacement has been studied in patients deemed to be at too high a risk for surgical replacement. Short- and intermediate-term outcomes have been good in these patients, but long-term data are lacking.³⁷

Surveillance after surgery

The type of operation determines postoperative surveillance.

After isolated aortic valve repair or replacement, patients should continue with surveillance at least annually to monitor for progressive aortopathy, as they remain at increased risk of dissection or rupture after isolated valve surgery, especially if they had aortic insufficiency preoperatively.³⁸

After definitive surgery with replacement or repair of the ascending aorta, no clear recommendations have been established for continued surveillance. However, it is reasonable to image these patients with either MRI or CT angiography 3 to 5 years after their surgery to monitor for anastomotic complications.

CASE QUESTIONS ANSWERED

Our patient should undergo repeat TTE in 1 year. He should also undergo CT angiography of the ascending aorta if it is not seen by TTE. He can participate in low-intensity sports but should avoid intense weight training. His parents, siblings, and children should be screened for bicuspid aortic valve or associated aortopathies.

Bicuspid aortic valve may initially be asymptomatic, but it is associated with progressive valvular and aortic abnormalities that can lead to chronic heart failure and sudden death. Regular monitoring is required with an eye toward surgery when indicated.

See related editorial

This article reviews inheritance patterns and conditions associated with bicuspid aortic valve. We discuss diagnosis, management, and monitoring, and offer surgical recommendations. Special guidance for dental procedures, pregnancy, and athletes is also provided.

A YOUNG MAN WITH PALPITATIONS AND A MURMUR

A 34-year-old man presented to an outpatient clinic with occasional palpitations over the past several months. He reported that he had been diagnosed with a murmur as a child but had received no further testing.

Physical examination at this time revealed a faint systolic crescendo-decrescendo murmur along the right sternal border without radiation to the carotid arteries or to the apex. Transthoracic echocardiography (TTE) showed a bicuspid aortic valve with fusion of the right and left coronary cusps, with no aortic valve stenosis or insufficiency. There was mild dilation of the aortic root, but the mid-ascending aorta could not be evaluated because of limited acoustic windows.

Is further diagnostic testing needed, and if so, what? May he participate in exertional physical activity? Does his newborn son need evaluation?

ABNORMALITIES OCCUR DURING EMBRYOGENESIS

Bicuspid aortic valve develops because of abnormal valvulogenesis. Adjacent cusps fail to separate from each other, resulting in only 2 cusps, with 1 usually larger than the other. Morphology varies according to which commissures are fused.¹

Bicuspid aortic valve is associated with abnormalities in the coronary artery anatomy in about 2% of patients, including anomalous origins of the coronary arteries and upwardly displaced coronary ostia.² Such features need to be considered before surgical intervention.

Bicuspid aortic valve can be found in 1% to 2% of the general population, with a male-to-female predominance of 3:1.^1,3,4 It is one of the most common congenital cardiac malformations and is the leading congenital cause of aortic valve stenosis.^1,3 However, routine screening of newborns for the condition is not recommended, and most cases are diagnosed incidentally.

GENETIC FACTORS PROMINENT

Bicuspid aortic valve is thought to be primarily inherited in an autosomal-dominant pattern, but there is evidence of genetic heterogeneity, and the pattern may be variable.^5,6

No single gene responsible for bicuspid aortic valve has been identified. The condition may occur as a component of different pleiotropic genetic syndromes such as Loeys-Dietz, DiGeorge, and Marfan syndromes,^7,8 as well as in patients with Turner syndrome and Williams syndrome.^8–11 It also commonly coexists with other congenital heart diseases, including ventricular septal defect, isolated aortic arch obstruction, and patent ductus arteriosus.⁹

Studies have found a 15% rate of familial clustering.^6,12 In a study of 142 patients with bicuspid aortic valve, 20% of first-degree relatives had some cardiac abnormality found by screening, of whom 68% had bicuspid aortic valve. Of these, 71% were newly detected abnormalities.¹³

CHARACTERISTIC CLICK AND MURMUR

Physical examination findings of a functionally normal bicuspid aortic valve include a systolic ejection click followed by an early peaking systolic murmur at the apex or left lower sternal border. With progression of aortic stenosis, the ejection murmur has a harsher sound, with later peaking, and the S2 sound diminishes or becomes inaudible.¹⁴ If aortic regurgitation is present, a diastolic decrescendo murmur is heard best at the left lower sternal border.

DISEASE PROGRESSION

Although bicuspid aortic valve is typically asymp­tomatic at first, it is commonly associated with progressive valvulopathy and thoracic aortic disease.^1,3,4,15 It can lead to chronic heart failure and increase the risk of acute aortic syndromes and sudden cardiac death.¹⁵

Michelena et al¹⁶ studied 212 cases of asymp­tomatic bicuspid aortic valve. Although the survival rate 20 years after diagnosis was the same as for an age-matched cohort in the general population, the frequency of adverse cardiovascular events and surgical interventions was higher.

Aortic stenosis progresses rapidly

Aortic stenosis associated with a bicuspid aortic valve tends to affect younger patients and progress more rapidly than when associated with a tricuspid valve.¹⁷

In a study of 542 patients with congenital bicuspid aortic valve undergoing aortic valve replacement,³ 75% had isolated aortic stenosis, 10% had aortic stenosis with some degree of aortic insufficiency, and 13% had isolated aortic insufficiency. Given the tendency of aortic stenosis to progress rapidly, early surgery is often pursued.^17,18

Aneurysmal disease is common

The thoracic aorta is at increased risk of aneurysmal disease, coarctation, and dissection in patients with a bicuspid aortic valve.^1,6,15

Michelena et al¹⁶ reported that in patients without an aneurysm at the time of bicuspid aortic valve diagnosis, the 25-year risk of aneurysm formation was approximately 26%. In patients with an aneurysm at the time of diagnosis, the 15-year risk of aortic surgery after the diagnosis of aneurysm was about 46% and the risk of aortic dissection after aneurysm diagnosis was 7%.¹⁵ Compared with the general population, the age-adjusted relative risk of aortic aneurysm in patients with bicuspid aortic valve was 86.2, and that of aortic dissection was 8.4. Although the absolute incidence of dissection is low in these patients, it is markedly higher than in the general population, particularly in older patients (age > 50) and those with an aneurysm at the time of diagnosis.¹⁵

The risk of infective endocarditis

Patients with bicuspid aortic valve are highly prone to infective endocarditis for reasons that remain poorly understood. The pathogens in most cases are staphylococci or viridans streptococci.¹⁹ Patients with infective endocarditis typically require emergency surgery. Complications including valvular abscess, myocardial abscess, and overt heart failure are common.¹⁹

Lamas and Eykyn²⁰ studied 408 cases of native valve endocarditis; in 12.3%, the patient had a bicuspid aortic valve. In this subset, all were male, the mean age was 39 at diagnosis, 82% needed surgery, and the death rate was 14%.

Patients with bicuspid aortic valve do not routinely need antibiotics before dental and surgical procedures, but if they have had endocarditis in the past, they need antibiotics to prevent a recurrence.²¹

REGULAR MONITORING NEEDED

Because complications may be life-threatening, early detection of progressive disease by regular screening is critical. Echocardiographic evaluation of valvular function, ventricular dimensions and function, and diameter of the aortic root and ascending aorta should be performed in every patient with bicuspid aortic valve. If initial imaging is normal and there is no aortic dilation, imaging should be repeated every 5 to 10 years. If any abnormality is found, repeat imaging is needed every year.²²

Magnetic resonance imaging (MRI) or computed tomographic (CT) angiography may be required to better assess the aorta for patients requiring a surgical intervention, or when aortic dimensions are not clearly visualized on TTE. MRI has 2 advantages over CT angiography: it poses no radiation risk, and it provides more information on left ventricular function and dimensions, in addition to valve assessment.^23,24

No published study has compared MRI or CT angiography and transesophageal echocardiography (TEE), but in a study of 174 patients with dilated aortic root, combined TTE and TEE detected aortic valve morphology accurately in 98% of cases. As TEE is more invasive, it is not recommended for regular surveillance (Figures 1 and 2).²⁵

FAMILY SCREENING RECOMMENDED

Close relatives should be evaluated for aortic valve and thoracic aortic disease.^12,13,23,26

The American College of Cardiology (ACC) and the American Heart Association (AHA), backed by radiologic and cardiovascular associations, concur in recommending echocardiographic screening and routine screening of the thoracic aorta for aortic root dilation in first-degree relatives (ie, siblings, parents, and children) of patients with bicuspid aortic valve (class I recommendation).^22,27,28

A comprehensive physical examination is recommended for family members in addition to TTE, with careful assessment of the aortic valve in short and long axes, and of the aortic root.¹⁴ If the aorta cannot be adequately evaluated with TTE, further assessment should be pursued with CT angiography or MRI.

