Streptococcus pneumoniae (the “pneumococcus”) causes a variety of clinical syndromes that range from otitis media to bacteremia, meningitis, and pneumonia. Hardest hit are immunocompromised people and those at the extremes of age. Therefore, preventing disease through pneumococcal vaccination is very important in these groups.

This review summarizes the current guidelines from the Advisory Committee on Immunization Practices (ACIP) of the US Centers for Disease Control and Prevention (CDC) for pneumococcal immunization in adults.

STRIKES THE VERY YOUNG, VERY OLD, AND IMMUNOCOMPROMISED

Invasive pneumococcal disease is defined as infection in which S pneumoniae can be found in a normally sterile site such as the cerebrospinal fluid or blood, and it includes bacteremic pneumonia.¹ By far the most common type of pneumococcal disease is pneumonia, followed by bacteremia and meningitis (Figure 1)^2,3; about 25% of patients with pneumococcal pneumonia also have bacteremia.²

Invasive pneumococcal disease most often occurs in children age 2 and younger, adults age 65 and older, and people who are immunocompromised. In 2010, the incidence was 3.8 per 100,000 in people ages 18 to 34 but was 10 times higher in the elderly and those with compromised immunity.¹

Even now that vaccines are available, invasive pneumococcal disease continues to cause 4,000 deaths per year in the United States.¹

TWO INACTIVATED VACCINES

S pneumoniae is a gram-positive coccus with an outer capsule composed of polysaccharides that protect the bacterium from being ingested and killed by host phagocytic cells. Some 91 serotypes of this organism have been identified on the basis of genetic differences in capsular polysaccharide composition.

Currently, two inactivated vaccines are available that elicit antibody responses to the most common pneumococcal serotypes that infect humans.

• PPSV23 (pneumococcal polysaccharide vaccine-23, or Pneumovax 23) contains purified capsular polysaccharides from 23 pneumococcal serotypes.
• PCV13 (pneumococcal conjugate vaccine-13, or Prevnar 13) contains purified capsular polysaccharides from 13 serotypes that are covalently bound to (conjugated with) a carrier protein.

PPSV23 AND PCV13 ARE NOT THE SAME

Apart from the number of serotypes covered, the two vaccines differ in important ways. Both of them elicit a B-cell-mediated immune response, but only PCV13 produces a T-cell-dependent response, which is essential for maturation of the B-cell response and development of immune memory.

PPSV23 generally provides 3 to 5 years of immunity, and repeat doses do not offer additive or “boosted” protection. It is ineffective in children under 2 years of age.

Pneumococcal conjugate vaccine has been available since 2000 for children starting at 2 months of age. Since then it has directly reduced the incidence of invasive pneumococcal disease in children and indirectly in adults. The impact on pneumococcal disease rates in adults has probably been related to reduction in rates of pneumococcal nasopharyngeal carriage in children, another unique benefit of conjugated vaccines.³

In December 2011, the US Food and Drug Administration (FDA) approved PCV13 for adults on the basis of immunologic studies and anticipation that clinical efficacy would be similar to that observed in children.

HOW EFFECTIVE ARE THEY?

The efficacy and safety of PPSV23 and PCV13 have been studied in a variety of patient populations. Though antibody responses to PCV13 were similar to or better than those with PPSV23, no studies of specific correlations between immunologic responses and disease outcomes are available.^4,5

In large studies in healthy adults, both vaccines reduced the incidence of invasive pneumococcal disease. A study in more than 47,000 adults age 65 and older showed a significant reduction in pneumococcal bacteremia (hazard ratio 0.56, 95% confidence interval 0.33–0.93) in those who received PPSV23 compared with those who received placebo.⁶ However, PPSV23 was not effective in preventing nonbacteremic and noninvasive pneumococcal community-acquired pneumonia when all bacterial serotypes were considered.⁶

In a placebo-controlled trial in more than 84,000 people age 65 and older, PCV13 prevented both nonbacteremic and bacteremic community-acquired pneumococcal pneumonia due to serotypes included in the vaccine (relative risk reduction 45%, P < .007) and overall invasive pneumococcal disease due to serotypes included in the vaccine (relative risk reduction 70%, P < .001).⁷

Both vaccines have also demonstrated efficacy in immunocompromised adults. Several studies showed an equivalent or superior antibody response to a seven-valent pneumococcal conjugate vaccine (PCV7, which has been replaced by PCV13) compared with PPSV23 in adults with human immunodeficiency virus (HIV) infection.^8,9 While specific clinical studies of the efficacy of PCV13 among immunocompromised people are not available, a study of vaccination with PCV7 in 496 people in Malawi, of whom 88% were infected with HIV, found that the vaccine was effective in preventing invasive pneumococcal disease (hazard ratio 26%, 95% confidence interval 0.10–0.70).¹⁰

AT-RISK PATIENT POPULATIONS

Since both PPSV23 and PCV13 are approved for use in adults, it is important to understand appropriate indications for their use. The ACIP recommends pneumococcal vaccination in adults at an increased risk of invasive pneumococcal disease: ie, people age 65 and older, at-risk people ages 19 to 64, and people who are immunocompromised or asplenic.

A more robust antibody response has been shown with PCV13 compared to PPSV23 in healthy people.⁵ Of note, when PPSV23 is given before PCV13, there is a diminished immune response to PCV13.^11,12 Therefore, unvaccinated people who will receive both PCV13 and PPSV23 should be given the conjugate vaccine PCV13 first. (See Commonly asked questions.)

ADULTS AGE 65 AND OLDER: ONE DOSE EACH OF PCV13 AND PPSV23

Before September 2014, the ACIP recommended one dose of PPSV23 for adults age 65 and older to prevent invasive pneumococcal disease.¹³ With evidence that PCV13 also produces an antibody response and is clinically effective against pneumococcal pneumonia in older people, the ACIP now recommends that all adults age 65 and older receive one dose of PCV13 and one dose of PPSV23.^{3, 14}

Based on antibody studies, the ACIP recommends giving PCV13 first and PPSV23 12 months after.^11,12 Patients who received PPSV23 at age 65 or older should receive PCV13 at least 1 year after PPSV23 (Figure 2).^3,14 Patients who had previously received one dose of PPSV23 before age 65 who are now age 65 or older should receive one dose of PCV13 at least 1 year after PPSV23 and an additional dose of PPSV23 at least 5 years after the first dose of PPSV23 and at least 1 year after the dose of PCV13.³ Patients who received a dose of PCV13 before age 65 do not need an additional dose after age 65.

The Centers for Medicare and Medicaid Services have updated the reimbursement for pneumococcal vaccines to include both PCV13 and PPSV23. Patients can receive one dose of pneumococcal vaccine followed by a different, second pneumococcal vaccine at least 11 full months after the month in which the first pneumococcal vaccine was administered.¹⁵

AT-RISK PATIENTS AGES 19 TO 64

Before 2012, the ACIP recommended that patients at risk, including immunocompromised patients and those without a spleen, with cerebrospinal fluid leaks, or with cochlear implants, receive only PPSV23 before age 65.¹³ In 2010, 50% of cases of invasive pneumococcal disease in immunocompromised adults were due to serotypes contained in PCV13.¹⁶ Additionally, according to CDC data from 2013, in adults ages 19 to 64 at risk of pneumococcal disease, only 21.2% had received pneumococcal vaccine.¹⁷ With information on epidemiology, safety, and efficacy, as well as expanded FDA approval of PCV13 for adults in 2011, the ACIP updated its guidelines for pneumococcal immunization of adults with immunocompromising conditions in October 2012.¹⁶ The updated guidelines now include giving PCV13 to adults at increased risk of invasive pneumococcal disease.¹⁶

Adults under age 65 at risk of invasive pneumococcal disease can be further divided into those who are immunocompetent with comorbid conditions, and those with cochlear implants or cerebrospinal fluid leak. (Table 1).¹⁶

Patients with cochlear implants or cerebrospinal fluid leaks should receive one dose of PCV13 followed by one dose of PPSV23 8 weeks later. If PPSV23 is given first in this group, PCV13 can be given 1 year later.

Immunocompetent patients with comorbid conditions, including cigarette smoking, chronic heart, liver, or lung disease, asthma, cirrhosis, and diabetes mellitus, should receive one dose of PPSV23 before age 65 (Table 1).¹⁶

IMMUNOCOMPROMISED AND ASPLENIC PATIENTS

Immunocompromised patients at risk for invasive pneumococcal disease include patients with functional or anatomic asplenia or immunocompromising conditions such as HIV infection, chronic renal failure, generalized malignancy, solid organ transplant, iatrogenic immunosuppression (eg, due to corticosteroid therapy), and other immunocompromising conditions.¹⁶ Patients on corticosteroid therapy are considered immunosuppressed if they take 20 mg or more of prednisone daily (or an equivalent corticosteroid dose) for at least 14 days.¹⁶ These immunocompromised patients should receive one dose of PCV13, followed by a PPSV23 dose 8 weeks later and a second PPSV23 dose 5 years after the first.¹⁶

Information from reference 16.

The time between vaccinations is also important. If PCV13 is given first, PPSV23 can be given after at least 8 weeks. If PPSV23 is given first, PCV13 should be given after 12 months. The time between PPSV23 doses is 5 years (Figure 3).¹⁶

ADDRESSING BARRIERS TO PNEUMOCOCCAL VACCINATION

In 2013, only 59.7% of adults age 65 and older and 21.1% of younger, at-risk adults with immunocompromising conditions had received pneumococcal vaccination.¹⁷ Healthcare providers have the opportunity to improve pneumococcal vaccination rates. The National Foundation for Infectious Diseases (www.nfid.org) summarized challenges in vaccinating at-risk patients and recommended strategies to overcome barriers.¹⁸

Challenges include the cost of vaccine coverage, limited time (with competing priorities during office appointments or hospitalizations), patient refusal, and knowledge gaps.

Strategies to overcome barriers include incorporating vaccination into protocols and procedures; educating healthcare providers and patients about pneumococcal disease, vaccines, costs, and reimbursement; engaging nonclinical staff members; and monitoring local vaccination rates. However, the most important factor affecting whether adults are vaccinated is whether the healthcare provider recommends it.

AN OPPORTUNITY TO IMPROVE

In the last 30 years, great strides have been made in recognizing and preventing pneumococcal disease, but challenges remain. Adherence to the new ACIP guidelines for pneumococcal vaccination in immunocompromised, at risk and elderly patients is important in reducing invasive pneumococcal disease.

Healthcare providers have the opportunity to improve pneumococcal vaccination rates at outpatient appointments to decrease the burden of invasive pneumococcal disease in at-risk populations. A comprehensive understanding of the guideline recommendations for pneumococcal vaccination can aid the provider in identifying patients who are eligible for vaccination.

Adult pneumococcal immunization rates are low due to missed opportunities. Healthcare providers can improve these rates by viewing every patient encounter as a chance to provide vaccination.

Streptococcus pneumoniae (the “pneumococcus”) causes a variety of clinical syndromes that range from otitis media to bacteremia, meningitis, and pneumonia. Hardest hit are immunocompromised people and those at the extremes of age. Therefore, preventing disease through pneumococcal vaccination is very important in these groups.

This review summarizes the current guidelines from the Advisory Committee on Immunization Practices (ACIP) of the US Centers for Disease Control and Prevention (CDC) for pneumococcal immunization in adults.

STRIKES THE VERY YOUNG, VERY OLD, AND IMMUNOCOMPROMISED

Invasive pneumococcal disease is defined as infection in which S pneumoniae can be found in a normally sterile site such as the cerebrospinal fluid or blood, and it includes bacteremic pneumonia.¹ By far the most common type of pneumococcal disease is pneumonia, followed by bacteremia and meningitis (Figure 1)^2,3; about 25% of patients with pneumococcal pneumonia also have bacteremia.²

Invasive pneumococcal disease most often occurs in children age 2 and younger, adults age 65 and older, and people who are immunocompromised. In 2010, the incidence was 3.8 per 100,000 in people ages 18 to 34 but was 10 times higher in the elderly and those with compromised immunity.¹

Even now that vaccines are available, invasive pneumococcal disease continues to cause 4,000 deaths per year in the United States.¹

TWO INACTIVATED VACCINES

S pneumoniae is a gram-positive coccus with an outer capsule composed of polysaccharides that protect the bacterium from being ingested and killed by host phagocytic cells. Some 91 serotypes of this organism have been identified on the basis of genetic differences in capsular polysaccharide composition.

Currently, two inactivated vaccines are available that elicit antibody responses to the most common pneumococcal serotypes that infect humans.

• PPSV23 (pneumococcal polysaccharide vaccine-23, or Pneumovax 23) contains purified capsular polysaccharides from 23 pneumococcal serotypes.
• PCV13 (pneumococcal conjugate vaccine-13, or Prevnar 13) contains purified capsular polysaccharides from 13 serotypes that are covalently bound to (conjugated with) a carrier protein.

PPSV23 AND PCV13 ARE NOT THE SAME

Apart from the number of serotypes covered, the two vaccines differ in important ways. Both of them elicit a B-cell-mediated immune response, but only PCV13 produces a T-cell-dependent response, which is essential for maturation of the B-cell response and development of immune memory.

PPSV23 generally provides 3 to 5 years of immunity, and repeat doses do not offer additive or “boosted” protection. It is ineffective in children under 2 years of age.

Pneumococcal conjugate vaccine has been available since 2000 for children starting at 2 months of age. Since then it has directly reduced the incidence of invasive pneumococcal disease in children and indirectly in adults. The impact on pneumococcal disease rates in adults has probably been related to reduction in rates of pneumococcal nasopharyngeal carriage in children, another unique benefit of conjugated vaccines.³

In December 2011, the US Food and Drug Administration (FDA) approved PCV13 for adults on the basis of immunologic studies and anticipation that clinical efficacy would be similar to that observed in children.

HOW EFFECTIVE ARE THEY?

The efficacy and safety of PPSV23 and PCV13 have been studied in a variety of patient populations. Though antibody responses to PCV13 were similar to or better than those with PPSV23, no studies of specific correlations between immunologic responses and disease outcomes are available.^4,5

In large studies in healthy adults, both vaccines reduced the incidence of invasive pneumococcal disease. A study in more than 47,000 adults age 65 and older showed a significant reduction in pneumococcal bacteremia (hazard ratio 0.56, 95% confidence interval 0.33–0.93) in those who received PPSV23 compared with those who received placebo.⁶ However, PPSV23 was not effective in preventing nonbacteremic and noninvasive pneumococcal community-acquired pneumonia when all bacterial serotypes were considered.⁶

In a placebo-controlled trial in more than 84,000 people age 65 and older, PCV13 prevented both nonbacteremic and bacteremic community-acquired pneumococcal pneumonia due to serotypes included in the vaccine (relative risk reduction 45%, P < .007) and overall invasive pneumococcal disease due to serotypes included in the vaccine (relative risk reduction 70%, P < .001).⁷

Both vaccines have also demonstrated efficacy in immunocompromised adults. Several studies showed an equivalent or superior antibody response to a seven-valent pneumococcal conjugate vaccine (PCV7, which has been replaced by PCV13) compared with PPSV23 in adults with human immunodeficiency virus (HIV) infection.^8,9 While specific clinical studies of the efficacy of PCV13 among immunocompromised people are not available, a study of vaccination with PCV7 in 496 people in Malawi, of whom 88% were infected with HIV, found that the vaccine was effective in preventing invasive pneumococcal disease (hazard ratio 26%, 95% confidence interval 0.10–0.70).¹⁰

AT-RISK PATIENT POPULATIONS

Since both PPSV23 and PCV13 are approved for use in adults, it is important to understand appropriate indications for their use. The ACIP recommends pneumococcal vaccination in adults at an increased risk of invasive pneumococcal disease: ie, people age 65 and older, at-risk people ages 19 to 64, and people who are immunocompromised or asplenic.

A more robust antibody response has been shown with PCV13 compared to PPSV23 in healthy people.⁵ Of note, when PPSV23 is given before PCV13, there is a diminished immune response to PCV13.^11,12 Therefore, unvaccinated people who will receive both PCV13 and PPSV23 should be given the conjugate vaccine PCV13 first. (See Commonly asked questions.)

ADULTS AGE 65 AND OLDER: ONE DOSE EACH OF PCV13 AND PPSV23

Before September 2014, the ACIP recommended one dose of PPSV23 for adults age 65 and older to prevent invasive pneumococcal disease.¹³ With evidence that PCV13 also produces an antibody response and is clinically effective against pneumococcal pneumonia in older people, the ACIP now recommends that all adults age 65 and older receive one dose of PCV13 and one dose of PPSV23.^{3, 14}

Based on antibody studies, the ACIP recommends giving PCV13 first and PPSV23 12 months after.^11,12 Patients who received PPSV23 at age 65 or older should receive PCV13 at least 1 year after PPSV23 (Figure 2).^3,14 Patients who had previously received one dose of PPSV23 before age 65 who are now age 65 or older should receive one dose of PCV13 at least 1 year after PPSV23 and an additional dose of PPSV23 at least 5 years after the first dose of PPSV23 and at least 1 year after the dose of PCV13.³ Patients who received a dose of PCV13 before age 65 do not need an additional dose after age 65.

The Centers for Medicare and Medicaid Services have updated the reimbursement for pneumococcal vaccines to include both PCV13 and PPSV23. Patients can receive one dose of pneumococcal vaccine followed by a different, second pneumococcal vaccine at least 11 full months after the month in which the first pneumococcal vaccine was administered.¹⁵

AT-RISK PATIENTS AGES 19 TO 64

Before 2012, the ACIP recommended that patients at risk, including immunocompromised patients and those without a spleen, with cerebrospinal fluid leaks, or with cochlear implants, receive only PPSV23 before age 65.¹³ In 2010, 50% of cases of invasive pneumococcal disease in immunocompromised adults were due to serotypes contained in PCV13.¹⁶ Additionally, according to CDC data from 2013, in adults ages 19 to 64 at risk of pneumococcal disease, only 21.2% had received pneumococcal vaccine.¹⁷ With information on epidemiology, safety, and efficacy, as well as expanded FDA approval of PCV13 for adults in 2011, the ACIP updated its guidelines for pneumococcal immunization of adults with immunocompromising conditions in October 2012.¹⁶ The updated guidelines now include giving PCV13 to adults at increased risk of invasive pneumococcal disease.¹⁶

Adults under age 65 at risk of invasive pneumococcal disease can be further divided into those who are immunocompetent with comorbid conditions, and those with cochlear implants or cerebrospinal fluid leak. (Table 1).¹⁶

Patients with cochlear implants or cerebrospinal fluid leaks should receive one dose of PCV13 followed by one dose of PPSV23 8 weeks later. If PPSV23 is given first in this group, PCV13 can be given 1 year later.

Immunocompetent patients with comorbid conditions, including cigarette smoking, chronic heart, liver, or lung disease, asthma, cirrhosis, and diabetes mellitus, should receive one dose of PPSV23 before age 65 (Table 1).¹⁶

IMMUNOCOMPROMISED AND ASPLENIC PATIENTS

Immunocompromised patients at risk for invasive pneumococcal disease include patients with functional or anatomic asplenia or immunocompromising conditions such as HIV infection, chronic renal failure, generalized malignancy, solid organ transplant, iatrogenic immunosuppression (eg, due to corticosteroid therapy), and other immunocompromising conditions.¹⁶ Patients on corticosteroid therapy are considered immunosuppressed if they take 20 mg or more of prednisone daily (or an equivalent corticosteroid dose) for at least 14 days.¹⁶ These immunocompromised patients should receive one dose of PCV13, followed by a PPSV23 dose 8 weeks later and a second PPSV23 dose 5 years after the first.¹⁶

Information from reference 16.

The time between vaccinations is also important. If PCV13 is given first, PPSV23 can be given after at least 8 weeks. If PPSV23 is given first, PCV13 should be given after 12 months. The time between PPSV23 doses is 5 years (Figure 3).¹⁶

ADDRESSING BARRIERS TO PNEUMOCOCCAL VACCINATION

In 2013, only 59.7% of adults age 65 and older and 21.1% of younger, at-risk adults with immunocompromising conditions had received pneumococcal vaccination.¹⁷ Healthcare providers have the opportunity to improve pneumococcal vaccination rates. The National Foundation for Infectious Diseases (www.nfid.org) summarized challenges in vaccinating at-risk patients and recommended strategies to overcome barriers.¹⁸

Challenges include the cost of vaccine coverage, limited time (with competing priorities during office appointments or hospitalizations), patient refusal, and knowledge gaps.

Strategies to overcome barriers include incorporating vaccination into protocols and procedures; educating healthcare providers and patients about pneumococcal disease, vaccines, costs, and reimbursement; engaging nonclinical staff members; and monitoring local vaccination rates. However, the most important factor affecting whether adults are vaccinated is whether the healthcare provider recommends it.

AN OPPORTUNITY TO IMPROVE

In the last 30 years, great strides have been made in recognizing and preventing pneumococcal disease, but challenges remain. Adherence to the new ACIP guidelines for pneumococcal vaccination in immunocompromised, at risk and elderly patients is important in reducing invasive pneumococcal disease.

Healthcare providers have the opportunity to improve pneumococcal vaccination rates at outpatient appointments to decrease the burden of invasive pneumococcal disease in at-risk populations. A comprehensive understanding of the guideline recommendations for pneumococcal vaccination can aid the provider in identifying patients who are eligible for vaccination.

Adult pneumococcal immunization rates are low due to missed opportunities. Healthcare providers can improve these rates by viewing every patient encounter as a chance to provide vaccination.

Streptococcus pneumoniae (the “pneumococcus”) causes a variety of clinical syndromes that range from otitis media to bacteremia, meningitis, and pneumonia. Hardest hit are immunocompromised people and those at the extremes of age. Therefore, preventing disease through pneumococcal vaccination is very important in these groups.

This review summarizes the current guidelines from the Advisory Committee on Immunization Practices (ACIP) of the US Centers for Disease Control and Prevention (CDC) for pneumococcal immunization in adults.

STRIKES THE VERY YOUNG, VERY OLD, AND IMMUNOCOMPROMISED

Invasive pneumococcal disease is defined as infection in which S pneumoniae can be found in a normally sterile site such as the cerebrospinal fluid or blood, and it includes bacteremic pneumonia.¹ By far the most common type of pneumococcal disease is pneumonia, followed by bacteremia and meningitis (Figure 1)^2,3; about 25% of patients with pneumococcal pneumonia also have bacteremia.²

Invasive pneumococcal disease most often occurs in children age 2 and younger, adults age 65 and older, and people who are immunocompromised. In 2010, the incidence was 3.8 per 100,000 in people ages 18 to 34 but was 10 times higher in the elderly and those with compromised immunity.¹

Even now that vaccines are available, invasive pneumococcal disease continues to cause 4,000 deaths per year in the United States.¹

TWO INACTIVATED VACCINES

S pneumoniae is a gram-positive coccus with an outer capsule composed of polysaccharides that protect the bacterium from being ingested and killed by host phagocytic cells. Some 91 serotypes of this organism have been identified on the basis of genetic differences in capsular polysaccharide composition.

Currently, two inactivated vaccines are available that elicit antibody responses to the most common pneumococcal serotypes that infect humans.

• PPSV23 (pneumococcal polysaccharide vaccine-23, or Pneumovax 23) contains purified capsular polysaccharides from 23 pneumococcal serotypes.
• PCV13 (pneumococcal conjugate vaccine-13, or Prevnar 13) contains purified capsular polysaccharides from 13 serotypes that are covalently bound to (conjugated with) a carrier protein.

PPSV23 AND PCV13 ARE NOT THE SAME

Apart from the number of serotypes covered, the two vaccines differ in important ways. Both of them elicit a B-cell-mediated immune response, but only PCV13 produces a T-cell-dependent response, which is essential for maturation of the B-cell response and development of immune memory.

PPSV23 generally provides 3 to 5 years of immunity, and repeat doses do not offer additive or “boosted” protection. It is ineffective in children under 2 years of age.

Pneumococcal conjugate vaccine has been available since 2000 for children starting at 2 months of age. Since then it has directly reduced the incidence of invasive pneumococcal disease in children and indirectly in adults. The impact on pneumococcal disease rates in adults has probably been related to reduction in rates of pneumococcal nasopharyngeal carriage in children, another unique benefit of conjugated vaccines.³

In December 2011, the US Food and Drug Administration (FDA) approved PCV13 for adults on the basis of immunologic studies and anticipation that clinical efficacy would be similar to that observed in children.

HOW EFFECTIVE ARE THEY?

The efficacy and safety of PPSV23 and PCV13 have been studied in a variety of patient populations. Though antibody responses to PCV13 were similar to or better than those with PPSV23, no studies of specific correlations between immunologic responses and disease outcomes are available.^4,5

In large studies in healthy adults, both vaccines reduced the incidence of invasive pneumococcal disease. A study in more than 47,000 adults age 65 and older showed a significant reduction in pneumococcal bacteremia (hazard ratio 0.56, 95% confidence interval 0.33–0.93) in those who received PPSV23 compared with those who received placebo.⁶ However, PPSV23 was not effective in preventing nonbacteremic and noninvasive pneumococcal community-acquired pneumonia when all bacterial serotypes were considered.⁶

In a placebo-controlled trial in more than 84,000 people age 65 and older, PCV13 prevented both nonbacteremic and bacteremic community-acquired pneumococcal pneumonia due to serotypes included in the vaccine (relative risk reduction 45%, P < .007) and overall invasive pneumococcal disease due to serotypes included in the vaccine (relative risk reduction 70%, P < .001).⁷

Both vaccines have also demonstrated efficacy in immunocompromised adults. Several studies showed an equivalent or superior antibody response to a seven-valent pneumococcal conjugate vaccine (PCV7, which has been replaced by PCV13) compared with PPSV23 in adults with human immunodeficiency virus (HIV) infection.^8,9 While specific clinical studies of the efficacy of PCV13 among immunocompromised people are not available, a study of vaccination with PCV7 in 496 people in Malawi, of whom 88% were infected with HIV, found that the vaccine was effective in preventing invasive pneumococcal disease (hazard ratio 26%, 95% confidence interval 0.10–0.70).¹⁰

AT-RISK PATIENT POPULATIONS

Since both PPSV23 and PCV13 are approved for use in adults, it is important to understand appropriate indications for their use. The ACIP recommends pneumococcal vaccination in adults at an increased risk of invasive pneumococcal disease: ie, people age 65 and older, at-risk people ages 19 to 64, and people who are immunocompromised or asplenic.

A more robust antibody response has been shown with PCV13 compared to PPSV23 in healthy people.⁵ Of note, when PPSV23 is given before PCV13, there is a diminished immune response to PCV13.^11,12 Therefore, unvaccinated people who will receive both PCV13 and PPSV23 should be given the conjugate vaccine PCV13 first. (See Commonly asked questions.)

ADULTS AGE 65 AND OLDER: ONE DOSE EACH OF PCV13 AND PPSV23

Before September 2014, the ACIP recommended one dose of PPSV23 for adults age 65 and older to prevent invasive pneumococcal disease.¹³ With evidence that PCV13 also produces an antibody response and is clinically effective against pneumococcal pneumonia in older people, the ACIP now recommends that all adults age 65 and older receive one dose of PCV13 and one dose of PPSV23.^{3, 14}

Based on antibody studies, the ACIP recommends giving PCV13 first and PPSV23 12 months after.^11,12 Patients who received PPSV23 at age 65 or older should receive PCV13 at least 1 year after PPSV23 (Figure 2).^3,14 Patients who had previously received one dose of PPSV23 before age 65 who are now age 65 or older should receive one dose of PCV13 at least 1 year after PPSV23 and an additional dose of PPSV23 at least 5 years after the first dose of PPSV23 and at least 1 year after the dose of PCV13.³ Patients who received a dose of PCV13 before age 65 do not need an additional dose after age 65.

The Centers for Medicare and Medicaid Services have updated the reimbursement for pneumococcal vaccines to include both PCV13 and PPSV23. Patients can receive one dose of pneumococcal vaccine followed by a different, second pneumococcal vaccine at least 11 full months after the month in which the first pneumococcal vaccine was administered.¹⁵

AT-RISK PATIENTS AGES 19 TO 64

Before 2012, the ACIP recommended that patients at risk, including immunocompromised patients and those without a spleen, with cerebrospinal fluid leaks, or with cochlear implants, receive only PPSV23 before age 65.¹³ In 2010, 50% of cases of invasive pneumococcal disease in immunocompromised adults were due to serotypes contained in PCV13.¹⁶ Additionally, according to CDC data from 2013, in adults ages 19 to 64 at risk of pneumococcal disease, only 21.2% had received pneumococcal vaccine.¹⁷ With information on epidemiology, safety, and efficacy, as well as expanded FDA approval of PCV13 for adults in 2011, the ACIP updated its guidelines for pneumococcal immunization of adults with immunocompromising conditions in October 2012.¹⁶ The updated guidelines now include giving PCV13 to adults at increased risk of invasive pneumococcal disease.¹⁶

Adults under age 65 at risk of invasive pneumococcal disease can be further divided into those who are immunocompetent with comorbid conditions, and those with cochlear implants or cerebrospinal fluid leak. (Table 1).¹⁶

Patients with cochlear implants or cerebrospinal fluid leaks should receive one dose of PCV13 followed by one dose of PPSV23 8 weeks later. If PPSV23 is given first in this group, PCV13 can be given 1 year later.

Immunocompetent patients with comorbid conditions, including cigarette smoking, chronic heart, liver, or lung disease, asthma, cirrhosis, and diabetes mellitus, should receive one dose of PPSV23 before age 65 (Table 1).¹⁶

IMMUNOCOMPROMISED AND ASPLENIC PATIENTS

Immunocompromised patients at risk for invasive pneumococcal disease include patients with functional or anatomic asplenia or immunocompromising conditions such as HIV infection, chronic renal failure, generalized malignancy, solid organ transplant, iatrogenic immunosuppression (eg, due to corticosteroid therapy), and other immunocompromising conditions.¹⁶ Patients on corticosteroid therapy are considered immunosuppressed if they take 20 mg or more of prednisone daily (or an equivalent corticosteroid dose) for at least 14 days.¹⁶ These immunocompromised patients should receive one dose of PCV13, followed by a PPSV23 dose 8 weeks later and a second PPSV23 dose 5 years after the first.¹⁶

Information from reference 16.

The time between vaccinations is also important. If PCV13 is given first, PPSV23 can be given after at least 8 weeks. If PPSV23 is given first, PCV13 should be given after 12 months. The time between PPSV23 doses is 5 years (Figure 3).¹⁶

ADDRESSING BARRIERS TO PNEUMOCOCCAL VACCINATION

In 2013, only 59.7% of adults age 65 and older and 21.1% of younger, at-risk adults with immunocompromising conditions had received pneumococcal vaccination.¹⁷ Healthcare providers have the opportunity to improve pneumococcal vaccination rates. The National Foundation for Infectious Diseases (www.nfid.org) summarized challenges in vaccinating at-risk patients and recommended strategies to overcome barriers.¹⁸

Challenges include the cost of vaccine coverage, limited time (with competing priorities during office appointments or hospitalizations), patient refusal, and knowledge gaps.

Strategies to overcome barriers include incorporating vaccination into protocols and procedures; educating healthcare providers and patients about pneumococcal disease, vaccines, costs, and reimbursement; engaging nonclinical staff members; and monitoring local vaccination rates. However, the most important factor affecting whether adults are vaccinated is whether the healthcare provider recommends it.

AN OPPORTUNITY TO IMPROVE

In the last 30 years, great strides have been made in recognizing and preventing pneumococcal disease, but challenges remain. Adherence to the new ACIP guidelines for pneumococcal vaccination in immunocompromised, at risk and elderly patients is important in reducing invasive pneumococcal disease.

Healthcare providers have the opportunity to improve pneumococcal vaccination rates at outpatient appointments to decrease the burden of invasive pneumococcal disease in at-risk populations. A comprehensive understanding of the guideline recommendations for pneumococcal vaccination can aid the provider in identifying patients who are eligible for vaccination.

Adult pneumococcal immunization rates are low due to missed opportunities. Healthcare providers can improve these rates by viewing every patient encounter as a chance to provide vaccination.

For some patients with chronic pancreatitis, the best option is to remove the entire pancreas. This does not necessarily doom the patient to diabetes mellitus, because we can harvest the islet cells and reinsert them so that, lodged in the liver, they can continue making insulin. However, this approach is underemphasized in the general medical literature and is likely underutilized in the United States.

Here, we discuss chronic pancreatitis, the indications for and contraindications to this procedure, its outcomes, and the management of patients who undergo it.

CHRONIC PANCREATITIS IS PROGRESSIVE AND PAINFUL

Chronic pancreatitis is a progressive condition characterized by chronic inflammation, irreversible fibrosis, and scarring, resulting in loss of both exocrine and endocrine tissue.

According to a National Institutes of Health database, pancreatitis is the seventh most common digestive disease diagnosis on hospitalization, with annual healthcare costs exceeding $3 billion.¹ Although data are scarce, by some estimates the incidence of chronic pancreatitis ranges from 4 to 14 per 100,000 person-years, and the prevalence ranges from 26.4 to 52 per 100,000.^2–4 Moreover, a meta-analysis⁵ found that acute pancreatitis progresses to chronic pancreatitis in 10% of patients who have a first episode of acute pancreatitis and in 36% who have recurrent episodes.

Historically, alcoholism was and still is the most common cause of chronic pancreatitis, contributing to 60% to 90% of cases in Western countries.^6,7 However, cases due to nonalcoholic causes have been increasing, and in more than one-fourth of patients, no identifiable cause is found.^6,8 Smoking is an independent risk factor.^6,8,9 Some cases can be linked to genetic abnormalities, particularly in children.¹⁰

The clinical manifestations of chronic pancreatitis include exocrine pancreatic insufficiency (leading to malnutrition and steatorrhea), endocrine insufficiency (causing diabetes mellitus), and intractable pain.¹¹ Pain is the predominant clinical symptom early in the disease and is often debilitating and difficult to manage. Uncontrolled pain has a devastating impact on quality of life and may become complicated by narcotic dependence.

The pain of chronic pancreatitis is often multifactorial, with mechanisms that include increased intraductal pressure from obstruction of the pancreatic duct, pancreatic ischemia, neuronal injury, and neuroimmune interactions between neuronal processes and chronic inflammation.¹²

Treatment: Medical and surgical

In chronic pancreatitis, the aim of treatment is to alleviate deficiencies of exocrine and endocrine function and mitigate the pain. Patients who smoke or drink alcohol should be strongly encouraged to quit.