EXERCISE RESTRICTIONS

The 2015 ACC/AHA guidelines for competitive athletes with cardiovascular abnormalities recommend annual screening with TTE or MRI angiography for athletes with bicuspid aortic valve and coexisting dilation of the ascending aorta (aortic diameter 40–42 mm in men and 36–39 mm in women) (class I recommendation, level of evidence C).²⁹

Athletes with a bicuspid aortic valve and a normal aortic root and ascending aorta may participate in all competitive activities.²⁹ However, those with a dilated aorta should avoid strenuous activities because of the increased risk of rupture.³⁰ The ACC/AHA recommendations²⁹ depend on the diameter of the ascending aorta and the nature of the sport:

• For an aortic diameter 40 to 42 mm in men or 36 to 39 mm in women, and no features of connective tissue disease or familial thoracic ascending aortic syndrome, low- and moderate-intensity sports with a low likelihood of significant body contact may be considered; consider avoiding intense weight training (class IIb, level of evidence C)
• For an aortic diameter 43 to 45 mm, low-intensity sports with a low likelihood of body contact may be considered (class IIb, level of evidence C)
• For an aortic diameter greater than 43 mm in men or greater than 40 mm in women, sports involving body collision should be avoided (class III, level of evidence C)
• For an aortic diameter greater than 45 mm, sports activities should be avoided (class III, level of evidence C).

PREGNANCY CONSIDERATIONS

Bicuspid aortic valve is associated with aortic dissection, mainly in the third trimester.³¹ Patients should ideally undergo echocardiographic screening before conception. The 2010 ACC/AHA guidelines for managing thoracic aortic disease recommend monthly or bimonthly echocardiography until delivery in pregnant women with a dilated thoracic aorta.²²

Patients with bicuspid aortic valve and aortic root enlargement of more than 40 mm should have preconception counseling about surgery for aortic root replacement before becoming pregnant. If the diagnosis of enlarged aortic root is made during pregnancy, echocardiographic surveillance at 4- to 6-week intervals is indicated.³²

SURGICAL MANAGEMENT

In the past, beta-blockers and angiotensin-converting enzyme inhibitors were recommended to minimize shear stress, with the goal of slowing progression of aortic dilation. However, evidence to support their use is inadequate.^33,34

The only definitive treatment is surgery, with various procedures that lower the risk of death or dissection.^24,35

The dimensions of the aortic root or ascending aorta should be examined vigilantly, according to the 2014 ACC/AHA guidelines²⁷:

• Repairing the aortic sinuses or replacing the ascending aorta is indicated if the diameter of the aortic sinuses or ascending aorta is greater than 5.5 cm (class I, level of evidence B)
• Repairing the aortic sinuses or replacing the ascending aorta is reasonable if the diameter of the aortic sinuses or ascending aorta is greater than 5.0 cm and the patient has a risk factor for dissection such as a family history of aortic dissection or an increase in diameter of 0.5 cm or greater per year (class IIa, level of evidence C)
• Replacement of the ascending aorta is reasonable if the diameter of the ascending aorta is greater than 4.5 cm and the patient is undergoing aortic valve surgery for severe aortic stenosis or regurgitation.

Valve repair or replacement

Aortic valve repair or replacement is sometimes done separately from aortic root repair.

The value of aortic valve repair is debatable, but a series of 728 patients at Cleveland Clinic showed a very low mortality rate (0.41%) and an annual reoperation rate of 2.6% during up to 15 years of follow-up.³⁶

Aortic valve replacement is usually considered for patients with severe valve dysfunction, abnormal left ventricular dimensions, or symptoms. It is important to determine if the patient is a good surgical candidate and to refer early for surgical evaluation to avoid the higher risk of death associated with emergency surgery.³⁶

Transcatheter aortic valve replacement has been studied in patients deemed to be at too high a risk for surgical replacement. Short- and intermediate-term outcomes have been good in these patients, but long-term data are lacking.³⁷

Surveillance after surgery

The type of operation determines postoperative surveillance.

After isolated aortic valve repair or replacement, patients should continue with surveillance at least annually to monitor for progressive aortopathy, as they remain at increased risk of dissection or rupture after isolated valve surgery, especially if they had aortic insufficiency preoperatively.³⁸

After definitive surgery with replacement or repair of the ascending aorta, no clear recommendations have been established for continued surveillance. However, it is reasonable to image these patients with either MRI or CT angiography 3 to 5 years after their surgery to monitor for anastomotic complications.

CASE QUESTIONS ANSWERED

Our patient should undergo repeat TTE in 1 year. He should also undergo CT angiography of the ascending aorta if it is not seen by TTE. He can participate in low-intensity sports but should avoid intense weight training. His parents, siblings, and children should be screened for bicuspid aortic valve or associated aortopathies.

A 64-year-old man with hypertension but  without known structural heart disease presents for a second opinion on management of his atrial fibrillation. The condition was first diagnosed at age 38, when he experienced palpitations and shortness of breath on exertion; at times he also experienced decreased endurance and fatigue without overt palpitations. At first, these episodes occurred about twice a year, and the patient was managed with a beta-blocker for rate control and an oral anticoagulant.

Over the past 10 years, the episodes have become more frequent and longer-lasting and have required frequent cardioversions. He was given flecainide for rhythm control but continued to have frequent episodes, and so about 1 year ago he was switched to amiodarone, which controlled his rhythm better. However, after reading about side effects of amiodarone, he decided to seek a second opinion.

He was evaluated by our team and eventually underwent radiofrequency ablation. During the procedure, he was noted to have diffuse scarring and fibrosis of his left atrium, and afterward he continued to require antiarrhythmic drugs to maintain sinus rhythm.

Should he have been referred sooner? What factors should primary care physicians consider when referring a patient with atrial fibrillation for ablation?

THE EPIDEMIC OF ATRIAL FIBRILLATION

Atrial fibrillation is a large and growing public health problem. In 2010, it was estimated to affect 2.7 to 6.1 million people in the United States, and with the rapid aging of our population, its prevalence is expected to rise to between 5.6 and 12 million by 2050.^1–3 It is associated with significant morbidity, poor quality of life, and increased risk of death, heart failure, stroke, and cognitive impairment.

The number of new cases per year has increased over the years despite research and preventive measures, which may reflect aging of the population and increased survival rates in patients with cardiovascular or comorbid conditions.^1,4

Thus, atrial fibrillation is one of the most common cardiovascular conditions encountered by primary care physicians and cardiologists, putting them at the forefront of its management. Proper treatment in its early stages and referral to a specialist for advanced management may alter its natural history and improve clinical outcomes.

HOW DOES ATRIAL FIBRILLATION ARISE AND PERSIST?

Much is still unknown about the pathogenesis of atrial fibrillation, but considerable progress has been made in the past few decades, opening the door for clinical ablative strategies.

Multiple wavelet hypothesis

Until the late 1980s, the most widely accepted conceptual mechanism of atrial fibrillation was the multiple wavelet hypothesis developed by Moe et al.⁵ According to this hypothesis, atrial fibrillation begins with multiple independent wavelets occurring simultaneously and spreading randomly throughout both atria, and it persists if there are a minimum number of coexisting wavelets, increased atrial mass, and heterogeneous conduction delays across the atrial tissue.

The surgical maze procedure, in which a series of incisions arranged in a maze-like pattern is created in the left atrium, was predicated on this model. The theory was that these surgical lesions would compartmentalize the atria into discrete electrical segments and thereby reduce  the number of circulating random wavelets.^6,7

However, experimental and clinical studies suggest that although randomly propagating wavelets can contribute to maintaining atrial fibrillation, focal triggers are noted in most cases.

Focal triggers

In 1997, Jaïs et al⁸ observed that atrial fibrillation is often triggered by a rapidly firing ectopic focus and that ablation of that focus can eliminate it. These ectopic foci are often found at or near the ostia of the pulmonary veins or near the superior vena cava.^8,9 It is now well established that ectopic foci in the pulmonary veins are crucial triggers that initiate atrial fibrillation.

Trigger-and-substrate theory

The substrate for maintaining atrial fibrillation consists of an abnormal left atrium with heterogeneous fibrosis (scarring) and conduction delays. Any heart disease that increases left atrial pressure could lead to atrial dilation and remodeling, which could be substrates for atrial fibrillation. Extensive atrial remodeling and scarring are associated with progression and persistence of atrial fibrillation and make rhythm control more challenging.

Atrial fibrillation begets atrial fibrillation

As shown in the case above, over time, paroxysmal atrial fibrillation often progresses to persistent and long-standing atrial fibrillation if not aggressively managed initially.