Loss of exocrine function is mainly managed with oral pancreatic enzyme supplements, and diabetes control is often attained with insulin therapy.¹³ Besides helping digestion, pancreatic enzyme therapy in the form of nonenteric tablets may also reduce pain and pancreatitis attacks.¹⁴ The mechanism may be by degrading cholecystokinin-releasing factor in the duodenum, lowering cholecystokinin levels and thereby reducing pain.¹²

Nonnarcotic analgesics are often the first line of therapy for pain management, but many patients need narcotic analgesics. Along with narcotics, adjunctive agents such as tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, and gabapentinoids have been used to treat chronic pancreatitis pain, but with limited success.¹⁵

In patients for whom medical pain management has failed, one can consider another option, such as nerve block, neurolysis, or endoscopic or surgical therapy. Neuromodulators are often prescribed by pain clinics.¹⁵ Percutaneous and endoscopic celiac ganglion blocks can be an option but rarely achieve substantial or permanent pain relief, and the induced transient responses (on average 2 to 4 months) often cannot be repeated.^14–17

Surgical options to relieve pain try to preserve pancreatic function and vary depending on the degree of severity and nature of pancreatic damage. In broad terms, the surgical procedures can be divided into two types:

• Drainage procedures (eg, pseudocyst drainage; minimally invasive endoscopic duct drainage via sphincterotomy or stent placement, or both; pancreaticojejunostomy)
• Resectional procedures (eg, distal pancreatectomy, isolated head resection, pancreaticoduodenectomy, Whipple procedure, total pancreatectomy).

In carefully selected patients, total pancreatectomy can be offered to remove the cause of the pain.¹⁸ This procedure is most often performed in patients who have small-duct disease or a genetic cause or for whom other surgical procedures have failed.¹¹

HISTORY OF THE PROCEDURE

Islet cell transplantation grew out of visionary work by Paul Lacy and David Scharp at the University of Washington at Seattle, whose research focused on isolating and transplanting islet cells in rodent models. The topic has been reviewed by Jahansouz et al.¹⁹ In the 1970s, experiments in pancreatectomized dogs showed that transplanting unpurified pancreatic islet tissue that was dispersed by collagenase digestion into the spleen or portal vein could prevent diabetes.^20,21 In 1974, the first human trials of transplanting islet cells were conducted, using isolated islets from cadaveric donors to treat diabetes.¹⁹

In the past, pancreatectomy was performed to treat painful chronic pancreatitis, but it was viewed as undesirable because removing the gland would inevitably cause insulin-dependent diabetes.²² That changed in 1977 at the University of Minnesota, with the first reported islet cell autotransplant after pancreatectomy. The patient remained pain-free and insulin-independent long-term.²³ This seminal case showed that endocrine function could be preserved by autotransplant of islets prepared from the excised pancreas.²⁴

In 1992, Pyzdrowski et al²⁵ reported that intrahepatic transplant of as few as 265,000 islets was enough to prevent the need for insulin therapy. Since this technique was first described, there have been many advances, and now more than 30 centers worldwide do it.

PRIMARY INDICATION: INTRACTABLE PAIN

Interest has been growing in using total pancreatectomy and islet autotransplant to treat recurrent acute pancreatitis, chronic pancreatitis, and hereditary pancreatitis. The rationale is that removing the offending tissue eliminates pancreatitis, pain, and cancer risk, while preserving and replacing the islet cells prevents the development of brittle diabetes with loss of insulin and glucagon.²⁶

Proposed criteria for total pancreatectomy and islet autotransplant

Bellin et al¹⁴ proposed five criteria for patient selection for this procedure based on imaging studies, pancreatic function tests, and histopathology to detect pancreatic fibrosis. Patients must fulfill all five of the following criteria:

Criterion 1. Diagnosis of chronic pancreatitis, based on chronic abdominal pain lasting more than 6 months with either at least one of the following:

• Pancreatic calcifications on computed tomography
• At least two of the following: four or more of nine criteria on endoscopic ultrasonography described by Catalano et al,²⁷ a compatible ductal or parenchymal abnormality on secretin magnetic resonance cholangiopancreatography; abnormal endoscopic pancreatic function test (peak HCO₂ ≤ 80 mmol/L)
• Histopathologically confirmed diagnosis of chronic pancreatitis
• Compatible clinical history and documented hereditary pancreatitis (PRSS1 gene mutation)

OR

• History of recurrent acute pancreatitis (more than one episode of characteristic pain associated with imaging diagnostic of acute pancreatitis or elevated serum amylase or lipase > 3 times the upper limit of normal).

Criterion 2. At least one of the following:

• Daily narcotic dependence
• Pain resulting in impaired quality of life, which may include inability to attend school, recurrent hospitalizations, or inability to participate in usual age-appropriate activities.

Criterion 3. Complete evaluation with no reversible cause of pancreatitis present or untreated.

Criterion 4. Failure to respond to maximal medical and endoscopic therapy.

Criterion 5. Adequate islet cell function (nondiabetic or C-peptide-positive). Patients with C-peptide-negative diabetes meeting criteria 1 to 4 are candidates for total pancreatectomy alone.

The primary goal is to treat intractable pain and improve quality of life in selected patients with chronic pancreatitis or recurrent acute pancreatitis when endoscopic and prior surgical therapies have failed, and whose impairment due to pain is substantial enough to accept the risk of postoperative insulin-dependent diabetes and lifelong commitment to pancreatic enzyme replacement therapy.^15,26 Patients with a known genetic cause of chronic pancreatitis should be offered special consideration for the procedure, as their disease is unlikely to remit.

CONTRAINDICATIONS

Total pancreatectomy and islet autotransplant should not be performed in patients with active alcoholism, illicit drug use, or untreated or poorly controlled psychiatric illnesses that could impair the patient’s ability to adhere to a complicated postoperative medical regimen.

A poor support network may be a relative contraindication in view of the cost and complexity of diabetic and pancreatic enzyme replacement therapy.^18,26

Islet cell autotransplant is contraindicated in patients with conditions such as C-peptide-negative or type 1 diabetes or a history of portal vein thrombosis, portal hypertension, significant liver disease, high-risk cardiopulmonary disease, or pancreatic cancer (Table 1).²⁶

WHEN TO CONSIDER REFERRAL FOR THIS PROCEDURE

The choice of total pancreatectomy and islet autotransplant vs conventional surgery must be individualized on the basis of each patient’s anatomy, comorbidities, symptom burden, presence or degree of diabetes, and rate of disease progression. The most important factors to consider in determining the need for and timing of this procedure are the patient’s pain, narcotic requirements, and impaired ability to function.²⁶

Sooner rather than later?

An argument can be made for performing this procedure sooner in the course of the disease rather than later when all else has failed. First, prolonged pain can result in central sensitization, in which the threshold for perceiving pain is lowered by damage to the nociceptive neurons from repeated stimulation and inflammation.²⁸

Further, prolonged opioid therapy can lead to opioid-induced hyperalgesia, which may also render patients more sensitive to pain and aggravate their preexisting pain.^26,28

In addition, although operative drainage procedures and partial resections are often considered the gold standard for chronic pancreatitis management, patients who undergo partial pancreatectomy or lateral pancreaticojejunostomy (Puestow procedure) have fewer islet cells left to harvest (about 50% fewer) if they subsequently undergo total pancreatectomy and islet cell autotransplant.^22,26

Therefore, performing this procedure earlier may help the patient avoid chronic pain syndromes and complications of chronic opioid use, including hyperalgesia, and give the best chance of harvesting enough islet cells to prevent or minimize diabetes afterward.¹¹

REMOVING THE PANCREAS, RETURNING THE ISLET CELLS

During this procedure, the blood supply to the pancreas must be preserved until just before its removal to minimize warm ischemia of the islet cells.^18,29 Although there are several surgical variations, a pylorus-preserving total pancreatectomy with duodenectomy is typically performed, usually with splenectomy to preserve perfusion to the body and tail.³⁰

The resected pancreas is taken to the islet isolation laboratory. There, the pancreatic duct is cannulated to fill the organ with a cold collagenase solution, followed by gentle mechanical dispersion using the semiautomated Ricordi method,³¹ which separates the islet cells from the exocrine tissue.³²

The number of islet cells is quantified as islet equivalents; 1 islet equivalent is equal to the volume of an islet with a diameter of 150 µm. Islet equivalents per kilogram of body weight is the unit commonly used to report the graft amount transplanted.³³

After digestion, the islet cells can be purified or partially purified by a gradient separation method using a Cobe 2991 cell processor (Terumo Corporation, Tokyo, Japan),³⁴ or can be transplanted as an unpurified preparation. In islet cell autotransplant for chronic pancreatitis, purification is not always necessary due to the small tissue volume extracted from the often atrophic and fibrotic pancreas.³² The decision to purify depends on the postdigest tissue volume; usually, a tissue volume greater than 0.25 mL/kg body weight is an indication to at least partially purify.^18,35

The final preparation is returned to the operating room, and after heparin is given, the islets are infused into the portal system using a stump of the splenic vein, or alternatively through direct puncture of the portal vein or cannulation of the umbilical vein.^32,36 If the portal vein pressure reaches 25 cm H₂O, the infusion is stopped and the remaining islets can be placed in the peritoneal cavity or elsewhere.¹⁸ Transplant of the islets into the liver or peritoneum allows the islets to secrete insulin into the hepatic portal circulation, which is the route used by the native pancreas.²²

CONTROLLING GLUCOSE DURING AND AFTER THE PROCEDURE

Animal studies have shown that hyperglycemia impairs islet revascularization,³⁷ and glucose toxicity may cause dysfunction and structural lesions of the transplanted islets.^11,38

Therefore, during and after the procedure, most centers maintain euglycemia by an intravenous insulin infusion and subsequently move to subcutaneous insulin when the patient starts eating again. Some centers continue insulin at discharge and gradually taper it over months, even in patients who can possibly achieve euglycemia without it.

OUTCOMES

Many institutions have reported their clinical outcomes in terms of pain relief, islet function, glycemic control, and improvement of quality of life. The largest series have been from the University of Minnesota, Leicester General Hospital, the University of Cincinnati, and the Medical University of South Carolina.

Insulin independence is common but wanes with time

The ability to achieve insulin independence after islet autotransplant appears to be related to the number of islets transplanted, with the best results when more than 2,000 or 3,000 islet equivalents/kg are transplanted.^39,40

Sutherland et al¹⁸ reported that of 409 patients who underwent islet cell autotransplant at the University of Minnesota (the largest series reported to date), 30% were insulin-independent at 3 years, 33% had partial graft function (defined by positive C-peptide), and 82% achieved a mean hemoglobin A_1c of less than 7%. However, in the subset who received more than 5,000 islet equivalents/kg, nearly three-fourths of patients were insulin-independent at 3 years.

The Leicester General Hospital group presented long-term data on 46 patients who underwent total pancreatectomy and islet cell autotransplant. Twelve of the 46 had shown periods of insulin independence for a median of 16.5 months, and 5 remained insulin-free at the time of the publication.⁴¹ Over the 10 years of follow-up, insulin requirements and hemoglobin A_1c increased notably. However, all of the patients tested C-peptide-positive, suggesting long-lasting graft function.

Most recently, the University of Cincinnati group reported long-term data on 116 patients. The insulin independence rate was 38% at 1 year, decreasing to 27% at 5 years. The number of patients with partial graft function was 38% at 1 year and 35% at 5 years.⁴²

Thus, all three institutions confirmed that the autotransplanted islets continue to secrete insulin long-term, but that function decreases over time.

Pancreatectomy reduces pain

Multiple studies have shown that total pancreatectomy reduces pain in patients with chronic pancreatitis. Ahmad et al⁴³ reported a marked reduction in narcotic use (mean morphine equivalents 206 mg/day before surgery, compared with 90 mg after), and a 58% reduction in pain as demonstrated by narcotic independence.

In the University of Minnesota series, 85% of the 409 patients had less pain at 2 years, and 59% were able to stop taking narcotics.¹⁸

The University of Cincinnati group reported a narcotic independence rate of 55% at 1 year, which continued to improve to 73% at 5 years.⁴²

Although the source of pain is removed, pain persists or recurs in 10% to 20% of patients after total pancreatectomy and islet cell autotransplant, showing that the pathogenesis of pain is complex, and some uncertainty exists about it.²⁶

Quality of life

Reports evaluating health-related quality of life after total pancreatectomy and islet autotransplant are limited.

The University of Cincinnati group reported the long-term outcomes of quality of life as measured by the Short Form 36 Health Survey.⁴² Ninety-two percent of patients reported overall improvement in their health at 1 year, and 85% continued to report improved health more than 5 years after the surgery.

In a series of 20 patients, 79% to 90% reported improvements in the seven various domains of the Pain Disability Index. In addition, 60% showed improvement in depression and 70% showed improvement in anxiety. The greatest improvements were in those who had not undergone prior pancreatic surgery, who were younger, and in those with higher levels of preoperative pain.³⁰

Similarly, in a series of 74 patients, the Medical University of South Carolina group reported significant improvement in physical and mental health components of the Short Form 12 Health Survey and an associated decrease in daily narcotic requirements. Moreover, the need to start or increase the dose of insulin after the surgery was not associated with a lower quality of life.⁴⁴

OFF-SITE ISLET CELL ISOLATION

Despite the positive outcomes in terms of pain relief and insulin independence in many patients after total pancreatectomy and islet cell autotransplant, few medical centers have an on-site islet-processing facility. Since the mid-1990s, a few centers have been able to circumvent this limitation by working with off-site islet cell isolation laboratories.^45,46

Whether and when to consider this procedure must be individualized

The University of California, Los Angeles, first reported on a series of nine patients who received autologous islet cells after near-total or total pancreatectomy using a remote islet cell isolation facility, with results comparable to those of other large institutions.⁴⁵

Similarly, the procedure has been performed at Cleveland Clinic since 2007 with the collaboration of an off-site islet cell isolation laboratory at the University of Pittsburgh. A cohort study from this collaboration published in 2015 showed that in 36 patients (mean follow-up 28 months, range 3–26 months), 33% were insulin-independent, with a C-peptide-positive rate of 70%. This is the largest cohort to date from a center utilizing an off-site islet isolation facility.⁴⁷

In view of the positive outcomes at these centers, lack of a local islet-processing facility should no longer be a barrier to total pancreatectomy and islet cell autotransplant.

PATIENT CARE AFTER THE PROCEDURE

A multidisciplinary team is an essential component of the postoperative management of patients who undergo total pancreatectomy and islet cell autotransplant.

For patients who had been receiving narcotics for a long time before surgery or who were receiving frequent doses, an experienced pain management physician should be involved in the patient’s postoperative care.

Because islet function can wane over time, testing for diabetes should be done at least annually for the rest of the patient’s life and should include fasting plasma glucose, hemoglobin A_1c, and C-peptide, along with self-monitored blood glucose.²⁶

All patients who have surgically induced exocrine insufficiency are at risk of malabsorption and fat-soluble vitamin deficiencies.⁴⁸ Hence, lifelong pancreatic enzyme replacement therapy is mandatory. Nutritional monitoring should include assessment of steatorrhea, body composition, and fat-soluble vitamin levels (vitamins A, D, and E) at least every year.²⁶ Patients with chronic pancreatitis are at increased risk for low bone density from malabsorption of vitamin D and calcium; therefore, it is recommended that a dual-energy x-ray absorptiometry bone density scan be obtained.^26,49

Patients who undergo splenectomy as part of their procedure will require appropriate precautions and ongoing vaccinations as recommended by the US Centers for Disease Control and Prevention.^26,50,51

WHAT TO EXPECT FOR THE FUTURE

The National Institute of Diabetes and Digestive and Kidney Diseases has reviewed the potential future research directions for total pancreatectomy and islet autotransplant.¹⁵

The more islet cells transplanted, the better the chance of insulin independence

Patient selection remains challenging despite the availability of criteria¹⁵ and guidelines.²⁶ More research is needed to better assess preoperative beta-cell function and to predict postoperative outcomes. Mixed meal-tolerance testing is adopted by most clinical centers to predict posttransplant beta-cell function. The use of arginine instead of glucagon in a stimulation test for insulin and C-peptide response has been validated and may allow more accurate assessment.^52,53

Another targeted area of research is the advancement of safety and metabolic outcomes. Techniques to minimize warm ischemic time and complications are being evaluated. Islet isolation methods that yield more islets, reduce beta-cell apoptosis, and can isolate islets from glands with malignancy should be further investigated.⁵⁴ Further, enhanced islet infusion methods that achieve lower portal venous pressures and minimize portal vein thrombosis are needed.

Unfortunately, the function of transplanted islet grafts declines over time. This phenomenon is at least partially attributed to the immediate blood-mediated inflammatory response,^55,56 along with islet hypoxia,⁵⁷ leading to islet apoptosis. Research on different strategies is expanding our knowledge in islet engraftment and posttransplant beta-cell apoptosis, with the expectation that the transplanted islet lifespan will increase. Alternative transplant sites with low inflammatory reaction, such as the omental pouch,⁵⁸ muscle,⁵⁹ and bone marrow,⁶⁰ have shown encouraging data. Other approaches, such as adjuvant anti-inflammatory agents and heparinization, have been proposed.¹⁵

Research into complications is also of clinical importance. There is growing attention to hypoglycemia unrelated to exogenous insulin use in posttransplant patients. One hypothesis is that glucagon secretion, a counterregulatory response to hypoglycemia, is defective if the islet cells are transplanted into the liver, and that implanting them into another site may avoid this effect.⁶¹

For some patients with chronic pancreatitis, the best option is to remove the entire pancreas. This does not necessarily doom the patient to diabetes mellitus, because we can harvest the islet cells and reinsert them so that, lodged in the liver, they can continue making insulin. However, this approach is underemphasized in the general medical literature and is likely underutilized in the United States.

Here, we discuss chronic pancreatitis, the indications for and contraindications to this procedure, its outcomes, and the management of patients who undergo it.

CHRONIC PANCREATITIS IS PROGRESSIVE AND PAINFUL

Chronic pancreatitis is a progressive condition characterized by chronic inflammation, irreversible fibrosis, and scarring, resulting in loss of both exocrine and endocrine tissue.

According to a National Institutes of Health database, pancreatitis is the seventh most common digestive disease diagnosis on hospitalization, with annual healthcare costs exceeding $3 billion.¹ Although data are scarce, by some estimates the incidence of chronic pancreatitis ranges from 4 to 14 per 100,000 person-years, and the prevalence ranges from 26.4 to 52 per 100,000.^2–4 Moreover, a meta-analysis⁵ found that acute pancreatitis progresses to chronic pancreatitis in 10% of patients who have a first episode of acute pancreatitis and in 36% who have recurrent episodes.

Historically, alcoholism was and still is the most common cause of chronic pancreatitis, contributing to 60% to 90% of cases in Western countries.^6,7 However, cases due to nonalcoholic causes have been increasing, and in more than one-fourth of patients, no identifiable cause is found.^6,8 Smoking is an independent risk factor.^6,8,9 Some cases can be linked to genetic abnormalities, particularly in children.¹⁰

The clinical manifestations of chronic pancreatitis include exocrine pancreatic insufficiency (leading to malnutrition and steatorrhea), endocrine insufficiency (causing diabetes mellitus), and intractable pain.¹¹ Pain is the predominant clinical symptom early in the disease and is often debilitating and difficult to manage. Uncontrolled pain has a devastating impact on quality of life and may become complicated by narcotic dependence.

The pain of chronic pancreatitis is often multifactorial, with mechanisms that include increased intraductal pressure from obstruction of the pancreatic duct, pancreatic ischemia, neuronal injury, and neuroimmune interactions between neuronal processes and chronic inflammation.¹²

Treatment: Medical and surgical

In chronic pancreatitis, the aim of treatment is to alleviate deficiencies of exocrine and endocrine function and mitigate the pain. Patients who smoke or drink alcohol should be strongly encouraged to quit.

Loss of exocrine function is mainly managed with oral pancreatic enzyme supplements, and diabetes control is often attained with insulin therapy.¹³ Besides helping digestion, pancreatic enzyme therapy in the form of nonenteric tablets may also reduce pain and pancreatitis attacks.¹⁴ The mechanism may be by degrading cholecystokinin-releasing factor in the duodenum, lowering cholecystokinin levels and thereby reducing pain.¹²

Nonnarcotic analgesics are often the first line of therapy for pain management, but many patients need narcotic analgesics. Along with narcotics, adjunctive agents such as tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, and gabapentinoids have been used to treat chronic pancreatitis pain, but with limited success.¹⁵

In patients for whom medical pain management has failed, one can consider another option, such as nerve block, neurolysis, or endoscopic or surgical therapy. Neuromodulators are often prescribed by pain clinics.¹⁵ Percutaneous and endoscopic celiac ganglion blocks can be an option but rarely achieve substantial or permanent pain relief, and the induced transient responses (on average 2 to 4 months) often cannot be repeated.^14–17

Surgical options to relieve pain try to preserve pancreatic function and vary depending on the degree of severity and nature of pancreatic damage. In broad terms, the surgical procedures can be divided into two types:

• Drainage procedures (eg, pseudocyst drainage; minimally invasive endoscopic duct drainage via sphincterotomy or stent placement, or both; pancreaticojejunostomy)
• Resectional procedures (eg, distal pancreatectomy, isolated head resection, pancreaticoduodenectomy, Whipple procedure, total pancreatectomy).

In carefully selected patients, total pancreatectomy can be offered to remove the cause of the pain.¹⁸ This procedure is most often performed in patients who have small-duct disease or a genetic cause or for whom other surgical procedures have failed.¹¹

HISTORY OF THE PROCEDURE

Islet cell transplantation grew out of visionary work by Paul Lacy and David Scharp at the University of Washington at Seattle, whose research focused on isolating and transplanting islet cells in rodent models. The topic has been reviewed by Jahansouz et al.¹⁹ In the 1970s, experiments in pancreatectomized dogs showed that transplanting unpurified pancreatic islet tissue that was dispersed by collagenase digestion into the spleen or portal vein could prevent diabetes.^20,21 In 1974, the first human trials of transplanting islet cells were conducted, using isolated islets from cadaveric donors to treat diabetes.¹⁹

In the past, pancreatectomy was performed to treat painful chronic pancreatitis, but it was viewed as undesirable because removing the gland would inevitably cause insulin-dependent diabetes.²² That changed in 1977 at the University of Minnesota, with the first reported islet cell autotransplant after pancreatectomy. The patient remained pain-free and insulin-independent long-term.²³ This seminal case showed that endocrine function could be preserved by autotransplant of islets prepared from the excised pancreas.²⁴

In 1992, Pyzdrowski et al²⁵ reported that intrahepatic transplant of as few as 265,000 islets was enough to prevent the need for insulin therapy. Since this technique was first described, there have been many advances, and now more than 30 centers worldwide do it.

PRIMARY INDICATION: INTRACTABLE PAIN

Interest has been growing in using total pancreatectomy and islet autotransplant to treat recurrent acute pancreatitis, chronic pancreatitis, and hereditary pancreatitis. The rationale is that removing the offending tissue eliminates pancreatitis, pain, and cancer risk, while preserving and replacing the islet cells prevents the development of brittle diabetes with loss of insulin and glucagon.²⁶

Proposed criteria for total pancreatectomy and islet autotransplant

Bellin et al¹⁴ proposed five criteria for patient selection for this procedure based on imaging studies, pancreatic function tests, and histopathology to detect pancreatic fibrosis. Patients must fulfill all five of the following criteria:

Criterion 1. Diagnosis of chronic pancreatitis, based on chronic abdominal pain lasting more than 6 months with either at least one of the following:

• Pancreatic calcifications on computed tomography
• At least two of the following: four or more of nine criteria on endoscopic ultrasonography described by Catalano et al,²⁷ a compatible ductal or parenchymal abnormality on secretin magnetic resonance cholangiopancreatography; abnormal endoscopic pancreatic function test (peak HCO₂ ≤ 80 mmol/L)
• Histopathologically confirmed diagnosis of chronic pancreatitis
• Compatible clinical history and documented hereditary pancreatitis (PRSS1 gene mutation)

OR

• History of recurrent acute pancreatitis (more than one episode of characteristic pain associated with imaging diagnostic of acute pancreatitis or elevated serum amylase or lipase > 3 times the upper limit of normal).

Criterion 2. At least one of the following:

• Daily narcotic dependence
• Pain resulting in impaired quality of life, which may include inability to attend school, recurrent hospitalizations, or inability to participate in usual age-appropriate activities.

Criterion 3. Complete evaluation with no reversible cause of pancreatitis present or untreated.

Criterion 4. Failure to respond to maximal medical and endoscopic therapy.

Criterion 5. Adequate islet cell function (nondiabetic or C-peptide-positive). Patients with C-peptide-negative diabetes meeting criteria 1 to 4 are candidates for total pancreatectomy alone.

The primary goal is to treat intractable pain and improve quality of life in selected patients with chronic pancreatitis or recurrent acute pancreatitis when endoscopic and prior surgical therapies have failed, and whose impairment due to pain is substantial enough to accept the risk of postoperative insulin-dependent diabetes and lifelong commitment to pancreatic enzyme replacement therapy.^15,26 Patients with a known genetic cause of chronic pancreatitis should be offered special consideration for the procedure, as their disease is unlikely to remit.

CONTRAINDICATIONS

Total pancreatectomy and islet autotransplant should not be performed in patients with active alcoholism, illicit drug use, or untreated or poorly controlled psychiatric illnesses that could impair the patient’s ability to adhere to a complicated postoperative medical regimen.

A poor support network may be a relative contraindication in view of the cost and complexity of diabetic and pancreatic enzyme replacement therapy.^18,26

Islet cell autotransplant is contraindicated in patients with conditions such as C-peptide-negative or type 1 diabetes or a history of portal vein thrombosis, portal hypertension, significant liver disease, high-risk cardiopulmonary disease, or pancreatic cancer (Table 1).²⁶

WHEN TO CONSIDER REFERRAL FOR THIS PROCEDURE

The choice of total pancreatectomy and islet autotransplant vs conventional surgery must be individualized on the basis of each patient’s anatomy, comorbidities, symptom burden, presence or degree of diabetes, and rate of disease progression. The most important factors to consider in determining the need for and timing of this procedure are the patient’s pain, narcotic requirements, and impaired ability to function.²⁶

Sooner rather than later?

An argument can be made for performing this procedure sooner in the course of the disease rather than later when all else has failed. First, prolonged pain can result in central sensitization, in which the threshold for perceiving pain is lowered by damage to the nociceptive neurons from repeated stimulation and inflammation.²⁸

Further, prolonged opioid therapy can lead to opioid-induced hyperalgesia, which may also render patients more sensitive to pain and aggravate their preexisting pain.^26,28

In addition, although operative drainage procedures and partial resections are often considered the gold standard for chronic pancreatitis management, patients who undergo partial pancreatectomy or lateral pancreaticojejunostomy (Puestow procedure) have fewer islet cells left to harvest (about 50% fewer) if they subsequently undergo total pancreatectomy and islet cell autotransplant.^22,26

Therefore, performing this procedure earlier may help the patient avoid chronic pain syndromes and complications of chronic opioid use, including hyperalgesia, and give the best chance of harvesting enough islet cells to prevent or minimize diabetes afterward.¹¹

REMOVING THE PANCREAS, RETURNING THE ISLET CELLS

During this procedure, the blood supply to the pancreas must be preserved until just before its removal to minimize warm ischemia of the islet cells.^18,29 Although there are several surgical variations, a pylorus-preserving total pancreatectomy with duodenectomy is typically performed, usually with splenectomy to preserve perfusion to the body and tail.³⁰

The resected pancreas is taken to the islet isolation laboratory. There, the pancreatic duct is cannulated to fill the organ with a cold collagenase solution, followed by gentle mechanical dispersion using the semiautomated Ricordi method,³¹ which separates the islet cells from the exocrine tissue.³²

The number of islet cells is quantified as islet equivalents; 1 islet equivalent is equal to the volume of an islet with a diameter of 150 µm. Islet equivalents per kilogram of body weight is the unit commonly used to report the graft amount transplanted.³³

After digestion, the islet cells can be purified or partially purified by a gradient separation method using a Cobe 2991 cell processor (Terumo Corporation, Tokyo, Japan),³⁴ or can be transplanted as an unpurified preparation. In islet cell autotransplant for chronic pancreatitis, purification is not always necessary due to the small tissue volume extracted from the often atrophic and fibrotic pancreas.³² The decision to purify depends on the postdigest tissue volume; usually, a tissue volume greater than 0.25 mL/kg body weight is an indication to at least partially purify.^18,35

The final preparation is returned to the operating room, and after heparin is given, the islets are infused into the portal system using a stump of the splenic vein, or alternatively through direct puncture of the portal vein or cannulation of the umbilical vein.^32,36 If the portal vein pressure reaches 25 cm H₂O, the infusion is stopped and the remaining islets can be placed in the peritoneal cavity or elsewhere.¹⁸ Transplant of the islets into the liver or peritoneum allows the islets to secrete insulin into the hepatic portal circulation, which is the route used by the native pancreas.²²

CONTROLLING GLUCOSE DURING AND AFTER THE PROCEDURE

Animal studies have shown that hyperglycemia impairs islet revascularization,³⁷ and glucose toxicity may cause dysfunction and structural lesions of the transplanted islets.^11,38

Therefore, during and after the procedure, most centers maintain euglycemia by an intravenous insulin infusion and subsequently move to subcutaneous insulin when the patient starts eating again. Some centers continue insulin at discharge and gradually taper it over months, even in patients who can possibly achieve euglycemia without it.

OUTCOMES

Many institutions have reported their clinical outcomes in terms of pain relief, islet function, glycemic control, and improvement of quality of life. The largest series have been from the University of Minnesota, Leicester General Hospital, the University of Cincinnati, and the Medical University of South Carolina.

Insulin independence is common but wanes with time

The ability to achieve insulin independence after islet autotransplant appears to be related to the number of islets transplanted, with the best results when more than 2,000 or 3,000 islet equivalents/kg are transplanted.^39,40

Sutherland et al¹⁸ reported that of 409 patients who underwent islet cell autotransplant at the University of Minnesota (the largest series reported to date), 30% were insulin-independent at 3 years, 33% had partial graft function (defined by positive C-peptide), and 82% achieved a mean hemoglobin A_1c of less than 7%. However, in the subset who received more than 5,000 islet equivalents/kg, nearly three-fourths of patients were insulin-independent at 3 years.

The Leicester General Hospital group presented long-term data on 46 patients who underwent total pancreatectomy and islet cell autotransplant. Twelve of the 46 had shown periods of insulin independence for a median of 16.5 months, and 5 remained insulin-free at the time of the publication.⁴¹ Over the 10 years of follow-up, insulin requirements and hemoglobin A_1c increased notably. However, all of the patients tested C-peptide-positive, suggesting long-lasting graft function.

Most recently, the University of Cincinnati group reported long-term data on 116 patients. The insulin independence rate was 38% at 1 year, decreasing to 27% at 5 years. The number of patients with partial graft function was 38% at 1 year and 35% at 5 years.⁴²

Thus, all three institutions confirmed that the autotransplanted islets continue to secrete insulin long-term, but that function decreases over time.

Pancreatectomy reduces pain

Multiple studies have shown that total pancreatectomy reduces pain in patients with chronic pancreatitis. Ahmad et al⁴³ reported a marked reduction in narcotic use (mean morphine equivalents 206 mg/day before surgery, compared with 90 mg after), and a 58% reduction in pain as demonstrated by narcotic independence.

In the University of Minnesota series, 85% of the 409 patients had less pain at 2 years, and 59% were able to stop taking narcotics.¹⁸

The University of Cincinnati group reported a narcotic independence rate of 55% at 1 year, which continued to improve to 73% at 5 years.⁴²

Although the source of pain is removed, pain persists or recurs in 10% to 20% of patients after total pancreatectomy and islet cell autotransplant, showing that the pathogenesis of pain is complex, and some uncertainty exists about it.²⁶

Quality of life

Reports evaluating health-related quality of life after total pancreatectomy and islet autotransplant are limited.

The University of Cincinnati group reported the long-term outcomes of quality of life as measured by the Short Form 36 Health Survey.⁴² Ninety-two percent of patients reported overall improvement in their health at 1 year, and 85% continued to report improved health more than 5 years after the surgery.

In a series of 20 patients, 79% to 90% reported improvements in the seven various domains of the Pain Disability Index. In addition, 60% showed improvement in depression and 70% showed improvement in anxiety. The greatest improvements were in those who had not undergone prior pancreatic surgery, who were younger, and in those with higher levels of preoperative pain.³⁰

Similarly, in a series of 74 patients, the Medical University of South Carolina group reported significant improvement in physical and mental health components of the Short Form 12 Health Survey and an associated decrease in daily narcotic requirements. Moreover, the need to start or increase the dose of insulin after the surgery was not associated with a lower quality of life.⁴⁴

OFF-SITE ISLET CELL ISOLATION

Despite the positive outcomes in terms of pain relief and insulin independence in many patients after total pancreatectomy and islet cell autotransplant, few medical centers have an on-site islet-processing facility. Since the mid-1990s, a few centers have been able to circumvent this limitation by working with off-site islet cell isolation laboratories.^45,46

Whether and when to consider this procedure must be individualized

The University of California, Los Angeles, first reported on a series of nine patients who received autologous islet cells after near-total or total pancreatectomy using a remote islet cell isolation facility, with results comparable to those of other large institutions.⁴⁵

Similarly, the procedure has been performed at Cleveland Clinic since 2007 with the collaboration of an off-site islet cell isolation laboratory at the University of Pittsburgh. A cohort study from this collaboration published in 2015 showed that in 36 patients (mean follow-up 28 months, range 3–26 months), 33% were insulin-independent, with a C-peptide-positive rate of 70%. This is the largest cohort to date from a center utilizing an off-site islet isolation facility.⁴⁷

In view of the positive outcomes at these centers, lack of a local islet-processing facility should no longer be a barrier to total pancreatectomy and islet cell autotransplant.

PATIENT CARE AFTER THE PROCEDURE

A multidisciplinary team is an essential component of the postoperative management of patients who undergo total pancreatectomy and islet cell autotransplant.