In 1972, Davies and Pomerance¹⁰ performed 100 autopsies and found that the people who had had atrial fibrillation for longer than 1 month had lost muscle mass in the sinus node and internodal tract, and their atria were dilated. The study introduced the concept that atrial fibrillation itself causes pathologic changes in the atrium.

Wijffels et al,¹¹ in an experiment in goats, showed that atrial fibrillation produced by rapid bursts of atrial pacing was initially paroxysmal. However, as they continued to induce atrial fibrillation over and over again, it lasted progressively longer until it would persist for more than 24 hours. Thus, in a relatively short time, the atria went from supporting paroxysmal fibrillation to supporting persistent fibrillation.

Atrial fibrillation leads to electrophysiologic and anatomic remodeling in the atrium, which leads to a shorter action potential duration and a shorter refractory period. This in turn makes it easier for atrial fibrillation to persist.¹²

Because atrial fibrillation tends to progress, intervening early may improve its outcomes. Early ablation has been shown to improve the chances of staying in sinus rhythm in both paroxysmal and persistent atrial fibrillation.^13–15

The goal of ablation is to prevent atrial fibrillation by eliminating the trigger that initiates it, altering the arrhythmogenic substrate, or both.

Pulmonary vein isolation

The most common ablation strategy is to electrically isolate the pulmonary veins by creating circumferential lesions around their antra. This creates a nonconducting rim of scar tissue, electrically disconnecting the pulmonary veins from the atrium.

Ablation outside of the pulmonary veins

Because recurrence rates are high in patients with persistent atrial fibrillation who undergo pulmonary vein ablation alone, the search continues for adjunctive strategies to improve outcomes. Although these strategies have a sound rationale based on experimental data and anecdotal evidence in humans, they have not yet been convincingly shown to be helpful in large clinical studies. Nonetheless, it is possible that more extensive substrate ablation—atrial “debulking”—could improve outcomes by reducing the amount of tissue that can fibrillate.

Linear ablation. Creating lines of ablation (as in the maze procedure) isolates different segments of the left atrium. Often, these lines are created along the roof of the left atrium between the right and left upper pulmonary veins and from the mitral valve to the left inferior pulmonary vein. The benefit of linear ablation has not been proven, and gaps in such lines may introduce atrial flutter.

Triggers not in the pulmonary veins. Common sites of nonpulmonary vein triggers include the posterior wall of the left atrium, the superior vena cava, the coronary sinus, and along the ligament of Marshall. Provocative maneuvers such as isoproterenol infusion can help find those triggers, which can then be ablated. A limitation is that there is no protocol proven to reproducibly elicit triggers.

Complex fractionated atrial electrograms are areas in the atrium with highly fractionated, low voltage potentials. They may be critical sites of substrate for atrial fibrillation, and many electrophysiologists target them in patients with persistent atrial fibrillation. But despite initial enthusiasm, doing so has not resulted in better outcomes in persistent atrial fibrillation.

Rotors. Animal studies have shown that atrial fibrillation can be triggered or maintained by localized sources of organized reentrant circuits (rotors) or focal impulses. Recent studies have shown that these electrical rotors and focal sources could potentially be mapped and ablated in humans. But positive results in initial reports have not been reproduced, and this remains an area of controversy.

Our practice. We isolate the pulmonary veins with antral ablations, ablate the posterior wall, and extend the ablation toward the septum and inferior to the right pulmonary veins, with good long-term outcomes.¹⁴ The rationale behind ablating the posterior wall is that it shares embryologic origins with the pulmonary veins and may be a common source of triggers in atrial fibrillation.

We do not routinely create empiric ablation lines in the left or right atrium unless the patient has atrial flutter. Empiric ablation lines have not been convincingly shown to provide additional benefit compared with our extensive ablation approach, which involves the posterior wall. Empiric ablation of the appendage or coronary sinus is typically reserved for repeat ablation in patients with recurrent persistent atrial fibrillation.

RATIONALE FOR TREATING ATRIAL FIBRILLATION WITH ABLATION

To control symptoms

At this time, the primary aim of atrial fibrillation ablation is to reduce symptoms and improve quality of life. In theory, ablation could also decrease the risk of stroke, heart failure, and death. However, these outcomes have not been systematically evaluated in any large randomized controlled trial.

To control rhythm and improve survival

Randomized controlled trials of rhythm vs rate control of atrial fibrillation^16–18 have failed to demonstrate that restoring sinus rhythm is associated with better survival. All of these trials used antiarrhythmic drugs for rhythm control. However, nonrandomized studies^19,20 showed that maintaining sinus rhythm is associated with a significant reduction in mortality rates, whereas the use of antiarrhythmic drugs increased mortality risk.

This suggests that the beneficial effect of restoring sinus rhythm may be offset by adverse effects of antiarrhythmic drugs, and if rhythm control could be achieved by a method other than antiarrhythmic drug therapy, it may be superior to rate control. On the other hand, these data may be affected by residual confounding. This topic deserves further research, but maintaining sinus rhythm is typically preferred whenever possible.

Discontinuing anticoagulation is not a goal at this time

Retrospective studies have reported a low risk of stroke in patients who discontinue anticoagulation several months after undergoing atrial fibrillation ablation.^21–23 However, atrial fibrillation can recur, and risk of stroke increases with age.

Therefore, guidelines²⁴ still recommend continuing anticoagulation after ablation. Generally, we do not offer ablation with a goal of discontinuing anticoagulation. That said, stopping anticoagulation may be considered after long-term suppression of paroxysmal atrial fibrillation on a case-by-case basis in patients deemed to be at low risk. Left atrial appendage closure devices may eventually allow concomitant atrial fibrillation ablation and closure of the appendage, so that anticoagulation could then be stopped. This remains a topic of investigation.

Who should be considered for ablation?

There are no absolute age or comorbidity contraindications to ablation. Everyone who has atrial fibrillation deserves, in our opinion, a referral to the electrophysiology clinic.

Atrial fibrillation ablation is most often performed by electrophysiologists using a minimally invasive endovascular approach. The patient can be under either moderate sedation or general anesthesia; we prefer general anesthesia for patient comfort, safety, and efficacy.

We use an electrogram-based technique to target and eliminate electrical potentials and ensure continuity of ablation sets, with additional guidance by 3-dimensional cardiac mapping systems and intracardiac echocardiography. We also use contact force-sensing catheters to ensure catheter-tissue contact during ablation and to avoid excessive contact, which may enhance the safety of the procedure.

Energy: Hot or cold

Two types of energy can be used for ablation:

Radiofrequency energy (low voltage, high frequency—30 kHz to 1.5 mHz) is delivered to the endocardial surface via a point-source catheter. The radiofrequency energy produces controlled, focal thermal ablation.

In a randomized trial,²⁵ these ablation technologies were shown to be equivalent for preventing recurrences of atrial fibrillation. We use both in our practice. The choice depends primarily on the planned ablation set, given that balloon cryoablation can achieve antral isolation of the pulmonary veins but allows little or no substrate modification.

Improved ablation technology

Contact force-sensing catheters. Radio­frequency ablation catheters are now equipped with a pressure sensor at the tip that measures how hard the catheter is pressing on the heart wall.^26,27 In our experience, this has improved the outcomes of ablation procedures, primarily in persistent atrial fibrillation.²⁸

Complications of ablation

Although catheter ablation for atrial fibrillation is safe, it is still one of the most complex electrophysiologic procedures. Improvements in technology and techniques and accumulated experience over the past 15 years have made ablation safer, especially in tertiary care centers. But adverse outcomes are more frequent in low-volume centers.²⁹

Minor procedural complications include pericarditis, complications at the site of vascular access, and anesthesia-related complications. While they do not affect the long-term outcome for the patient, they may increase hospital length of stay and cause temporary inconvenience.

Major complications include cardiac perforation and tamponade, periprocedural stroke, pulmonary vein stenosis, atrioesophageal fistula, phrenic nerve paralysis, major bleeding, myocardial infarction, and death. In a worldwide survey published in 2005, when atrial fibrillation ablation was still novel, the rate of major complications was 6%.³⁰ By 2010, this had declined to 4.5%,³¹ and the rates of major complications may be significantly lower in more experienced centers.²⁹ In our practice, in 2015, the rate of major complications was 1.3% (unpublished data).

Outcomes of catheter ablation

Clinical outcomes depend on many factors including the type of atrial fibrillation (paroxysmal vs nonparoxysmal), overall health of the atria (atrial size and scarring), patient age and comorbidities, and most importantly, the center’s and operator’s experience.

In randomized controlled trials comparing ablation and antiarrhythmic drug therapy, the efficacy of ablation in maintaining sinus rhythm has been in the range of 66% to 86% vs 16% to 22% for drug therapy,^32,33 but these trials have been predominantly in middle-aged white men with paroxysmal atrial fibrillation. These trials also showed that catheter ablation reduced symptoms and improved quality of life. Ablation is less effective in persistent than in paroxysmal atrial fibrillation.³⁴

In a long-term study from our group,¹⁴ 660 (79.4%) of 831 patients who underwent ablation in 2005 were arrhythmia-free and not on antiarrhythmic drug therapy after a total of 1,019 ablations (an average of 1.2 ablations per patient) at a median of 55 months; 125 patients (15%, 41 with more than 1 ablation) continued to have atrial arrhythmia, controlled with drugs in 87 patients (69.6%). Only 38 patients (4.6%) continued to have drug-resistant atrial fibrillation and were treated with rate control with negative dromotropic agents.

Recent evidence

The largest randomized controlled trial of catheter ablation vs drug therapy for atrial fibrillation (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation [CABANA]) was completed recently, and the results were presented at a national meeting, although they have not yet been published in a peer-reviewed journal.³⁵

A total of 2,204 patients with atrial fibrillation (42.4% paroxysmal, 47.3% persistent, and 10.3% long-standing persistent) were randomized to either ablation or drug therapy. Median follow-up was 4 years. The crossover rate was high—9.2% of those randomized to ablation did not undergo it, and 27.5% of those randomized to drug therapy underwent ablation.

The incidence of the primary end point (a composite of death, disabling stroke, serious bleeding, and cardiac arrest) was not significantly different between the 2 groups in the intention-to-treat analysis; however, given the high crossover rates, the as-treated and per-protocol analyses become important, and as-treated and per-protocol analyses revealed a significant benefit of ablation compared with drug therapy. The hazard ratio (HR) for the primary composite outcome was 0.67 (P = .006) on as-treated analysis and 0.73 (P = .05) on per-protocol analysis. The HR for all-cause mortality was 0.60 (P = .005) on as-treated analysis.

PERIPROCEDURAL CONSIDERATIONS

Periprocedural anticoagulation

The risk of thromboembolism is increased during, immediately following, and for several weeks to months after atrial fibrillation ablation.^36,37

During the procedure, the risk is related to transseptal sheath placement, electrode catheters in the left atrium, and char formation on ablation catheters. These risks are mitigated with proper and careful sheath and catheter manipulation, maintenance of bubble-free irrigation through lines and sheaths, use of irrigated catheters, and initiation of heparin before transseptal access. Heparin is also infused during the procedure, with close monitoring of activated clotting time.

Postprocedurally, the transiently increased clotting risk could be due to damaged endothelium from the ablation itself and stunning of atrial tissue, which results in impaired contraction. Damaged endothelium improves as the tissue heals, and the stunning resolves by electrical reverse remodeling with sinus rhythm maintenance.

In view of these risks, the referring physician and electrophysiologist must pay careful attention to anticoagulation before and after ablation.

Before the procedure. It is safe to continue anticoagulation uninterrupted through the procedure.^38,39 If the patient is on warfarin, we want the international normalized ratio to be in the therapeutic range when we perform atrial fibrillation ablation, and the patient takes his or her usual dose on the day of the procedure. If taking a direct oral anticoagulant, patients typically skip a dose the day before ablation and again on the morning of the procedure, and resume taking it immediately afterward while in the anesthesia recovery room.

During the procedure, we start heparin before transseptal puncture, adjust it to achieve an activated clotting time of 300 to 400 seconds, and keep it in this range as long as there are sheaths or catheters in the left atrium.

After the procedure. The current guidelines²⁴ recommend that oral anticoagulation be continued without interruption for at least 2 months after the procedure, and in most cases indefinitely, depending on age and comorbidities. The decision to stop anticoagulation after 2 months is typically based on the stroke risk as assessed by the CHA₂DS₂-VASc score (www.chadsvasc.org) and not on the success of the ablation procedure.

ANTIARRHYTHMIC DRUGS AFTER THE PROCEDURE

Some patients actually experience more atrial fibrillation in the first weeks to months after the procedure. The mechanism in this setting may be different from that causing the arrhythmia in the first place. The causes of early recurrence of atrial arrhythmias include postablation inflammation, temporary autonomic imbalance, and delay of atrial radio­frequency lesion formation.^40,41 These arrhythmias may completely resolve as the ablation lesions heal and scars mature.

It has been hypothesized that short-term use of antiarrhythmic drugs after atrial fibrillation ablation is effective in preventing arrhythmias because it alters atrial electrophysiologic characteristics induced by the above transient factors. A recent systematic review of 6 clinical trials showed that short-term use of antiarrhythmic drugs reduces the risk of early arrhythmia recurrence but does not reduce recurrence in the long term.⁴²

In terms of outcomes, any arrhythmias that occur in the first 3 months do not necessarily affect long-term success. This is referred to as the “blanking period.” However, generally speaking, it is preferable to maintain sinus rhythm during that time to avoid further anatomic or electrical left atrial adverse remodeling. In many situations, patients continue taking the same antiarrhythmic agent or start on antiarrhythmic therapy in the first few months after ablation.^43,44

The mechanisms of late recurrence of atrial arrhythmias after ablation are thought to be different from those in early recurrence. Late recurrence has been ascribed to incomplete pulmonary vein isolation, recovery of pulmonary vein-left atrium connections, or recovery of any other lines of ablation created in the procedure.^45,46 For late recurrence of atrial arrhythmia, studies and guidelines suggest that repeat ablation may be an option.^24,47

PRACTICAL CONSIDERATIONS FOR PROCEDURAL PLANNING

Before the procedure, some electrophysiologists use cardiac computed tomography or magnetic resonance imaging to evaluate the pulmonary vein anatomy. This helps in planning and in selecting the appropriate tools for the procedure.

The patient is asked to fast on the day of the procedure. The procedure can take 3 to 6 hours, depending on the patient’s anatomy and the operator’s technique and experience. It can be performed with the patient under general anesthesia or conscious sedation. Currently, we use general anesthesia most of the time to maximize patient comfort.

After the procedure, our patients must stay in bed for 4 hours and stay overnight for observation. If no complications arise, they are discharged the next day.

A 64-year-old man with hypertension but  without known structural heart disease presents for a second opinion on management of his atrial fibrillation. The condition was first diagnosed at age 38, when he experienced palpitations and shortness of breath on exertion; at times he also experienced decreased endurance and fatigue without overt palpitations. At first, these episodes occurred about twice a year, and the patient was managed with a beta-blocker for rate control and an oral anticoagulant.

Over the past 10 years, the episodes have become more frequent and longer-lasting and have required frequent cardioversions. He was given flecainide for rhythm control but continued to have frequent episodes, and so about 1 year ago he was switched to amiodarone, which controlled his rhythm better. However, after reading about side effects of amiodarone, he decided to seek a second opinion.

He was evaluated by our team and eventually underwent radiofrequency ablation. During the procedure, he was noted to have diffuse scarring and fibrosis of his left atrium, and afterward he continued to require antiarrhythmic drugs to maintain sinus rhythm.

Should he have been referred sooner? What factors should primary care physicians consider when referring a patient with atrial fibrillation for ablation?

THE EPIDEMIC OF ATRIAL FIBRILLATION

Atrial fibrillation is a large and growing public health problem. In 2010, it was estimated to affect 2.7 to 6.1 million people in the United States, and with the rapid aging of our population, its prevalence is expected to rise to between 5.6 and 12 million by 2050.^1–3 It is associated with significant morbidity, poor quality of life, and increased risk of death, heart failure, stroke, and cognitive impairment.

The number of new cases per year has increased over the years despite research and preventive measures, which may reflect aging of the population and increased survival rates in patients with cardiovascular or comorbid conditions.^1,4

Thus, atrial fibrillation is one of the most common cardiovascular conditions encountered by primary care physicians and cardiologists, putting them at the forefront of its management. Proper treatment in its early stages and referral to a specialist for advanced management may alter its natural history and improve clinical outcomes.

HOW DOES ATRIAL FIBRILLATION ARISE AND PERSIST?

Much is still unknown about the pathogenesis of atrial fibrillation, but considerable progress has been made in the past few decades, opening the door for clinical ablative strategies.

Multiple wavelet hypothesis

Until the late 1980s, the most widely accepted conceptual mechanism of atrial fibrillation was the multiple wavelet hypothesis developed by Moe et al.⁵ According to this hypothesis, atrial fibrillation begins with multiple independent wavelets occurring simultaneously and spreading randomly throughout both atria, and it persists if there are a minimum number of coexisting wavelets, increased atrial mass, and heterogeneous conduction delays across the atrial tissue.