For patients who had been receiving narcotics for a long time before surgery or who were receiving frequent doses, an experienced pain management physician should be involved in the patient’s postoperative care.

Because islet function can wane over time, testing for diabetes should be done at least annually for the rest of the patient’s life and should include fasting plasma glucose, hemoglobin A_1c, and C-peptide, along with self-monitored blood glucose.²⁶

All patients who have surgically induced exocrine insufficiency are at risk of malabsorption and fat-soluble vitamin deficiencies.⁴⁸ Hence, lifelong pancreatic enzyme replacement therapy is mandatory. Nutritional monitoring should include assessment of steatorrhea, body composition, and fat-soluble vitamin levels (vitamins A, D, and E) at least every year.²⁶ Patients with chronic pancreatitis are at increased risk for low bone density from malabsorption of vitamin D and calcium; therefore, it is recommended that a dual-energy x-ray absorptiometry bone density scan be obtained.^26,49

Patients who undergo splenectomy as part of their procedure will require appropriate precautions and ongoing vaccinations as recommended by the US Centers for Disease Control and Prevention.^26,50,51

WHAT TO EXPECT FOR THE FUTURE

The National Institute of Diabetes and Digestive and Kidney Diseases has reviewed the potential future research directions for total pancreatectomy and islet autotransplant.¹⁵

The more islet cells transplanted, the better the chance of insulin independence

Patient selection remains challenging despite the availability of criteria¹⁵ and guidelines.²⁶ More research is needed to better assess preoperative beta-cell function and to predict postoperative outcomes. Mixed meal-tolerance testing is adopted by most clinical centers to predict posttransplant beta-cell function. The use of arginine instead of glucagon in a stimulation test for insulin and C-peptide response has been validated and may allow more accurate assessment.^52,53

Another targeted area of research is the advancement of safety and metabolic outcomes. Techniques to minimize warm ischemic time and complications are being evaluated. Islet isolation methods that yield more islets, reduce beta-cell apoptosis, and can isolate islets from glands with malignancy should be further investigated.⁵⁴ Further, enhanced islet infusion methods that achieve lower portal venous pressures and minimize portal vein thrombosis are needed.

Unfortunately, the function of transplanted islet grafts declines over time. This phenomenon is at least partially attributed to the immediate blood-mediated inflammatory response,^55,56 along with islet hypoxia,⁵⁷ leading to islet apoptosis. Research on different strategies is expanding our knowledge in islet engraftment and posttransplant beta-cell apoptosis, with the expectation that the transplanted islet lifespan will increase. Alternative transplant sites with low inflammatory reaction, such as the omental pouch,⁵⁸ muscle,⁵⁹ and bone marrow,⁶⁰ have shown encouraging data. Other approaches, such as adjuvant anti-inflammatory agents and heparinization, have been proposed.¹⁵

Research into complications is also of clinical importance. There is growing attention to hypoglycemia unrelated to exogenous insulin use in posttransplant patients. One hypothesis is that glucagon secretion, a counterregulatory response to hypoglycemia, is defective if the islet cells are transplanted into the liver, and that implanting them into another site may avoid this effect.⁶¹

For some patients with chronic pancreatitis, the best option is to remove the entire pancreas. This does not necessarily doom the patient to diabetes mellitus, because we can harvest the islet cells and reinsert them so that, lodged in the liver, they can continue making insulin. However, this approach is underemphasized in the general medical literature and is likely underutilized in the United States.

Here, we discuss chronic pancreatitis, the indications for and contraindications to this procedure, its outcomes, and the management of patients who undergo it.

CHRONIC PANCREATITIS IS PROGRESSIVE AND PAINFUL

Chronic pancreatitis is a progressive condition characterized by chronic inflammation, irreversible fibrosis, and scarring, resulting in loss of both exocrine and endocrine tissue.

According to a National Institutes of Health database, pancreatitis is the seventh most common digestive disease diagnosis on hospitalization, with annual healthcare costs exceeding $3 billion.¹ Although data are scarce, by some estimates the incidence of chronic pancreatitis ranges from 4 to 14 per 100,000 person-years, and the prevalence ranges from 26.4 to 52 per 100,000.^2–4 Moreover, a meta-analysis⁵ found that acute pancreatitis progresses to chronic pancreatitis in 10% of patients who have a first episode of acute pancreatitis and in 36% who have recurrent episodes.

Historically, alcoholism was and still is the most common cause of chronic pancreatitis, contributing to 60% to 90% of cases in Western countries.^6,7 However, cases due to nonalcoholic causes have been increasing, and in more than one-fourth of patients, no identifiable cause is found.^6,8 Smoking is an independent risk factor.^6,8,9 Some cases can be linked to genetic abnormalities, particularly in children.¹⁰

The clinical manifestations of chronic pancreatitis include exocrine pancreatic insufficiency (leading to malnutrition and steatorrhea), endocrine insufficiency (causing diabetes mellitus), and intractable pain.¹¹ Pain is the predominant clinical symptom early in the disease and is often debilitating and difficult to manage. Uncontrolled pain has a devastating impact on quality of life and may become complicated by narcotic dependence.

The pain of chronic pancreatitis is often multifactorial, with mechanisms that include increased intraductal pressure from obstruction of the pancreatic duct, pancreatic ischemia, neuronal injury, and neuroimmune interactions between neuronal processes and chronic inflammation.¹²

Treatment: Medical and surgical

In chronic pancreatitis, the aim of treatment is to alleviate deficiencies of exocrine and endocrine function and mitigate the pain. Patients who smoke or drink alcohol should be strongly encouraged to quit.

Loss of exocrine function is mainly managed with oral pancreatic enzyme supplements, and diabetes control is often attained with insulin therapy.¹³ Besides helping digestion, pancreatic enzyme therapy in the form of nonenteric tablets may also reduce pain and pancreatitis attacks.¹⁴ The mechanism may be by degrading cholecystokinin-releasing factor in the duodenum, lowering cholecystokinin levels and thereby reducing pain.¹²

Nonnarcotic analgesics are often the first line of therapy for pain management, but many patients need narcotic analgesics. Along with narcotics, adjunctive agents such as tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, and gabapentinoids have been used to treat chronic pancreatitis pain, but with limited success.¹⁵

In patients for whom medical pain management has failed, one can consider another option, such as nerve block, neurolysis, or endoscopic or surgical therapy. Neuromodulators are often prescribed by pain clinics.¹⁵ Percutaneous and endoscopic celiac ganglion blocks can be an option but rarely achieve substantial or permanent pain relief, and the induced transient responses (on average 2 to 4 months) often cannot be repeated.^14–17

Surgical options to relieve pain try to preserve pancreatic function and vary depending on the degree of severity and nature of pancreatic damage. In broad terms, the surgical procedures can be divided into two types:

• Drainage procedures (eg, pseudocyst drainage; minimally invasive endoscopic duct drainage via sphincterotomy or stent placement, or both; pancreaticojejunostomy)
• Resectional procedures (eg, distal pancreatectomy, isolated head resection, pancreaticoduodenectomy, Whipple procedure, total pancreatectomy).

In carefully selected patients, total pancreatectomy can be offered to remove the cause of the pain.¹⁸ This procedure is most often performed in patients who have small-duct disease or a genetic cause or for whom other surgical procedures have failed.¹¹

HISTORY OF THE PROCEDURE

Islet cell transplantation grew out of visionary work by Paul Lacy and David Scharp at the University of Washington at Seattle, whose research focused on isolating and transplanting islet cells in rodent models. The topic has been reviewed by Jahansouz et al.¹⁹ In the 1970s, experiments in pancreatectomized dogs showed that transplanting unpurified pancreatic islet tissue that was dispersed by collagenase digestion into the spleen or portal vein could prevent diabetes.^20,21 In 1974, the first human trials of transplanting islet cells were conducted, using isolated islets from cadaveric donors to treat diabetes.¹⁹

In the past, pancreatectomy was performed to treat painful chronic pancreatitis, but it was viewed as undesirable because removing the gland would inevitably cause insulin-dependent diabetes.²² That changed in 1977 at the University of Minnesota, with the first reported islet cell autotransplant after pancreatectomy. The patient remained pain-free and insulin-independent long-term.²³ This seminal case showed that endocrine function could be preserved by autotransplant of islets prepared from the excised pancreas.²⁴

In 1992, Pyzdrowski et al²⁵ reported that intrahepatic transplant of as few as 265,000 islets was enough to prevent the need for insulin therapy. Since this technique was first described, there have been many advances, and now more than 30 centers worldwide do it.

PRIMARY INDICATION: INTRACTABLE PAIN

Interest has been growing in using total pancreatectomy and islet autotransplant to treat recurrent acute pancreatitis, chronic pancreatitis, and hereditary pancreatitis. The rationale is that removing the offending tissue eliminates pancreatitis, pain, and cancer risk, while preserving and replacing the islet cells prevents the development of brittle diabetes with loss of insulin and glucagon.²⁶

Proposed criteria for total pancreatectomy and islet autotransplant

Bellin et al¹⁴ proposed five criteria for patient selection for this procedure based on imaging studies, pancreatic function tests, and histopathology to detect pancreatic fibrosis. Patients must fulfill all five of the following criteria:

Criterion 1. Diagnosis of chronic pancreatitis, based on chronic abdominal pain lasting more than 6 months with either at least one of the following:

• Pancreatic calcifications on computed tomography
• At least two of the following: four or more of nine criteria on endoscopic ultrasonography described by Catalano et al,²⁷ a compatible ductal or parenchymal abnormality on secretin magnetic resonance cholangiopancreatography; abnormal endoscopic pancreatic function test (peak HCO₂ ≤ 80 mmol/L)
• Histopathologically confirmed diagnosis of chronic pancreatitis
• Compatible clinical history and documented hereditary pancreatitis (PRSS1 gene mutation)

OR

• History of recurrent acute pancreatitis (more than one episode of characteristic pain associated with imaging diagnostic of acute pancreatitis or elevated serum amylase or lipase > 3 times the upper limit of normal).

Criterion 2. At least one of the following:

• Daily narcotic dependence
• Pain resulting in impaired quality of life, which may include inability to attend school, recurrent hospitalizations, or inability to participate in usual age-appropriate activities.

Criterion 3. Complete evaluation with no reversible cause of pancreatitis present or untreated.

Criterion 4. Failure to respond to maximal medical and endoscopic therapy.

Criterion 5. Adequate islet cell function (nondiabetic or C-peptide-positive). Patients with C-peptide-negative diabetes meeting criteria 1 to 4 are candidates for total pancreatectomy alone.

The primary goal is to treat intractable pain and improve quality of life in selected patients with chronic pancreatitis or recurrent acute pancreatitis when endoscopic and prior surgical therapies have failed, and whose impairment due to pain is substantial enough to accept the risk of postoperative insulin-dependent diabetes and lifelong commitment to pancreatic enzyme replacement therapy.^15,26 Patients with a known genetic cause of chronic pancreatitis should be offered special consideration for the procedure, as their disease is unlikely to remit.

CONTRAINDICATIONS

Total pancreatectomy and islet autotransplant should not be performed in patients with active alcoholism, illicit drug use, or untreated or poorly controlled psychiatric illnesses that could impair the patient’s ability to adhere to a complicated postoperative medical regimen.

A poor support network may be a relative contraindication in view of the cost and complexity of diabetic and pancreatic enzyme replacement therapy.^18,26

Islet cell autotransplant is contraindicated in patients with conditions such as C-peptide-negative or type 1 diabetes or a history of portal vein thrombosis, portal hypertension, significant liver disease, high-risk cardiopulmonary disease, or pancreatic cancer (Table 1).²⁶

WHEN TO CONSIDER REFERRAL FOR THIS PROCEDURE

The choice of total pancreatectomy and islet autotransplant vs conventional surgery must be individualized on the basis of each patient’s anatomy, comorbidities, symptom burden, presence or degree of diabetes, and rate of disease progression. The most important factors to consider in determining the need for and timing of this procedure are the patient’s pain, narcotic requirements, and impaired ability to function.²⁶

Sooner rather than later?

An argument can be made for performing this procedure sooner in the course of the disease rather than later when all else has failed. First, prolonged pain can result in central sensitization, in which the threshold for perceiving pain is lowered by damage to the nociceptive neurons from repeated stimulation and inflammation.²⁸

Further, prolonged opioid therapy can lead to opioid-induced hyperalgesia, which may also render patients more sensitive to pain and aggravate their preexisting pain.^26,28

In addition, although operative drainage procedures and partial resections are often considered the gold standard for chronic pancreatitis management, patients who undergo partial pancreatectomy or lateral pancreaticojejunostomy (Puestow procedure) have fewer islet cells left to harvest (about 50% fewer) if they subsequently undergo total pancreatectomy and islet cell autotransplant.^22,26

Therefore, performing this procedure earlier may help the patient avoid chronic pain syndromes and complications of chronic opioid use, including hyperalgesia, and give the best chance of harvesting enough islet cells to prevent or minimize diabetes afterward.¹¹

REMOVING THE PANCREAS, RETURNING THE ISLET CELLS

During this procedure, the blood supply to the pancreas must be preserved until just before its removal to minimize warm ischemia of the islet cells.^18,29 Although there are several surgical variations, a pylorus-preserving total pancreatectomy with duodenectomy is typically performed, usually with splenectomy to preserve perfusion to the body and tail.³⁰

The resected pancreas is taken to the islet isolation laboratory. There, the pancreatic duct is cannulated to fill the organ with a cold collagenase solution, followed by gentle mechanical dispersion using the semiautomated Ricordi method,³¹ which separates the islet cells from the exocrine tissue.³²

The number of islet cells is quantified as islet equivalents; 1 islet equivalent is equal to the volume of an islet with a diameter of 150 µm. Islet equivalents per kilogram of body weight is the unit commonly used to report the graft amount transplanted.³³

After digestion, the islet cells can be purified or partially purified by a gradient separation method using a Cobe 2991 cell processor (Terumo Corporation, Tokyo, Japan),³⁴ or can be transplanted as an unpurified preparation. In islet cell autotransplant for chronic pancreatitis, purification is not always necessary due to the small tissue volume extracted from the often atrophic and fibrotic pancreas.³² The decision to purify depends on the postdigest tissue volume; usually, a tissue volume greater than 0.25 mL/kg body weight is an indication to at least partially purify.^18,35

The final preparation is returned to the operating room, and after heparin is given, the islets are infused into the portal system using a stump of the splenic vein, or alternatively through direct puncture of the portal vein or cannulation of the umbilical vein.^32,36 If the portal vein pressure reaches 25 cm H₂O, the infusion is stopped and the remaining islets can be placed in the peritoneal cavity or elsewhere.¹⁸ Transplant of the islets into the liver or peritoneum allows the islets to secrete insulin into the hepatic portal circulation, which is the route used by the native pancreas.²²

CONTROLLING GLUCOSE DURING AND AFTER THE PROCEDURE

Animal studies have shown that hyperglycemia impairs islet revascularization,³⁷ and glucose toxicity may cause dysfunction and structural lesions of the transplanted islets.^11,38

Therefore, during and after the procedure, most centers maintain euglycemia by an intravenous insulin infusion and subsequently move to subcutaneous insulin when the patient starts eating again. Some centers continue insulin at discharge and gradually taper it over months, even in patients who can possibly achieve euglycemia without it.

OUTCOMES

Many institutions have reported their clinical outcomes in terms of pain relief, islet function, glycemic control, and improvement of quality of life. The largest series have been from the University of Minnesota, Leicester General Hospital, the University of Cincinnati, and the Medical University of South Carolina.

Insulin independence is common but wanes with time

The ability to achieve insulin independence after islet autotransplant appears to be related to the number of islets transplanted, with the best results when more than 2,000 or 3,000 islet equivalents/kg are transplanted.^39,40

Sutherland et al¹⁸ reported that of 409 patients who underwent islet cell autotransplant at the University of Minnesota (the largest series reported to date), 30% were insulin-independent at 3 years, 33% had partial graft function (defined by positive C-peptide), and 82% achieved a mean hemoglobin A_1c of less than 7%. However, in the subset who received more than 5,000 islet equivalents/kg, nearly three-fourths of patients were insulin-independent at 3 years.

The Leicester General Hospital group presented long-term data on 46 patients who underwent total pancreatectomy and islet cell autotransplant. Twelve of the 46 had shown periods of insulin independence for a median of 16.5 months, and 5 remained insulin-free at the time of the publication.⁴¹ Over the 10 years of follow-up, insulin requirements and hemoglobin A_1c increased notably. However, all of the patients tested C-peptide-positive, suggesting long-lasting graft function.

Most recently, the University of Cincinnati group reported long-term data on 116 patients. The insulin independence rate was 38% at 1 year, decreasing to 27% at 5 years. The number of patients with partial graft function was 38% at 1 year and 35% at 5 years.⁴²

Thus, all three institutions confirmed that the autotransplanted islets continue to secrete insulin long-term, but that function decreases over time.

Pancreatectomy reduces pain

Multiple studies have shown that total pancreatectomy reduces pain in patients with chronic pancreatitis. Ahmad et al⁴³ reported a marked reduction in narcotic use (mean morphine equivalents 206 mg/day before surgery, compared with 90 mg after), and a 58% reduction in pain as demonstrated by narcotic independence.

In the University of Minnesota series, 85% of the 409 patients had less pain at 2 years, and 59% were able to stop taking narcotics.¹⁸

The University of Cincinnati group reported a narcotic independence rate of 55% at 1 year, which continued to improve to 73% at 5 years.⁴²

Although the source of pain is removed, pain persists or recurs in 10% to 20% of patients after total pancreatectomy and islet cell autotransplant, showing that the pathogenesis of pain is complex, and some uncertainty exists about it.²⁶

Quality of life

Reports evaluating health-related quality of life after total pancreatectomy and islet autotransplant are limited.

The University of Cincinnati group reported the long-term outcomes of quality of life as measured by the Short Form 36 Health Survey.⁴² Ninety-two percent of patients reported overall improvement in their health at 1 year, and 85% continued to report improved health more than 5 years after the surgery.

In a series of 20 patients, 79% to 90% reported improvements in the seven various domains of the Pain Disability Index. In addition, 60% showed improvement in depression and 70% showed improvement in anxiety. The greatest improvements were in those who had not undergone prior pancreatic surgery, who were younger, and in those with higher levels of preoperative pain.³⁰

Similarly, in a series of 74 patients, the Medical University of South Carolina group reported significant improvement in physical and mental health components of the Short Form 12 Health Survey and an associated decrease in daily narcotic requirements. Moreover, the need to start or increase the dose of insulin after the surgery was not associated with a lower quality of life.⁴⁴

OFF-SITE ISLET CELL ISOLATION

Despite the positive outcomes in terms of pain relief and insulin independence in many patients after total pancreatectomy and islet cell autotransplant, few medical centers have an on-site islet-processing facility. Since the mid-1990s, a few centers have been able to circumvent this limitation by working with off-site islet cell isolation laboratories.^45,46

Whether and when to consider this procedure must be individualized

The University of California, Los Angeles, first reported on a series of nine patients who received autologous islet cells after near-total or total pancreatectomy using a remote islet cell isolation facility, with results comparable to those of other large institutions.⁴⁵

Similarly, the procedure has been performed at Cleveland Clinic since 2007 with the collaboration of an off-site islet cell isolation laboratory at the University of Pittsburgh. A cohort study from this collaboration published in 2015 showed that in 36 patients (mean follow-up 28 months, range 3–26 months), 33% were insulin-independent, with a C-peptide-positive rate of 70%. This is the largest cohort to date from a center utilizing an off-site islet isolation facility.⁴⁷

In view of the positive outcomes at these centers, lack of a local islet-processing facility should no longer be a barrier to total pancreatectomy and islet cell autotransplant.

PATIENT CARE AFTER THE PROCEDURE

A multidisciplinary team is an essential component of the postoperative management of patients who undergo total pancreatectomy and islet cell autotransplant.

For patients who had been receiving narcotics for a long time before surgery or who were receiving frequent doses, an experienced pain management physician should be involved in the patient’s postoperative care.

Because islet function can wane over time, testing for diabetes should be done at least annually for the rest of the patient’s life and should include fasting plasma glucose, hemoglobin A_1c, and C-peptide, along with self-monitored blood glucose.²⁶

All patients who have surgically induced exocrine insufficiency are at risk of malabsorption and fat-soluble vitamin deficiencies.⁴⁸ Hence, lifelong pancreatic enzyme replacement therapy is mandatory. Nutritional monitoring should include assessment of steatorrhea, body composition, and fat-soluble vitamin levels (vitamins A, D, and E) at least every year.²⁶ Patients with chronic pancreatitis are at increased risk for low bone density from malabsorption of vitamin D and calcium; therefore, it is recommended that a dual-energy x-ray absorptiometry bone density scan be obtained.^26,49

Patients who undergo splenectomy as part of their procedure will require appropriate precautions and ongoing vaccinations as recommended by the US Centers for Disease Control and Prevention.^26,50,51

WHAT TO EXPECT FOR THE FUTURE

The National Institute of Diabetes and Digestive and Kidney Diseases has reviewed the potential future research directions for total pancreatectomy and islet autotransplant.¹⁵

The more islet cells transplanted, the better the chance of insulin independence

Patient selection remains challenging despite the availability of criteria¹⁵ and guidelines.²⁶ More research is needed to better assess preoperative beta-cell function and to predict postoperative outcomes. Mixed meal-tolerance testing is adopted by most clinical centers to predict posttransplant beta-cell function. The use of arginine instead of glucagon in a stimulation test for insulin and C-peptide response has been validated and may allow more accurate assessment.^52,53

Another targeted area of research is the advancement of safety and metabolic outcomes. Techniques to minimize warm ischemic time and complications are being evaluated. Islet isolation methods that yield more islets, reduce beta-cell apoptosis, and can isolate islets from glands with malignancy should be further investigated.⁵⁴ Further, enhanced islet infusion methods that achieve lower portal venous pressures and minimize portal vein thrombosis are needed.

Unfortunately, the function of transplanted islet grafts declines over time. This phenomenon is at least partially attributed to the immediate blood-mediated inflammatory response,^55,56 along with islet hypoxia,⁵⁷ leading to islet apoptosis. Research on different strategies is expanding our knowledge in islet engraftment and posttransplant beta-cell apoptosis, with the expectation that the transplanted islet lifespan will increase. Alternative transplant sites with low inflammatory reaction, such as the omental pouch,⁵⁸ muscle,⁵⁹ and bone marrow,⁶⁰ have shown encouraging data. Other approaches, such as adjuvant anti-inflammatory agents and heparinization, have been proposed.¹⁵

Research into complications is also of clinical importance. There is growing attention to hypoglycemia unrelated to exogenous insulin use in posttransplant patients. One hypothesis is that glucagon secretion, a counterregulatory response to hypoglycemia, is defective if the islet cells are transplanted into the liver, and that implanting them into another site may avoid this effect.⁶¹

Children and adolescents with attention-deficit/hyperactivity disorder who are prescribed methylphenidate to manage their conditions stand at a higher risk for arrhythmia and other, more serious, cardiac conditions.

In a study published in the BMJ, Ju-Young Shin, Ph.D., and colleagues examined records of 1,224 patients aged 17 years and younger from a nationwide South Korean health insurance database submitted between January 2007 and December 2011. All of the patients had experienced a cardiovascular event and at least one recorded prescription for methylphenidate to treat attention-deficit/hyperactivity disorder (ADHD) (BMJ 2016;353:i2550 doi:10.1136/bmj.i2550).

©mik38/thinkstockphotos.com

Of the 1,224 subjects, 864 (70.5%) had experienced arrhythmias, and the mean duration of exposure to methylphenidate was 0.5 years. During periods of methylphenidate treatment, subjects had an increased risk of arrhythmia, as Dr. Shin and coinvestigators calculated an adjusted incidence rate ratio of 1.61 (95% confidence interval, 1.48-1.74). This incidence rate ratio jumped up to 2.01 (95% CI, 1.74-2.31) during the first 3 days of methylphenidate treatment.

The risk was even higher for subjects with congenital heart disease; this subgroup had an adjusted incidence rate ratio of 3.49 (95% CI, 2.33-5.22), compared with 1.34 (95% CI, 1.23-1.46) in patients without it. Both the median age of first exposure to methylphenidate and occurrence of the first cardiac event were in patients aged 11-13 years, reported Dr. Shin of the Centre for Clinical Epidemiology at Jewish General Hospital and McGill University, both in Montreal, and colleagues in Australia and Korea.

“These results are consistent with the biological plausibility that the mechanism of action relates to the effect of methylphenidate on the heart rate,” the authors concluded. “Delayed effects would be expected with myocardial infarction, while more immediate effects would be expected with arrhythmias, as we observed.”

Dr. Shin and colleagues cited several limitations. For example, coding mistakes and incomplete records could not be ruled out in their study. In addition, they said, the “outcome measures were limited to patients with diagnoses of cardiovascular adverse events, and we could have missed outcomes not diagnosed.”

Nevertheless, they said, in light of the increased use of methylphenidate to treat ADHD across the globe, the benefits of using the drug “should be carefully weighed against potential cardiovascular risks of these drugs in children and adolescents.”

Two of the authors disclosed receiving support via fellowships from Australia’s National Health and Medical Research Council.

[email protected]

Children and adolescents with attention-deficit/hyperactivity disorder who are prescribed methylphenidate to manage their conditions stand at a higher risk for arrhythmia and other, more serious, cardiac conditions.

In a study published in the BMJ, Ju-Young Shin, Ph.D., and colleagues examined records of 1,224 patients aged 17 years and younger from a nationwide South Korean health insurance database submitted between January 2007 and December 2011. All of the patients had experienced a cardiovascular event and at least one recorded prescription for methylphenidate to treat attention-deficit/hyperactivity disorder (ADHD) (BMJ 2016;353:i2550 doi:10.1136/bmj.i2550).

©mik38/thinkstockphotos.com

Of the 1,224 subjects, 864 (70.5%) had experienced arrhythmias, and the mean duration of exposure to methylphenidate was 0.5 years. During periods of methylphenidate treatment, subjects had an increased risk of arrhythmia, as Dr. Shin and coinvestigators calculated an adjusted incidence rate ratio of 1.61 (95% confidence interval, 1.48-1.74). This incidence rate ratio jumped up to 2.01 (95% CI, 1.74-2.31) during the first 3 days of methylphenidate treatment.

The risk was even higher for subjects with congenital heart disease; this subgroup had an adjusted incidence rate ratio of 3.49 (95% CI, 2.33-5.22), compared with 1.34 (95% CI, 1.23-1.46) in patients without it. Both the median age of first exposure to methylphenidate and occurrence of the first cardiac event were in patients aged 11-13 years, reported Dr. Shin of the Centre for Clinical Epidemiology at Jewish General Hospital and McGill University, both in Montreal, and colleagues in Australia and Korea.

“These results are consistent with the biological plausibility that the mechanism of action relates to the effect of methylphenidate on the heart rate,” the authors concluded. “Delayed effects would be expected with myocardial infarction, while more immediate effects would be expected with arrhythmias, as we observed.”

Dr. Shin and colleagues cited several limitations. For example, coding mistakes and incomplete records could not be ruled out in their study. In addition, they said, the “outcome measures were limited to patients with diagnoses of cardiovascular adverse events, and we could have missed outcomes not diagnosed.”

Nevertheless, they said, in light of the increased use of methylphenidate to treat ADHD across the globe, the benefits of using the drug “should be carefully weighed against potential cardiovascular risks of these drugs in children and adolescents.”

Two of the authors disclosed receiving support via fellowships from Australia’s National Health and Medical Research Council.

[email protected]

Children and adolescents with attention-deficit/hyperactivity disorder who are prescribed methylphenidate to manage their conditions stand at a higher risk for arrhythmia and other, more serious, cardiac conditions.

In a study published in the BMJ, Ju-Young Shin, Ph.D., and colleagues examined records of 1,224 patients aged 17 years and younger from a nationwide South Korean health insurance database submitted between January 2007 and December 2011. All of the patients had experienced a cardiovascular event and at least one recorded prescription for methylphenidate to treat attention-deficit/hyperactivity disorder (ADHD) (BMJ 2016;353:i2550 doi:10.1136/bmj.i2550).

©mik38/thinkstockphotos.com

Of the 1,224 subjects, 864 (70.5%) had experienced arrhythmias, and the mean duration of exposure to methylphenidate was 0.5 years. During periods of methylphenidate treatment, subjects had an increased risk of arrhythmia, as Dr. Shin and coinvestigators calculated an adjusted incidence rate ratio of 1.61 (95% confidence interval, 1.48-1.74). This incidence rate ratio jumped up to 2.01 (95% CI, 1.74-2.31) during the first 3 days of methylphenidate treatment.

The risk was even higher for subjects with congenital heart disease; this subgroup had an adjusted incidence rate ratio of 3.49 (95% CI, 2.33-5.22), compared with 1.34 (95% CI, 1.23-1.46) in patients without it. Both the median age of first exposure to methylphenidate and occurrence of the first cardiac event were in patients aged 11-13 years, reported Dr. Shin of the Centre for Clinical Epidemiology at Jewish General Hospital and McGill University, both in Montreal, and colleagues in Australia and Korea.

“These results are consistent with the biological plausibility that the mechanism of action relates to the effect of methylphenidate on the heart rate,” the authors concluded. “Delayed effects would be expected with myocardial infarction, while more immediate effects would be expected with arrhythmias, as we observed.”

Dr. Shin and colleagues cited several limitations. For example, coding mistakes and incomplete records could not be ruled out in their study. In addition, they said, the “outcome measures were limited to patients with diagnoses of cardiovascular adverse events, and we could have missed outcomes not diagnosed.”

Nevertheless, they said, in light of the increased use of methylphenidate to treat ADHD across the globe, the benefits of using the drug “should be carefully weighed against potential cardiovascular risks of these drugs in children and adolescents.”

Two of the authors disclosed receiving support via fellowships from Australia’s National Health and Medical Research Council.

[email protected]

In 2009, the US Preventive Services Task Force issued an I statement for routine skin cancer screening, noting a lack of evidence to support the balance of benefits and harms from screening,¹ a recommendation that is likely to be upheld this year. As dermatologists and melanoma specialists, we have abundant anecdotal evidence of the value of screening; however, population-based screening performed exclusively by dermatologists is not practical. There are approximately 170,000,000 adults 35 years and older and only 9600 practicing dermatologists in the United States, requiring each dermatologist to screen nearly 18,000 individuals per year to meet the needs of the population.

Only 8% to 15% of people in the United States report having received a recent skin examination by a physician.^2,3 Partnering with our primary care provider (PCP) colleagues has the potential to reach more patients and to improve skin cancer screening rates more rapidly. The workforce in primary care is substantially larger than dermatology by approximately 30-fold, and PCPs are more likely than dermatologists to practice in rural areas, thus reaching patients with limited access to dermatologists. Skin cancer screening can be included in the routine PCP visit, reducing the need for an additional physician visit for the patient. Patients visit their PCP more frequently as they age, which parallels the risk for developing and dying from melanoma and also provides an opportunity to introduce skin cancer education and screening to a population at higher risk who may not otherwise seek it on their own.⁴ Providing PCPs with the training and tools to perform melanoma screening shifts the responsibility of initiating screening from the patient alone to a shared responsibility of patient and provider. Dermatologists, in turn, need to be available to examine those patients found to have a suspicious lesion, treat newly diagnosed skin cancer, and follow those patients at highest risk of developing skin cancer, including those who are immunosuppressed, have multiple atypical moles, or have a personal or family history of melanoma.

Evidence from the SCREEN (Skin Cancer Research to provide Evidence for Effectiveness of Screening in Northern Germany) project supports PCP-based screening. In the 5 years following a 1-year pilot screening program, there was nearly a 50% reduction in melanoma mortality.⁵ Unfortunately, these encouraging results were not confirmed once the pilot project was translated into a national skin cancer screening program.⁶ However, there are lessons to be learned from the German project and we propose that PCP-led screening is feasible and practical in the United States and we currently have a pilot program in our institution, the University of Pittsburgh Medical Center (Pittsburgh, Pennsylvania).

In the SCREEN project and in routine practice across the United States, screening is primarily driven by patients. Generally, higher-risk patients such as men and the elderly are the least likely group to seek skin cancer screening. In our program, PCPs are offered training in skin cancer screening using a validated web-based program and alerted through the electronic health record to offer skin cancer screening annually to patients 35 years and older who present for routine primary care visits.⁷ This approach reduces self-referral bias by promoting physician initiation rather than patient initiation of screening, which can occur while the patient is already in the PCP’s office.

Melanoma thickness can be measured among screened patients, unscreened patients, and historic controls and compared to determine if this approach is effective. Health care utilization data can help to inform us if this approach leads to more skin biopsies and procedures or to an increased rate of dermatology referrals. As health care payment and delivery models evolve, there is greater emphasis on outcomes and team-based care. We believe that this approach will allow us to form effective teams of PCPs, dermatologists, and other experts in melanoma, public health, and informatics to reduce melanoma mortality in a cost-effective manner.

In 2009, the US Preventive Services Task Force issued an I statement for routine skin cancer screening, noting a lack of evidence to support the balance of benefits and harms from screening,¹ a recommendation that is likely to be upheld this year. As dermatologists and melanoma specialists, we have abundant anecdotal evidence of the value of screening; however, population-based screening performed exclusively by dermatologists is not practical. There are approximately 170,000,000 adults 35 years and older and only 9600 practicing dermatologists in the United States, requiring each dermatologist to screen nearly 18,000 individuals per year to meet the needs of the population.

Only 8% to 15% of people in the United States report having received a recent skin examination by a physician.^2,3 Partnering with our primary care provider (PCP) colleagues has the potential to reach more patients and to improve skin cancer screening rates more rapidly. The workforce in primary care is substantially larger than dermatology by approximately 30-fold, and PCPs are more likely than dermatologists to practice in rural areas, thus reaching patients with limited access to dermatologists. Skin cancer screening can be included in the routine PCP visit, reducing the need for an additional physician visit for the patient. Patients visit their PCP more frequently as they age, which parallels the risk for developing and dying from melanoma and also provides an opportunity to introduce skin cancer education and screening to a population at higher risk who may not otherwise seek it on their own.⁴ Providing PCPs with the training and tools to perform melanoma screening shifts the responsibility of initiating screening from the patient alone to a shared responsibility of patient and provider. Dermatologists, in turn, need to be available to examine those patients found to have a suspicious lesion, treat newly diagnosed skin cancer, and follow those patients at highest risk of developing skin cancer, including those who are immunosuppressed, have multiple atypical moles, or have a personal or family history of melanoma.