The surgical maze procedure, in which a series of incisions arranged in a maze-like pattern is created in the left atrium, was predicated on this model. The theory was that these surgical lesions would compartmentalize the atria into discrete electrical segments and thereby reduce  the number of circulating random wavelets.^6,7

However, experimental and clinical studies suggest that although randomly propagating wavelets can contribute to maintaining atrial fibrillation, focal triggers are noted in most cases.

Focal triggers

In 1997, Jaïs et al⁸ observed that atrial fibrillation is often triggered by a rapidly firing ectopic focus and that ablation of that focus can eliminate it. These ectopic foci are often found at or near the ostia of the pulmonary veins or near the superior vena cava.^8,9 It is now well established that ectopic foci in the pulmonary veins are crucial triggers that initiate atrial fibrillation.

Trigger-and-substrate theory

The substrate for maintaining atrial fibrillation consists of an abnormal left atrium with heterogeneous fibrosis (scarring) and conduction delays. Any heart disease that increases left atrial pressure could lead to atrial dilation and remodeling, which could be substrates for atrial fibrillation. Extensive atrial remodeling and scarring are associated with progression and persistence of atrial fibrillation and make rhythm control more challenging.

Atrial fibrillation begets atrial fibrillation

As shown in the case above, over time, paroxysmal atrial fibrillation often progresses to persistent and long-standing atrial fibrillation if not aggressively managed initially.

In 1972, Davies and Pomerance¹⁰ performed 100 autopsies and found that the people who had had atrial fibrillation for longer than 1 month had lost muscle mass in the sinus node and internodal tract, and their atria were dilated. The study introduced the concept that atrial fibrillation itself causes pathologic changes in the atrium.

Wijffels et al,¹¹ in an experiment in goats, showed that atrial fibrillation produced by rapid bursts of atrial pacing was initially paroxysmal. However, as they continued to induce atrial fibrillation over and over again, it lasted progressively longer until it would persist for more than 24 hours. Thus, in a relatively short time, the atria went from supporting paroxysmal fibrillation to supporting persistent fibrillation.

Atrial fibrillation leads to electrophysiologic and anatomic remodeling in the atrium, which leads to a shorter action potential duration and a shorter refractory period. This in turn makes it easier for atrial fibrillation to persist.¹²

Because atrial fibrillation tends to progress, intervening early may improve its outcomes. Early ablation has been shown to improve the chances of staying in sinus rhythm in both paroxysmal and persistent atrial fibrillation.^13–15

The goal of ablation is to prevent atrial fibrillation by eliminating the trigger that initiates it, altering the arrhythmogenic substrate, or both.

Pulmonary vein isolation

The most common ablation strategy is to electrically isolate the pulmonary veins by creating circumferential lesions around their antra. This creates a nonconducting rim of scar tissue, electrically disconnecting the pulmonary veins from the atrium.

Ablation outside of the pulmonary veins

Because recurrence rates are high in patients with persistent atrial fibrillation who undergo pulmonary vein ablation alone, the search continues for adjunctive strategies to improve outcomes. Although these strategies have a sound rationale based on experimental data and anecdotal evidence in humans, they have not yet been convincingly shown to be helpful in large clinical studies. Nonetheless, it is possible that more extensive substrate ablation—atrial “debulking”—could improve outcomes by reducing the amount of tissue that can fibrillate.

Linear ablation. Creating lines of ablation (as in the maze procedure) isolates different segments of the left atrium. Often, these lines are created along the roof of the left atrium between the right and left upper pulmonary veins and from the mitral valve to the left inferior pulmonary vein. The benefit of linear ablation has not been proven, and gaps in such lines may introduce atrial flutter.

Triggers not in the pulmonary veins. Common sites of nonpulmonary vein triggers include the posterior wall of the left atrium, the superior vena cava, the coronary sinus, and along the ligament of Marshall. Provocative maneuvers such as isoproterenol infusion can help find those triggers, which can then be ablated. A limitation is that there is no protocol proven to reproducibly elicit triggers.

Complex fractionated atrial electrograms are areas in the atrium with highly fractionated, low voltage potentials. They may be critical sites of substrate for atrial fibrillation, and many electrophysiologists target them in patients with persistent atrial fibrillation. But despite initial enthusiasm, doing so has not resulted in better outcomes in persistent atrial fibrillation.

Rotors. Animal studies have shown that atrial fibrillation can be triggered or maintained by localized sources of organized reentrant circuits (rotors) or focal impulses. Recent studies have shown that these electrical rotors and focal sources could potentially be mapped and ablated in humans. But positive results in initial reports have not been reproduced, and this remains an area of controversy.

Our practice. We isolate the pulmonary veins with antral ablations, ablate the posterior wall, and extend the ablation toward the septum and inferior to the right pulmonary veins, with good long-term outcomes.¹⁴ The rationale behind ablating the posterior wall is that it shares embryologic origins with the pulmonary veins and may be a common source of triggers in atrial fibrillation.

We do not routinely create empiric ablation lines in the left or right atrium unless the patient has atrial flutter. Empiric ablation lines have not been convincingly shown to provide additional benefit compared with our extensive ablation approach, which involves the posterior wall. Empiric ablation of the appendage or coronary sinus is typically reserved for repeat ablation in patients with recurrent persistent atrial fibrillation.

RATIONALE FOR TREATING ATRIAL FIBRILLATION WITH ABLATION

To control symptoms

At this time, the primary aim of atrial fibrillation ablation is to reduce symptoms and improve quality of life. In theory, ablation could also decrease the risk of stroke, heart failure, and death. However, these outcomes have not been systematically evaluated in any large randomized controlled trial.

To control rhythm and improve survival

Randomized controlled trials of rhythm vs rate control of atrial fibrillation^16–18 have failed to demonstrate that restoring sinus rhythm is associated with better survival. All of these trials used antiarrhythmic drugs for rhythm control. However, nonrandomized studies^19,20 showed that maintaining sinus rhythm is associated with a significant reduction in mortality rates, whereas the use of antiarrhythmic drugs increased mortality risk.

This suggests that the beneficial effect of restoring sinus rhythm may be offset by adverse effects of antiarrhythmic drugs, and if rhythm control could be achieved by a method other than antiarrhythmic drug therapy, it may be superior to rate control. On the other hand, these data may be affected by residual confounding. This topic deserves further research, but maintaining sinus rhythm is typically preferred whenever possible.

Discontinuing anticoagulation is not a goal at this time

Retrospective studies have reported a low risk of stroke in patients who discontinue anticoagulation several months after undergoing atrial fibrillation ablation.^21–23 However, atrial fibrillation can recur, and risk of stroke increases with age.

Therefore, guidelines²⁴ still recommend continuing anticoagulation after ablation. Generally, we do not offer ablation with a goal of discontinuing anticoagulation. That said, stopping anticoagulation may be considered after long-term suppression of paroxysmal atrial fibrillation on a case-by-case basis in patients deemed to be at low risk. Left atrial appendage closure devices may eventually allow concomitant atrial fibrillation ablation and closure of the appendage, so that anticoagulation could then be stopped. This remains a topic of investigation.

Who should be considered for ablation?

There are no absolute age or comorbidity contraindications to ablation. Everyone who has atrial fibrillation deserves, in our opinion, a referral to the electrophysiology clinic.

Atrial fibrillation ablation is most often performed by electrophysiologists using a minimally invasive endovascular approach. The patient can be under either moderate sedation or general anesthesia; we prefer general anesthesia for patient comfort, safety, and efficacy.

We use an electrogram-based technique to target and eliminate electrical potentials and ensure continuity of ablation sets, with additional guidance by 3-dimensional cardiac mapping systems and intracardiac echocardiography. We also use contact force-sensing catheters to ensure catheter-tissue contact during ablation and to avoid excessive contact, which may enhance the safety of the procedure.

Energy: Hot or cold

Two types of energy can be used for ablation:

Radiofrequency energy (low voltage, high frequency—30 kHz to 1.5 mHz) is delivered to the endocardial surface via a point-source catheter. The radiofrequency energy produces controlled, focal thermal ablation.

In a randomized trial,²⁵ these ablation technologies were shown to be equivalent for preventing recurrences of atrial fibrillation. We use both in our practice. The choice depends primarily on the planned ablation set, given that balloon cryoablation can achieve antral isolation of the pulmonary veins but allows little or no substrate modification.

Improved ablation technology

Contact force-sensing catheters. Radio­frequency ablation catheters are now equipped with a pressure sensor at the tip that measures how hard the catheter is pressing on the heart wall.^26,27 In our experience, this has improved the outcomes of ablation procedures, primarily in persistent atrial fibrillation.²⁸

Complications of ablation

Although catheter ablation for atrial fibrillation is safe, it is still one of the most complex electrophysiologic procedures. Improvements in technology and techniques and accumulated experience over the past 15 years have made ablation safer, especially in tertiary care centers. But adverse outcomes are more frequent in low-volume centers.²⁹

Minor procedural complications include pericarditis, complications at the site of vascular access, and anesthesia-related complications. While they do not affect the long-term outcome for the patient, they may increase hospital length of stay and cause temporary inconvenience.