Evidence from the SCREEN (Skin Cancer Research to provide Evidence for Effectiveness of Screening in Northern Germany) project supports PCP-based screening. In the 5 years following a 1-year pilot screening program, there was nearly a 50% reduction in melanoma mortality.⁵ Unfortunately, these encouraging results were not confirmed once the pilot project was translated into a national skin cancer screening program.⁶ However, there are lessons to be learned from the German project and we propose that PCP-led screening is feasible and practical in the United States and we currently have a pilot program in our institution, the University of Pittsburgh Medical Center (Pittsburgh, Pennsylvania).

In the SCREEN project and in routine practice across the United States, screening is primarily driven by patients. Generally, higher-risk patients such as men and the elderly are the least likely group to seek skin cancer screening. In our program, PCPs are offered training in skin cancer screening using a validated web-based program and alerted through the electronic health record to offer skin cancer screening annually to patients 35 years and older who present for routine primary care visits.⁷ This approach reduces self-referral bias by promoting physician initiation rather than patient initiation of screening, which can occur while the patient is already in the PCP’s office.

Melanoma thickness can be measured among screened patients, unscreened patients, and historic controls and compared to determine if this approach is effective. Health care utilization data can help to inform us if this approach leads to more skin biopsies and procedures or to an increased rate of dermatology referrals. As health care payment and delivery models evolve, there is greater emphasis on outcomes and team-based care. We believe that this approach will allow us to form effective teams of PCPs, dermatologists, and other experts in melanoma, public health, and informatics to reduce melanoma mortality in a cost-effective manner.

In 2009, the US Preventive Services Task Force issued an I statement for routine skin cancer screening, noting a lack of evidence to support the balance of benefits and harms from screening,¹ a recommendation that is likely to be upheld this year. As dermatologists and melanoma specialists, we have abundant anecdotal evidence of the value of screening; however, population-based screening performed exclusively by dermatologists is not practical. There are approximately 170,000,000 adults 35 years and older and only 9600 practicing dermatologists in the United States, requiring each dermatologist to screen nearly 18,000 individuals per year to meet the needs of the population.

Only 8% to 15% of people in the United States report having received a recent skin examination by a physician.^2,3 Partnering with our primary care provider (PCP) colleagues has the potential to reach more patients and to improve skin cancer screening rates more rapidly. The workforce in primary care is substantially larger than dermatology by approximately 30-fold, and PCPs are more likely than dermatologists to practice in rural areas, thus reaching patients with limited access to dermatologists. Skin cancer screening can be included in the routine PCP visit, reducing the need for an additional physician visit for the patient. Patients visit their PCP more frequently as they age, which parallels the risk for developing and dying from melanoma and also provides an opportunity to introduce skin cancer education and screening to a population at higher risk who may not otherwise seek it on their own.⁴ Providing PCPs with the training and tools to perform melanoma screening shifts the responsibility of initiating screening from the patient alone to a shared responsibility of patient and provider. Dermatologists, in turn, need to be available to examine those patients found to have a suspicious lesion, treat newly diagnosed skin cancer, and follow those patients at highest risk of developing skin cancer, including those who are immunosuppressed, have multiple atypical moles, or have a personal or family history of melanoma.

Evidence from the SCREEN (Skin Cancer Research to provide Evidence for Effectiveness of Screening in Northern Germany) project supports PCP-based screening. In the 5 years following a 1-year pilot screening program, there was nearly a 50% reduction in melanoma mortality.⁵ Unfortunately, these encouraging results were not confirmed once the pilot project was translated into a national skin cancer screening program.⁶ However, there are lessons to be learned from the German project and we propose that PCP-led screening is feasible and practical in the United States and we currently have a pilot program in our institution, the University of Pittsburgh Medical Center (Pittsburgh, Pennsylvania).

In the SCREEN project and in routine practice across the United States, screening is primarily driven by patients. Generally, higher-risk patients such as men and the elderly are the least likely group to seek skin cancer screening. In our program, PCPs are offered training in skin cancer screening using a validated web-based program and alerted through the electronic health record to offer skin cancer screening annually to patients 35 years and older who present for routine primary care visits.⁷ This approach reduces self-referral bias by promoting physician initiation rather than patient initiation of screening, which can occur while the patient is already in the PCP’s office.

Melanoma thickness can be measured among screened patients, unscreened patients, and historic controls and compared to determine if this approach is effective. Health care utilization data can help to inform us if this approach leads to more skin biopsies and procedures or to an increased rate of dermatology referrals. As health care payment and delivery models evolve, there is greater emphasis on outcomes and team-based care. We believe that this approach will allow us to form effective teams of PCPs, dermatologists, and other experts in melanoma, public health, and informatics to reduce melanoma mortality in a cost-effective manner.

The concept of field cancerization was first proposed in 1953 by Slaughter et al¹ in their study of oral squamous carcinomas. Their findings of multifocal patches of premalignant disease, abnormal tissue surrounding tumors, multiple localized primary tumors, and tumor recurrence following surgical resection was suggestive of a field of dysplastic cells with malignant potential.¹ Since then, modern molecular techniques have been used to establish a genetic basis for this model in many different types of cancer, including cutaneous malignancies.^2-4 The field begins from a singular stem cell, which undergoes one or more genetic changes that allow for a growth advantage compared to surrounding cells. The stem cell then divides, forming a patch of clonal daughter cells that displace the surrounding normal epithelium. Growth of this patch eventually leads to a dysplastic field of monoclonal cells, which notably does not yet show invasive growth or metastatic behavior. Over time, continued carcinogenic exposure results in additional genetic alterations among different cells in the field, which leads to new subclonal proliferations that share common clonal origin but exhibit unique genetic changes. Eventually, transformative events may occur, resulting in cells with invasive and metastatic properties, thus forming a carcinoma.⁵

In the case of cutaneous malignancies, UV radiation in the form of UVA and UVB rays is the most common source of carcinogenesis. It is well established that UV radiation has numerous effects on the body, including but not limited to local and systemic immunosuppression, alteration of signal transduction pathways, and the development of mutations in DNA via direct damage by UVB or indirect damage by free radical formation with UVA.^6,7 Normally, DNA is protected from UV radiation–induced genetic alteration by the p53 gene, TP53. As such, damage to this gene is highly associated with cancer induction. One study found that more than 90% of squamous cell carcinomas (SCCs) and more than 50% of basal cell carcinomas (BCCs) contain UV-like mutations in TP53.⁸ The concept of field cancerization suggests that because the skin surrounding cutaneous malignancies has been exposed to the same chronic UV light as the initial lesion, it is at an increased risk for genetic abnormalities and thus possible malignant transformation.

Actinic keratoses (AKs) are common neoplasms of the skin that generally are regarded as precancerous lesions or may be considered to be the earliest stage of SCC in situ.⁹ Actinic keratoses usually develop as a consequence of chronic exposure to UV radiation and often are clinically apparent as erythematous scaly papules in sun-exposed areas (Figure 1).¹⁰ They also are identified histologically as atypical keratinocytes along the basal layer of the epidermis with possible enlargement, hyperchromatic nuclei, lack of maturation, mitotic figures, inflammatory infiltrate, and/or hyperkeratosis.¹⁰ Furthermore, the genetic changes associated with AKs are well documented and are strongly associated with changes to p53.¹¹ Given these characteristics, AKs serve as good markers of genetic damage with potential for malignancy. In this study, we used histologically identified AKs to assess the presence of field damage in the tissue immediately surrounding excision specimens of SCCs, BCCs, and malignant melanomas (MMs).

Methods

This study was approved by the Program for the Protection of Human Subjects at the Icahn School of Medicine at Mount Sinai (New York, New York) prior to initiation. All cutaneous specimens submitted to the dermatopathology service for consultation between April 2013 and June 2013 were reviewed for inclusion in this study. Data collection was extended for MMs to include all specimens from January 2013 to June 2013 given the limited number of cases in the original data collection period.

Initial screening for this study was done electronically and assessed for a diagnosis of SCC (Figure 2), BCC (Figure 3), or MM (Figure 4) as determined by a board-certified dermatopathologist (G.G.). The resulting pool of specimens was then screened to include only excision specimens and to exclude curettage specimens and superficial specimens that lacked dermis. In this study, we chose to look at reexcisions rather than initial biopsies so that there was a greater likelihood of having an intact epidermis surrounding a malignancy that could be assessed for the presence of AKs as markers for field cancerization. Specimens were examined in full via serial transverse cross-sections at 3-mm intervals. Additional step sections were obtained at smaller intervals when margins were close or unclear.

Selected cases were reassessed by a board-certified dermatopathologist (G.G.) to confirm the diagnosis and to assess for the presence of at least 1 AK within the specimen sample that was separated from the original malignancy by histologically normal-appearing cells. Samples were also assessed for the presence of an AK within 0.1 mm of the distal lateral margins of the tissue sample. Information regarding patient age, gender, lesion location, lesion type, and specimen size was collected for each sample. In accordance with institutional review board protocol, research data were collected without any protected health information. All analyses and results were deidentified and stored on a password-protected computer database. Statistical analysis was performed using SPSS software. When applicable, P<.05 was considered to indicate statistical significance.

Results

There were 205 cases that passed the initial screening filters, of which 56 were excluded due to the presence of curettage or lack of a sufficient tissue sample. Of the remaining 149 cases, the distribution by malignancy type was tabulated along with the percentage of observed AKs. If an AK was observed, the percentage that had an AK at the lateral margins (marginal AK) was determined (Table 1). A χ² analysis determined that AKs were observed significantly more often in SCC specimens (57% [35/61]) than BCC (33% [21/64]) or malignant melanoma (25% [6/24]) specimens (P=.0125).

Statistics regarding patient age and gender as well as specimen size were stratified by malignancy type (Table 2). Using a receiver operating characteristic curve and the Youden index, an optimal cutoff of older than 67 years was determined to increase probability of observing an AK (P=.077) with sensitivity of 0.531 and specificity of 0.529. The distribution of specimen excision location for each malignancy type is shown in Table 3.

A multivariate analysis was performed to determine if the variables of patient age, gender, biopsy size, malignancy type (SCC, BCC, or MM), or cancer location (head, neck, trunk, arms, or legs) were independently useful in predicting whether an AK would be observed in the excision specimen. The significance of variables in the logistic regression model was assessed using a backward stepwise regression selection procedure entering variables if P<.15 and excluding variables if P>.25. Significant variables in predicting the occurrence of AK were SCC malignancy type (P=.007; odds ratio [OR], 2.61) and location on the head (P=.044; OR, 2.39) and arms (P=.042; OR, 2.55).

Comment

The χ² analysis of our data showed that SCC specimens were significantly more likely to have an associated AK than either BCCs or MMs (P=.0125), which is not surprising given that AKs are considered by many to be early-stage SCCs.¹² It is important to note, however, that BCCs and MMs both had nonnegligible rates of associated AKs. Although BCC and MM do not arise from the same background of genetic changes as SCC, this finding is noteworthy because it demonstrates definitive field damage with malignant potential in the area surrounding these cutaneous malignancies.

Our data also showed that there was a significantly greater association of AKs in malignancies located on the head (P=.044) and arms (P=.042), possibly because these 2 areas tend to be the most sun exposed and thus are more likely to have sustained field damage as evidenced by the higher percentage of AKs. A study by Jonason et al¹³ described a similar finding in which sun-exposed skin exhibited significantly more frequent (P=.04) and larger (P=.02) clonal patches of mutated p53 keratinocytes than sun-protected skin.

It is likely that the field damage surrounding the cutaneous lesions in our study is actually greater than what we reported because the AK was present at the margin of the excision specimens the majority of the time (56%), which suggests that there likely may have been more AKs found if a wider area surrounding the malignancy had been studied given that AKs often are at the periphery of the lesion and may be missed by a small excision. Fewer marginal AKs were observed with MM cases, possibly because the excision specimens were more than double the size of SCC or BCC excisions. Furthermore, there likely is to be more damage than what can be appreciated by visual changes alone.

Kanjilal et al¹⁴ used polymerase chain reaction and DNA sequencing to demonstrate numerous p53 mutations in nonmalignant-appearing skin surrounding BCCs and SCCs. Brennan et al¹⁵ found p53 mutations in surgical margins of excised SCCs considered to be tumor free by histopathologic analysis in more than half of the specimens studied. Notably, tumor recurrence was significantly more likely in areas where mutations were found and no tumor recurrence was seen in areas free of p53 mutations (P=.02).¹⁵ Tabor et al⁴ similarly found genetically altered fields in histologically clear surgical margins of SCCs but also showed that local tumor recurrence following excision had more molecular markers in common with the nonresected premalignant field than it did with the primary tumor. Thus, these studies provide a genetic basis for field damage that can exist even in histologically benign-appearing cells.

We believe our findings are clinically relevant, as they provide additional evidence for the theory of field cancerization as demonstrated by the nonnegligible rates of AKs and thus field damage with malignant potential in the skin immediately surrounding cutaneous malignancies. The limitations of our study, however, include a small sample size; no consideration of the effects of prior topical, field, or systemic treatments; and lack of a control group. Nevertheless, our findings emphasize the importance of assessing the extent of field damage when determining treatment strategies. Clinicians treating cutaneous malignancies should consider the need for field therapy, especially in sun-exposed regions, to avoid additional primary tumors.¹⁶ Further research is needed, however, to identify optimal methods for quantifying field damage clinically and determining the most effective treatment strategies.

The concept of field cancerization was first proposed in 1953 by Slaughter et al¹ in their study of oral squamous carcinomas. Their findings of multifocal patches of premalignant disease, abnormal tissue surrounding tumors, multiple localized primary tumors, and tumor recurrence following surgical resection was suggestive of a field of dysplastic cells with malignant potential.¹ Since then, modern molecular techniques have been used to establish a genetic basis for this model in many different types of cancer, including cutaneous malignancies.^2-4 The field begins from a singular stem cell, which undergoes one or more genetic changes that allow for a growth advantage compared to surrounding cells. The stem cell then divides, forming a patch of clonal daughter cells that displace the surrounding normal epithelium. Growth of this patch eventually leads to a dysplastic field of monoclonal cells, which notably does not yet show invasive growth or metastatic behavior. Over time, continued carcinogenic exposure results in additional genetic alterations among different cells in the field, which leads to new subclonal proliferations that share common clonal origin but exhibit unique genetic changes. Eventually, transformative events may occur, resulting in cells with invasive and metastatic properties, thus forming a carcinoma.⁵

In the case of cutaneous malignancies, UV radiation in the form of UVA and UVB rays is the most common source of carcinogenesis. It is well established that UV radiation has numerous effects on the body, including but not limited to local and systemic immunosuppression, alteration of signal transduction pathways, and the development of mutations in DNA via direct damage by UVB or indirect damage by free radical formation with UVA.^6,7 Normally, DNA is protected from UV radiation–induced genetic alteration by the p53 gene, TP53. As such, damage to this gene is highly associated with cancer induction. One study found that more than 90% of squamous cell carcinomas (SCCs) and more than 50% of basal cell carcinomas (BCCs) contain UV-like mutations in TP53.⁸ The concept of field cancerization suggests that because the skin surrounding cutaneous malignancies has been exposed to the same chronic UV light as the initial lesion, it is at an increased risk for genetic abnormalities and thus possible malignant transformation.

Actinic keratoses (AKs) are common neoplasms of the skin that generally are regarded as precancerous lesions or may be considered to be the earliest stage of SCC in situ.⁹ Actinic keratoses usually develop as a consequence of chronic exposure to UV radiation and often are clinically apparent as erythematous scaly papules in sun-exposed areas (Figure 1).¹⁰ They also are identified histologically as atypical keratinocytes along the basal layer of the epidermis with possible enlargement, hyperchromatic nuclei, lack of maturation, mitotic figures, inflammatory infiltrate, and/or hyperkeratosis.¹⁰ Furthermore, the genetic changes associated with AKs are well documented and are strongly associated with changes to p53.¹¹ Given these characteristics, AKs serve as good markers of genetic damage with potential for malignancy. In this study, we used histologically identified AKs to assess the presence of field damage in the tissue immediately surrounding excision specimens of SCCs, BCCs, and malignant melanomas (MMs).

Methods

This study was approved by the Program for the Protection of Human Subjects at the Icahn School of Medicine at Mount Sinai (New York, New York) prior to initiation. All cutaneous specimens submitted to the dermatopathology service for consultation between April 2013 and June 2013 were reviewed for inclusion in this study. Data collection was extended for MMs to include all specimens from January 2013 to June 2013 given the limited number of cases in the original data collection period.

Initial screening for this study was done electronically and assessed for a diagnosis of SCC (Figure 2), BCC (Figure 3), or MM (Figure 4) as determined by a board-certified dermatopathologist (G.G.). The resulting pool of specimens was then screened to include only excision specimens and to exclude curettage specimens and superficial specimens that lacked dermis. In this study, we chose to look at reexcisions rather than initial biopsies so that there was a greater likelihood of having an intact epidermis surrounding a malignancy that could be assessed for the presence of AKs as markers for field cancerization. Specimens were examined in full via serial transverse cross-sections at 3-mm intervals. Additional step sections were obtained at smaller intervals when margins were close or unclear.