Major complications include cardiac perforation and tamponade, periprocedural stroke, pulmonary vein stenosis, atrioesophageal fistula, phrenic nerve paralysis, major bleeding, myocardial infarction, and death. In a worldwide survey published in 2005, when atrial fibrillation ablation was still novel, the rate of major complications was 6%.³⁰ By 2010, this had declined to 4.5%,³¹ and the rates of major complications may be significantly lower in more experienced centers.²⁹ In our practice, in 2015, the rate of major complications was 1.3% (unpublished data).

Outcomes of catheter ablation

Clinical outcomes depend on many factors including the type of atrial fibrillation (paroxysmal vs nonparoxysmal), overall health of the atria (atrial size and scarring), patient age and comorbidities, and most importantly, the center’s and operator’s experience.

In randomized controlled trials comparing ablation and antiarrhythmic drug therapy, the efficacy of ablation in maintaining sinus rhythm has been in the range of 66% to 86% vs 16% to 22% for drug therapy,^32,33 but these trials have been predominantly in middle-aged white men with paroxysmal atrial fibrillation. These trials also showed that catheter ablation reduced symptoms and improved quality of life. Ablation is less effective in persistent than in paroxysmal atrial fibrillation.³⁴

In a long-term study from our group,¹⁴ 660 (79.4%) of 831 patients who underwent ablation in 2005 were arrhythmia-free and not on antiarrhythmic drug therapy after a total of 1,019 ablations (an average of 1.2 ablations per patient) at a median of 55 months; 125 patients (15%, 41 with more than 1 ablation) continued to have atrial arrhythmia, controlled with drugs in 87 patients (69.6%). Only 38 patients (4.6%) continued to have drug-resistant atrial fibrillation and were treated with rate control with negative dromotropic agents.

Recent evidence

The largest randomized controlled trial of catheter ablation vs drug therapy for atrial fibrillation (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation [CABANA]) was completed recently, and the results were presented at a national meeting, although they have not yet been published in a peer-reviewed journal.³⁵

A total of 2,204 patients with atrial fibrillation (42.4% paroxysmal, 47.3% persistent, and 10.3% long-standing persistent) were randomized to either ablation or drug therapy. Median follow-up was 4 years. The crossover rate was high—9.2% of those randomized to ablation did not undergo it, and 27.5% of those randomized to drug therapy underwent ablation.

The incidence of the primary end point (a composite of death, disabling stroke, serious bleeding, and cardiac arrest) was not significantly different between the 2 groups in the intention-to-treat analysis; however, given the high crossover rates, the as-treated and per-protocol analyses become important, and as-treated and per-protocol analyses revealed a significant benefit of ablation compared with drug therapy. The hazard ratio (HR) for the primary composite outcome was 0.67 (P = .006) on as-treated analysis and 0.73 (P = .05) on per-protocol analysis. The HR for all-cause mortality was 0.60 (P = .005) on as-treated analysis.

PERIPROCEDURAL CONSIDERATIONS

Periprocedural anticoagulation

The risk of thromboembolism is increased during, immediately following, and for several weeks to months after atrial fibrillation ablation.^36,37

During the procedure, the risk is related to transseptal sheath placement, electrode catheters in the left atrium, and char formation on ablation catheters. These risks are mitigated with proper and careful sheath and catheter manipulation, maintenance of bubble-free irrigation through lines and sheaths, use of irrigated catheters, and initiation of heparin before transseptal access. Heparin is also infused during the procedure, with close monitoring of activated clotting time.

Postprocedurally, the transiently increased clotting risk could be due to damaged endothelium from the ablation itself and stunning of atrial tissue, which results in impaired contraction. Damaged endothelium improves as the tissue heals, and the stunning resolves by electrical reverse remodeling with sinus rhythm maintenance.

In view of these risks, the referring physician and electrophysiologist must pay careful attention to anticoagulation before and after ablation.

Before the procedure. It is safe to continue anticoagulation uninterrupted through the procedure.^38,39 If the patient is on warfarin, we want the international normalized ratio to be in the therapeutic range when we perform atrial fibrillation ablation, and the patient takes his or her usual dose on the day of the procedure. If taking a direct oral anticoagulant, patients typically skip a dose the day before ablation and again on the morning of the procedure, and resume taking it immediately afterward while in the anesthesia recovery room.

During the procedure, we start heparin before transseptal puncture, adjust it to achieve an activated clotting time of 300 to 400 seconds, and keep it in this range as long as there are sheaths or catheters in the left atrium.

After the procedure. The current guidelines²⁴ recommend that oral anticoagulation be continued without interruption for at least 2 months after the procedure, and in most cases indefinitely, depending on age and comorbidities. The decision to stop anticoagulation after 2 months is typically based on the stroke risk as assessed by the CHA₂DS₂-VASc score (www.chadsvasc.org) and not on the success of the ablation procedure.

ANTIARRHYTHMIC DRUGS AFTER THE PROCEDURE

Some patients actually experience more atrial fibrillation in the first weeks to months after the procedure. The mechanism in this setting may be different from that causing the arrhythmia in the first place. The causes of early recurrence of atrial arrhythmias include postablation inflammation, temporary autonomic imbalance, and delay of atrial radio­frequency lesion formation.^40,41 These arrhythmias may completely resolve as the ablation lesions heal and scars mature.

It has been hypothesized that short-term use of antiarrhythmic drugs after atrial fibrillation ablation is effective in preventing arrhythmias because it alters atrial electrophysiologic characteristics induced by the above transient factors. A recent systematic review of 6 clinical trials showed that short-term use of antiarrhythmic drugs reduces the risk of early arrhythmia recurrence but does not reduce recurrence in the long term.⁴²

In terms of outcomes, any arrhythmias that occur in the first 3 months do not necessarily affect long-term success. This is referred to as the “blanking period.” However, generally speaking, it is preferable to maintain sinus rhythm during that time to avoid further anatomic or electrical left atrial adverse remodeling. In many situations, patients continue taking the same antiarrhythmic agent or start on antiarrhythmic therapy in the first few months after ablation.^43,44

The mechanisms of late recurrence of atrial arrhythmias after ablation are thought to be different from those in early recurrence. Late recurrence has been ascribed to incomplete pulmonary vein isolation, recovery of pulmonary vein-left atrium connections, or recovery of any other lines of ablation created in the procedure.^45,46 For late recurrence of atrial arrhythmia, studies and guidelines suggest that repeat ablation may be an option.^24,47

PRACTICAL CONSIDERATIONS FOR PROCEDURAL PLANNING

Before the procedure, some electrophysiologists use cardiac computed tomography or magnetic resonance imaging to evaluate the pulmonary vein anatomy. This helps in planning and in selecting the appropriate tools for the procedure.

The patient is asked to fast on the day of the procedure. The procedure can take 3 to 6 hours, depending on the patient’s anatomy and the operator’s technique and experience. It can be performed with the patient under general anesthesia or conscious sedation. Currently, we use general anesthesia most of the time to maximize patient comfort.

After the procedure, our patients must stay in bed for 4 hours and stay overnight for observation. If no complications arise, they are discharged the next day.

A 64-year-old man with hypertension but  without known structural heart disease presents for a second opinion on management of his atrial fibrillation. The condition was first diagnosed at age 38, when he experienced palpitations and shortness of breath on exertion; at times he also experienced decreased endurance and fatigue without overt palpitations. At first, these episodes occurred about twice a year, and the patient was managed with a beta-blocker for rate control and an oral anticoagulant.

Over the past 10 years, the episodes have become more frequent and longer-lasting and have required frequent cardioversions. He was given flecainide for rhythm control but continued to have frequent episodes, and so about 1 year ago he was switched to amiodarone, which controlled his rhythm better. However, after reading about side effects of amiodarone, he decided to seek a second opinion.

He was evaluated by our team and eventually underwent radiofrequency ablation. During the procedure, he was noted to have diffuse scarring and fibrosis of his left atrium, and afterward he continued to require antiarrhythmic drugs to maintain sinus rhythm.

Should he have been referred sooner? What factors should primary care physicians consider when referring a patient with atrial fibrillation for ablation?

THE EPIDEMIC OF ATRIAL FIBRILLATION

Atrial fibrillation is a large and growing public health problem. In 2010, it was estimated to affect 2.7 to 6.1 million people in the United States, and with the rapid aging of our population, its prevalence is expected to rise to between 5.6 and 12 million by 2050.^1–3 It is associated with significant morbidity, poor quality of life, and increased risk of death, heart failure, stroke, and cognitive impairment.

The number of new cases per year has increased over the years despite research and preventive measures, which may reflect aging of the population and increased survival rates in patients with cardiovascular or comorbid conditions.^1,4

Thus, atrial fibrillation is one of the most common cardiovascular conditions encountered by primary care physicians and cardiologists, putting them at the forefront of its management. Proper treatment in its early stages and referral to a specialist for advanced management may alter its natural history and improve clinical outcomes.

HOW DOES ATRIAL FIBRILLATION ARISE AND PERSIST?

Much is still unknown about the pathogenesis of atrial fibrillation, but considerable progress has been made in the past few decades, opening the door for clinical ablative strategies.

Multiple wavelet hypothesis

Until the late 1980s, the most widely accepted conceptual mechanism of atrial fibrillation was the multiple wavelet hypothesis developed by Moe et al.⁵ According to this hypothesis, atrial fibrillation begins with multiple independent wavelets occurring simultaneously and spreading randomly throughout both atria, and it persists if there are a minimum number of coexisting wavelets, increased atrial mass, and heterogeneous conduction delays across the atrial tissue.

The surgical maze procedure, in which a series of incisions arranged in a maze-like pattern is created in the left atrium, was predicated on this model. The theory was that these surgical lesions would compartmentalize the atria into discrete electrical segments and thereby reduce  the number of circulating random wavelets.^6,7

However, experimental and clinical studies suggest that although randomly propagating wavelets can contribute to maintaining atrial fibrillation, focal triggers are noted in most cases.

Focal triggers

In 1997, Jaïs et al⁸ observed that atrial fibrillation is often triggered by a rapidly firing ectopic focus and that ablation of that focus can eliminate it. These ectopic foci are often found at or near the ostia of the pulmonary veins or near the superior vena cava.^8,9 It is now well established that ectopic foci in the pulmonary veins are crucial triggers that initiate atrial fibrillation.

Trigger-and-substrate theory

The substrate for maintaining atrial fibrillation consists of an abnormal left atrium with heterogeneous fibrosis (scarring) and conduction delays. Any heart disease that increases left atrial pressure could lead to atrial dilation and remodeling, which could be substrates for atrial fibrillation. Extensive atrial remodeling and scarring are associated with progression and persistence of atrial fibrillation and make rhythm control more challenging.

Atrial fibrillation begets atrial fibrillation

As shown in the case above, over time, paroxysmal atrial fibrillation often progresses to persistent and long-standing atrial fibrillation if not aggressively managed initially.

In 1972, Davies and Pomerance¹⁰ performed 100 autopsies and found that the people who had had atrial fibrillation for longer than 1 month had lost muscle mass in the sinus node and internodal tract, and their atria were dilated. The study introduced the concept that atrial fibrillation itself causes pathologic changes in the atrium.

Wijffels et al,¹¹ in an experiment in goats, showed that atrial fibrillation produced by rapid bursts of atrial pacing was initially paroxysmal. However, as they continued to induce atrial fibrillation over and over again, it lasted progressively longer until it would persist for more than 24 hours. Thus, in a relatively short time, the atria went from supporting paroxysmal fibrillation to supporting persistent fibrillation.

Atrial fibrillation leads to electrophysiologic and anatomic remodeling in the atrium, which leads to a shorter action potential duration and a shorter refractory period. This in turn makes it easier for atrial fibrillation to persist.¹²

Because atrial fibrillation tends to progress, intervening early may improve its outcomes. Early ablation has been shown to improve the chances of staying in sinus rhythm in both paroxysmal and persistent atrial fibrillation.^13–15

The goal of ablation is to prevent atrial fibrillation by eliminating the trigger that initiates it, altering the arrhythmogenic substrate, or both.

Pulmonary vein isolation

The most common ablation strategy is to electrically isolate the pulmonary veins by creating circumferential lesions around their antra. This creates a nonconducting rim of scar tissue, electrically disconnecting the pulmonary veins from the atrium.

Ablation outside of the pulmonary veins

Because recurrence rates are high in patients with persistent atrial fibrillation who undergo pulmonary vein ablation alone, the search continues for adjunctive strategies to improve outcomes. Although these strategies have a sound rationale based on experimental data and anecdotal evidence in humans, they have not yet been convincingly shown to be helpful in large clinical studies. Nonetheless, it is possible that more extensive substrate ablation—atrial “debulking”—could improve outcomes by reducing the amount of tissue that can fibrillate.

Linear ablation. Creating lines of ablation (as in the maze procedure) isolates different segments of the left atrium. Often, these lines are created along the roof of the left atrium between the right and left upper pulmonary veins and from the mitral valve to the left inferior pulmonary vein. The benefit of linear ablation has not been proven, and gaps in such lines may introduce atrial flutter.

Triggers not in the pulmonary veins. Common sites of nonpulmonary vein triggers include the posterior wall of the left atrium, the superior vena cava, the coronary sinus, and along the ligament of Marshall. Provocative maneuvers such as isoproterenol infusion can help find those triggers, which can then be ablated. A limitation is that there is no protocol proven to reproducibly elicit triggers.

Complex fractionated atrial electrograms are areas in the atrium with highly fractionated, low voltage potentials. They may be critical sites of substrate for atrial fibrillation, and many electrophysiologists target them in patients with persistent atrial fibrillation. But despite initial enthusiasm, doing so has not resulted in better outcomes in persistent atrial fibrillation.

Rotors. Animal studies have shown that atrial fibrillation can be triggered or maintained by localized sources of organized reentrant circuits (rotors) or focal impulses. Recent studies have shown that these electrical rotors and focal sources could potentially be mapped and ablated in humans. But positive results in initial reports have not been reproduced, and this remains an area of controversy.

Our practice. We isolate the pulmonary veins with antral ablations, ablate the posterior wall, and extend the ablation toward the septum and inferior to the right pulmonary veins, with good long-term outcomes.¹⁴ The rationale behind ablating the posterior wall is that it shares embryologic origins with the pulmonary veins and may be a common source of triggers in atrial fibrillation.

We do not routinely create empiric ablation lines in the left or right atrium unless the patient has atrial flutter. Empiric ablation lines have not been convincingly shown to provide additional benefit compared with our extensive ablation approach, which involves the posterior wall. Empiric ablation of the appendage or coronary sinus is typically reserved for repeat ablation in patients with recurrent persistent atrial fibrillation.

RATIONALE FOR TREATING ATRIAL FIBRILLATION WITH ABLATION

To control symptoms

At this time, the primary aim of atrial fibrillation ablation is to reduce symptoms and improve quality of life. In theory, ablation could also decrease the risk of stroke, heart failure, and death. However, these outcomes have not been systematically evaluated in any large randomized controlled trial.

To control rhythm and improve survival

Randomized controlled trials of rhythm vs rate control of atrial fibrillation^16–18 have failed to demonstrate that restoring sinus rhythm is associated with better survival. All of these trials used antiarrhythmic drugs for rhythm control. However, nonrandomized studies^19,20 showed that maintaining sinus rhythm is associated with a significant reduction in mortality rates, whereas the use of antiarrhythmic drugs increased mortality risk.

This suggests that the beneficial effect of restoring sinus rhythm may be offset by adverse effects of antiarrhythmic drugs, and if rhythm control could be achieved by a method other than antiarrhythmic drug therapy, it may be superior to rate control. On the other hand, these data may be affected by residual confounding. This topic deserves further research, but maintaining sinus rhythm is typically preferred whenever possible.

Discontinuing anticoagulation is not a goal at this time

Retrospective studies have reported a low risk of stroke in patients who discontinue anticoagulation several months after undergoing atrial fibrillation ablation.^21–23 However, atrial fibrillation can recur, and risk of stroke increases with age.

Therefore, guidelines²⁴ still recommend continuing anticoagulation after ablation. Generally, we do not offer ablation with a goal of discontinuing anticoagulation. That said, stopping anticoagulation may be considered after long-term suppression of paroxysmal atrial fibrillation on a case-by-case basis in patients deemed to be at low risk. Left atrial appendage closure devices may eventually allow concomitant atrial fibrillation ablation and closure of the appendage, so that anticoagulation could then be stopped. This remains a topic of investigation.

Who should be considered for ablation?

There are no absolute age or comorbidity contraindications to ablation. Everyone who has atrial fibrillation deserves, in our opinion, a referral to the electrophysiology clinic.

Atrial fibrillation ablation is most often performed by electrophysiologists using a minimally invasive endovascular approach. The patient can be under either moderate sedation or general anesthesia; we prefer general anesthesia for patient comfort, safety, and efficacy.

We use an electrogram-based technique to target and eliminate electrical potentials and ensure continuity of ablation sets, with additional guidance by 3-dimensional cardiac mapping systems and intracardiac echocardiography. We also use contact force-sensing catheters to ensure catheter-tissue contact during ablation and to avoid excessive contact, which may enhance the safety of the procedure.

Energy: Hot or cold

Two types of energy can be used for ablation:

Radiofrequency energy (low voltage, high frequency—30 kHz to 1.5 mHz) is delivered to the endocardial surface via a point-source catheter. The radiofrequency energy produces controlled, focal thermal ablation.

In a randomized trial,²⁵ these ablation technologies were shown to be equivalent for preventing recurrences of atrial fibrillation. We use both in our practice. The choice depends primarily on the planned ablation set, given that balloon cryoablation can achieve antral isolation of the pulmonary veins but allows little or no substrate modification.

Improved ablation technology

Contact force-sensing catheters. Radio­frequency ablation catheters are now equipped with a pressure sensor at the tip that measures how hard the catheter is pressing on the heart wall.^26,27 In our experience, this has improved the outcomes of ablation procedures, primarily in persistent atrial fibrillation.²⁸

Complications of ablation

Although catheter ablation for atrial fibrillation is safe, it is still one of the most complex electrophysiologic procedures. Improvements in technology and techniques and accumulated experience over the past 15 years have made ablation safer, especially in tertiary care centers. But adverse outcomes are more frequent in low-volume centers.²⁹

Minor procedural complications include pericarditis, complications at the site of vascular access, and anesthesia-related complications. While they do not affect the long-term outcome for the patient, they may increase hospital length of stay and cause temporary inconvenience.

Major complications include cardiac perforation and tamponade, periprocedural stroke, pulmonary vein stenosis, atrioesophageal fistula, phrenic nerve paralysis, major bleeding, myocardial infarction, and death. In a worldwide survey published in 2005, when atrial fibrillation ablation was still novel, the rate of major complications was 6%.³⁰ By 2010, this had declined to 4.5%,³¹ and the rates of major complications may be significantly lower in more experienced centers.²⁹ In our practice, in 2015, the rate of major complications was 1.3% (unpublished data).

Outcomes of catheter ablation

Clinical outcomes depend on many factors including the type of atrial fibrillation (paroxysmal vs nonparoxysmal), overall health of the atria (atrial size and scarring), patient age and comorbidities, and most importantly, the center’s and operator’s experience.

In randomized controlled trials comparing ablation and antiarrhythmic drug therapy, the efficacy of ablation in maintaining sinus rhythm has been in the range of 66% to 86% vs 16% to 22% for drug therapy,^32,33 but these trials have been predominantly in middle-aged white men with paroxysmal atrial fibrillation. These trials also showed that catheter ablation reduced symptoms and improved quality of life. Ablation is less effective in persistent than in paroxysmal atrial fibrillation.³⁴

In a long-term study from our group,¹⁴ 660 (79.4%) of 831 patients who underwent ablation in 2005 were arrhythmia-free and not on antiarrhythmic drug therapy after a total of 1,019 ablations (an average of 1.2 ablations per patient) at a median of 55 months; 125 patients (15%, 41 with more than 1 ablation) continued to have atrial arrhythmia, controlled with drugs in 87 patients (69.6%). Only 38 patients (4.6%) continued to have drug-resistant atrial fibrillation and were treated with rate control with negative dromotropic agents.

Recent evidence

The largest randomized controlled trial of catheter ablation vs drug therapy for atrial fibrillation (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation [CABANA]) was completed recently, and the results were presented at a national meeting, although they have not yet been published in a peer-reviewed journal.³⁵

A total of 2,204 patients with atrial fibrillation (42.4% paroxysmal, 47.3% persistent, and 10.3% long-standing persistent) were randomized to either ablation or drug therapy. Median follow-up was 4 years. The crossover rate was high—9.2% of those randomized to ablation did not undergo it, and 27.5% of those randomized to drug therapy underwent ablation.

The incidence of the primary end point (a composite of death, disabling stroke, serious bleeding, and cardiac arrest) was not significantly different between the 2 groups in the intention-to-treat analysis; however, given the high crossover rates, the as-treated and per-protocol analyses become important, and as-treated and per-protocol analyses revealed a significant benefit of ablation compared with drug therapy. The hazard ratio (HR) for the primary composite outcome was 0.67 (P = .006) on as-treated analysis and 0.73 (P = .05) on per-protocol analysis. The HR for all-cause mortality was 0.60 (P = .005) on as-treated analysis.

PERIPROCEDURAL CONSIDERATIONS

Periprocedural anticoagulation

The risk of thromboembolism is increased during, immediately following, and for several weeks to months after atrial fibrillation ablation.^36,37

During the procedure, the risk is related to transseptal sheath placement, electrode catheters in the left atrium, and char formation on ablation catheters. These risks are mitigated with proper and careful sheath and catheter manipulation, maintenance of bubble-free irrigation through lines and sheaths, use of irrigated catheters, and initiation of heparin before transseptal access. Heparin is also infused during the procedure, with close monitoring of activated clotting time.

Postprocedurally, the transiently increased clotting risk could be due to damaged endothelium from the ablation itself and stunning of atrial tissue, which results in impaired contraction. Damaged endothelium improves as the tissue heals, and the stunning resolves by electrical reverse remodeling with sinus rhythm maintenance.

In view of these risks, the referring physician and electrophysiologist must pay careful attention to anticoagulation before and after ablation.

Before the procedure. It is safe to continue anticoagulation uninterrupted through the procedure.^38,39 If the patient is on warfarin, we want the international normalized ratio to be in the therapeutic range when we perform atrial fibrillation ablation, and the patient takes his or her usual dose on the day of the procedure. If taking a direct oral anticoagulant, patients typically skip a dose the day before ablation and again on the morning of the procedure, and resume taking it immediately afterward while in the anesthesia recovery room.

During the procedure, we start heparin before transseptal puncture, adjust it to achieve an activated clotting time of 300 to 400 seconds, and keep it in this range as long as there are sheaths or catheters in the left atrium.

After the procedure. The current guidelines²⁴ recommend that oral anticoagulation be continued without interruption for at least 2 months after the procedure, and in most cases indefinitely, depending on age and comorbidities. The decision to stop anticoagulation after 2 months is typically based on the stroke risk as assessed by the CHA₂DS₂-VASc score (www.chadsvasc.org) and not on the success of the ablation procedure.

ANTIARRHYTHMIC DRUGS AFTER THE PROCEDURE

Some patients actually experience more atrial fibrillation in the first weeks to months after the procedure. The mechanism in this setting may be different from that causing the arrhythmia in the first place. The causes of early recurrence of atrial arrhythmias include postablation inflammation, temporary autonomic imbalance, and delay of atrial radio­frequency lesion formation.^40,41 These arrhythmias may completely resolve as the ablation lesions heal and scars mature.

It has been hypothesized that short-term use of antiarrhythmic drugs after atrial fibrillation ablation is effective in preventing arrhythmias because it alters atrial electrophysiologic characteristics induced by the above transient factors. A recent systematic review of 6 clinical trials showed that short-term use of antiarrhythmic drugs reduces the risk of early arrhythmia recurrence but does not reduce recurrence in the long term.⁴²

In terms of outcomes, any arrhythmias that occur in the first 3 months do not necessarily affect long-term success. This is referred to as the “blanking period.” However, generally speaking, it is preferable to maintain sinus rhythm during that time to avoid further anatomic or electrical left atrial adverse remodeling. In many situations, patients continue taking the same antiarrhythmic agent or start on antiarrhythmic therapy in the first few months after ablation.^43,44

The mechanisms of late recurrence of atrial arrhythmias after ablation are thought to be different from those in early recurrence. Late recurrence has been ascribed to incomplete pulmonary vein isolation, recovery of pulmonary vein-left atrium connections, or recovery of any other lines of ablation created in the procedure.^45,46 For late recurrence of atrial arrhythmia, studies and guidelines suggest that repeat ablation may be an option.^24,47

PRACTICAL CONSIDERATIONS FOR PROCEDURAL PLANNING

Before the procedure, some electrophysiologists use cardiac computed tomography or magnetic resonance imaging to evaluate the pulmonary vein anatomy. This helps in planning and in selecting the appropriate tools for the procedure.

The patient is asked to fast on the day of the procedure. The procedure can take 3 to 6 hours, depending on the patient’s anatomy and the operator’s technique and experience. It can be performed with the patient under general anesthesia or conscious sedation. Currently, we use general anesthesia most of the time to maximize patient comfort.

After the procedure, our patients must stay in bed for 4 hours and stay overnight for observation. If no complications arise, they are discharged the next day.