Selected cases were reassessed by a board-certified dermatopathologist (G.G.) to confirm the diagnosis and to assess for the presence of at least 1 AK within the specimen sample that was separated from the original malignancy by histologically normal-appearing cells. Samples were also assessed for the presence of an AK within 0.1 mm of the distal lateral margins of the tissue sample. Information regarding patient age, gender, lesion location, lesion type, and specimen size was collected for each sample. In accordance with institutional review board protocol, research data were collected without any protected health information. All analyses and results were deidentified and stored on a password-protected computer database. Statistical analysis was performed using SPSS software. When applicable, P<.05 was considered to indicate statistical significance.

Results

There were 205 cases that passed the initial screening filters, of which 56 were excluded due to the presence of curettage or lack of a sufficient tissue sample. Of the remaining 149 cases, the distribution by malignancy type was tabulated along with the percentage of observed AKs. If an AK was observed, the percentage that had an AK at the lateral margins (marginal AK) was determined (Table 1). A χ² analysis determined that AKs were observed significantly more often in SCC specimens (57% [35/61]) than BCC (33% [21/64]) or malignant melanoma (25% [6/24]) specimens (P=.0125).

Statistics regarding patient age and gender as well as specimen size were stratified by malignancy type (Table 2). Using a receiver operating characteristic curve and the Youden index, an optimal cutoff of older than 67 years was determined to increase probability of observing an AK (P=.077) with sensitivity of 0.531 and specificity of 0.529. The distribution of specimen excision location for each malignancy type is shown in Table 3.

A multivariate analysis was performed to determine if the variables of patient age, gender, biopsy size, malignancy type (SCC, BCC, or MM), or cancer location (head, neck, trunk, arms, or legs) were independently useful in predicting whether an AK would be observed in the excision specimen. The significance of variables in the logistic regression model was assessed using a backward stepwise regression selection procedure entering variables if P<.15 and excluding variables if P>.25. Significant variables in predicting the occurrence of AK were SCC malignancy type (P=.007; odds ratio [OR], 2.61) and location on the head (P=.044; OR, 2.39) and arms (P=.042; OR, 2.55).

Comment

The χ² analysis of our data showed that SCC specimens were significantly more likely to have an associated AK than either BCCs or MMs (P=.0125), which is not surprising given that AKs are considered by many to be early-stage SCCs.¹² It is important to note, however, that BCCs and MMs both had nonnegligible rates of associated AKs. Although BCC and MM do not arise from the same background of genetic changes as SCC, this finding is noteworthy because it demonstrates definitive field damage with malignant potential in the area surrounding these cutaneous malignancies.

Our data also showed that there was a significantly greater association of AKs in malignancies located on the head (P=.044) and arms (P=.042), possibly because these 2 areas tend to be the most sun exposed and thus are more likely to have sustained field damage as evidenced by the higher percentage of AKs. A study by Jonason et al¹³ described a similar finding in which sun-exposed skin exhibited significantly more frequent (P=.04) and larger (P=.02) clonal patches of mutated p53 keratinocytes than sun-protected skin.

It is likely that the field damage surrounding the cutaneous lesions in our study is actually greater than what we reported because the AK was present at the margin of the excision specimens the majority of the time (56%), which suggests that there likely may have been more AKs found if a wider area surrounding the malignancy had been studied given that AKs often are at the periphery of the lesion and may be missed by a small excision. Fewer marginal AKs were observed with MM cases, possibly because the excision specimens were more than double the size of SCC or BCC excisions. Furthermore, there likely is to be more damage than what can be appreciated by visual changes alone.

Kanjilal et al¹⁴ used polymerase chain reaction and DNA sequencing to demonstrate numerous p53 mutations in nonmalignant-appearing skin surrounding BCCs and SCCs. Brennan et al¹⁵ found p53 mutations in surgical margins of excised SCCs considered to be tumor free by histopathologic analysis in more than half of the specimens studied. Notably, tumor recurrence was significantly more likely in areas where mutations were found and no tumor recurrence was seen in areas free of p53 mutations (P=.02).¹⁵ Tabor et al⁴ similarly found genetically altered fields in histologically clear surgical margins of SCCs but also showed that local tumor recurrence following excision had more molecular markers in common with the nonresected premalignant field than it did with the primary tumor. Thus, these studies provide a genetic basis for field damage that can exist even in histologically benign-appearing cells.

We believe our findings are clinically relevant, as they provide additional evidence for the theory of field cancerization as demonstrated by the nonnegligible rates of AKs and thus field damage with malignant potential in the skin immediately surrounding cutaneous malignancies. The limitations of our study, however, include a small sample size; no consideration of the effects of prior topical, field, or systemic treatments; and lack of a control group. Nevertheless, our findings emphasize the importance of assessing the extent of field damage when determining treatment strategies. Clinicians treating cutaneous malignancies should consider the need for field therapy, especially in sun-exposed regions, to avoid additional primary tumors.¹⁶ Further research is needed, however, to identify optimal methods for quantifying field damage clinically and determining the most effective treatment strategies.

The concept of field cancerization was first proposed in 1953 by Slaughter et al¹ in their study of oral squamous carcinomas. Their findings of multifocal patches of premalignant disease, abnormal tissue surrounding tumors, multiple localized primary tumors, and tumor recurrence following surgical resection was suggestive of a field of dysplastic cells with malignant potential.¹ Since then, modern molecular techniques have been used to establish a genetic basis for this model in many different types of cancer, including cutaneous malignancies.^2-4 The field begins from a singular stem cell, which undergoes one or more genetic changes that allow for a growth advantage compared to surrounding cells. The stem cell then divides, forming a patch of clonal daughter cells that displace the surrounding normal epithelium. Growth of this patch eventually leads to a dysplastic field of monoclonal cells, which notably does not yet show invasive growth or metastatic behavior. Over time, continued carcinogenic exposure results in additional genetic alterations among different cells in the field, which leads to new subclonal proliferations that share common clonal origin but exhibit unique genetic changes. Eventually, transformative events may occur, resulting in cells with invasive and metastatic properties, thus forming a carcinoma.⁵

In the case of cutaneous malignancies, UV radiation in the form of UVA and UVB rays is the most common source of carcinogenesis. It is well established that UV radiation has numerous effects on the body, including but not limited to local and systemic immunosuppression, alteration of signal transduction pathways, and the development of mutations in DNA via direct damage by UVB or indirect damage by free radical formation with UVA.^6,7 Normally, DNA is protected from UV radiation–induced genetic alteration by the p53 gene, TP53. As such, damage to this gene is highly associated with cancer induction. One study found that more than 90% of squamous cell carcinomas (SCCs) and more than 50% of basal cell carcinomas (BCCs) contain UV-like mutations in TP53.⁸ The concept of field cancerization suggests that because the skin surrounding cutaneous malignancies has been exposed to the same chronic UV light as the initial lesion, it is at an increased risk for genetic abnormalities and thus possible malignant transformation.

Actinic keratoses (AKs) are common neoplasms of the skin that generally are regarded as precancerous lesions or may be considered to be the earliest stage of SCC in situ.⁹ Actinic keratoses usually develop as a consequence of chronic exposure to UV radiation and often are clinically apparent as erythematous scaly papules in sun-exposed areas (Figure 1).¹⁰ They also are identified histologically as atypical keratinocytes along the basal layer of the epidermis with possible enlargement, hyperchromatic nuclei, lack of maturation, mitotic figures, inflammatory infiltrate, and/or hyperkeratosis.¹⁰ Furthermore, the genetic changes associated with AKs are well documented and are strongly associated with changes to p53.¹¹ Given these characteristics, AKs serve as good markers of genetic damage with potential for malignancy. In this study, we used histologically identified AKs to assess the presence of field damage in the tissue immediately surrounding excision specimens of SCCs, BCCs, and malignant melanomas (MMs).

Methods

This study was approved by the Program for the Protection of Human Subjects at the Icahn School of Medicine at Mount Sinai (New York, New York) prior to initiation. All cutaneous specimens submitted to the dermatopathology service for consultation between April 2013 and June 2013 were reviewed for inclusion in this study. Data collection was extended for MMs to include all specimens from January 2013 to June 2013 given the limited number of cases in the original data collection period.

Initial screening for this study was done electronically and assessed for a diagnosis of SCC (Figure 2), BCC (Figure 3), or MM (Figure 4) as determined by a board-certified dermatopathologist (G.G.). The resulting pool of specimens was then screened to include only excision specimens and to exclude curettage specimens and superficial specimens that lacked dermis. In this study, we chose to look at reexcisions rather than initial biopsies so that there was a greater likelihood of having an intact epidermis surrounding a malignancy that could be assessed for the presence of AKs as markers for field cancerization. Specimens were examined in full via serial transverse cross-sections at 3-mm intervals. Additional step sections were obtained at smaller intervals when margins were close or unclear.

Selected cases were reassessed by a board-certified dermatopathologist (G.G.) to confirm the diagnosis and to assess for the presence of at least 1 AK within the specimen sample that was separated from the original malignancy by histologically normal-appearing cells. Samples were also assessed for the presence of an AK within 0.1 mm of the distal lateral margins of the tissue sample. Information regarding patient age, gender, lesion location, lesion type, and specimen size was collected for each sample. In accordance with institutional review board protocol, research data were collected without any protected health information. All analyses and results were deidentified and stored on a password-protected computer database. Statistical analysis was performed using SPSS software. When applicable, P<.05 was considered to indicate statistical significance.

Results

There were 205 cases that passed the initial screening filters, of which 56 were excluded due to the presence of curettage or lack of a sufficient tissue sample. Of the remaining 149 cases, the distribution by malignancy type was tabulated along with the percentage of observed AKs. If an AK was observed, the percentage that had an AK at the lateral margins (marginal AK) was determined (Table 1). A χ² analysis determined that AKs were observed significantly more often in SCC specimens (57% [35/61]) than BCC (33% [21/64]) or malignant melanoma (25% [6/24]) specimens (P=.0125).

Statistics regarding patient age and gender as well as specimen size were stratified by malignancy type (Table 2). Using a receiver operating characteristic curve and the Youden index, an optimal cutoff of older than 67 years was determined to increase probability of observing an AK (P=.077) with sensitivity of 0.531 and specificity of 0.529. The distribution of specimen excision location for each malignancy type is shown in Table 3.

A multivariate analysis was performed to determine if the variables of patient age, gender, biopsy size, malignancy type (SCC, BCC, or MM), or cancer location (head, neck, trunk, arms, or legs) were independently useful in predicting whether an AK would be observed in the excision specimen. The significance of variables in the logistic regression model was assessed using a backward stepwise regression selection procedure entering variables if P<.15 and excluding variables if P>.25. Significant variables in predicting the occurrence of AK were SCC malignancy type (P=.007; odds ratio [OR], 2.61) and location on the head (P=.044; OR, 2.39) and arms (P=.042; OR, 2.55).

Comment

The χ² analysis of our data showed that SCC specimens were significantly more likely to have an associated AK than either BCCs or MMs (P=.0125), which is not surprising given that AKs are considered by many to be early-stage SCCs.¹² It is important to note, however, that BCCs and MMs both had nonnegligible rates of associated AKs. Although BCC and MM do not arise from the same background of genetic changes as SCC, this finding is noteworthy because it demonstrates definitive field damage with malignant potential in the area surrounding these cutaneous malignancies.

Our data also showed that there was a significantly greater association of AKs in malignancies located on the head (P=.044) and arms (P=.042), possibly because these 2 areas tend to be the most sun exposed and thus are more likely to have sustained field damage as evidenced by the higher percentage of AKs. A study by Jonason et al¹³ described a similar finding in which sun-exposed skin exhibited significantly more frequent (P=.04) and larger (P=.02) clonal patches of mutated p53 keratinocytes than sun-protected skin.

It is likely that the field damage surrounding the cutaneous lesions in our study is actually greater than what we reported because the AK was present at the margin of the excision specimens the majority of the time (56%), which suggests that there likely may have been more AKs found if a wider area surrounding the malignancy had been studied given that AKs often are at the periphery of the lesion and may be missed by a small excision. Fewer marginal AKs were observed with MM cases, possibly because the excision specimens were more than double the size of SCC or BCC excisions. Furthermore, there likely is to be more damage than what can be appreciated by visual changes alone.

Kanjilal et al¹⁴ used polymerase chain reaction and DNA sequencing to demonstrate numerous p53 mutations in nonmalignant-appearing skin surrounding BCCs and SCCs. Brennan et al¹⁵ found p53 mutations in surgical margins of excised SCCs considered to be tumor free by histopathologic analysis in more than half of the specimens studied. Notably, tumor recurrence was significantly more likely in areas where mutations were found and no tumor recurrence was seen in areas free of p53 mutations (P=.02).¹⁵ Tabor et al⁴ similarly found genetically altered fields in histologically clear surgical margins of SCCs but also showed that local tumor recurrence following excision had more molecular markers in common with the nonresected premalignant field than it did with the primary tumor. Thus, these studies provide a genetic basis for field damage that can exist even in histologically benign-appearing cells.

We believe our findings are clinically relevant, as they provide additional evidence for the theory of field cancerization as demonstrated by the nonnegligible rates of AKs and thus field damage with malignant potential in the skin immediately surrounding cutaneous malignancies. The limitations of our study, however, include a small sample size; no consideration of the effects of prior topical, field, or systemic treatments; and lack of a control group. Nevertheless, our findings emphasize the importance of assessing the extent of field damage when determining treatment strategies. Clinicians treating cutaneous malignancies should consider the need for field therapy, especially in sun-exposed regions, to avoid additional primary tumors.¹⁶ Further research is needed, however, to identify optimal methods for quantifying field damage clinically and determining the most effective treatment strategies.

Early in my career, an attorney asked me to review a malpractice case. “The question,” he said, “is whether liquid nitrogen is the standard of care for treating warts.”

Come again?

A young woman had visited an academic center, where a physician froze her warts. These blistered and turned purple. Alarmed, she went to an ER, where doctors admitted her for cellulitis and gave her intravenous antibiotics for several days.

I later submitted an essay based on this case to my malpractice insurer’s Risk Management Contest, in which I called for better communication between treating doctors and those who follow up. I placed second and got a check from my malpractice insurer. How cool is that?

I hadn’t thought about that case in years, until last month. Earvin is a late-middle-aged gent with psoriasis on his elbows and liver spots on his chest. He asked me to freeze them, as I had done before.

After lunch 2 days later, my secretary buzzed me. “The man on the phone is very unhappy,” she said. “He says he called this morning and no one called back. He says if he doesn’t hear from you, his next call will be to his attorney.”

I phoned Earvin. My apology for not having gotten the message before was met with frigid hostility. “That’s unconscionable,” he said.

“My skin swelled up like a balloon,” he told me. “I know what to expect with freezing, and this never happened before. I think this time you froze me with a heavy hand. When I didn’t hear from you, I went to an urgent care clinic down the street. They said it was infected and prescribed an antibiotic ointment. I had to wait an hour, and the ointment cost $49.”

I held my breath. “Actually,” I said, “I don’t think it’s infected.”

“They said it was infected,” said Earvin. “It is swollen. I’m afraid it is going to scar. The cream cost $49.”

Straining to keep my voice even, I replied, “Would you like me to have a look at it?”

“I live too far,” he said. “I don’t have a ride. Maybe I will come tomorrow if someone can take me.”

Later that day I called him back. “I live the next town over from you,” I said. “I will stop by on my way home.” He agreed, and told me the color of his house.

Earvin let me in looking less angry than fearful. One glance at his chest told me what I needed to know: There was no infection. His skin looked like what skin looks like after it’s been frozen. Other treated areas – the ones Earvin wasn’t worried about – looked the same to me, though clearly not to him. “This one was worse,” he said. “It’s gone down since this morning.”

After examining Earvin with my cell phone flashlight, I sat down across from him. “Let me be clear,” I said. “You are not infected. Some areas frozen at the same time in the same way blister more briskly than others. In the end they heal fine, and so will yours. You’re not going to scar.”

Earvin relaxed a little. “I was afraid I’d done something I didn’t need to. My mother had skin cancer on her chest, not far from where this one is. My skin was discolored and swollen. The doctor at urgent care said it was infected.” There was a pause, as Earvin slumped in his chair. “I feel better,” he allowed.

There it was, the whole package – thinking that was full of hopelessly muddled categories. Infection? Scarring? Skin cancer? Yes to all? And there was moral anxiety – disappointment in himself for doing something needless and now having to pay the price – as well as anger at me as the instrument of retribution. Who knows what else? There were so many strands, hopelessly coiled, impossible to disentangle.

And all wrapped up in elemental terror. What have I done? What has he done?

Earvin did not need treatment. He needed a hug. Metaphorically, that is what I gave him.

So much angst, so much anger, so much fear, so little time. To be frank, it gets tiring.

People like to quote the philosopher George Santayana. He said that those who cannot remember the past are condemned to repeat it.

I like to paraphrase the even greater philosopher Bill Murray of “Groundhog Day”: Those who do remember the past are condemned to repeat it anyway.

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years.

Early in my career, an attorney asked me to review a malpractice case. “The question,” he said, “is whether liquid nitrogen is the standard of care for treating warts.”

Come again?

A young woman had visited an academic center, where a physician froze her warts. These blistered and turned purple. Alarmed, she went to an ER, where doctors admitted her for cellulitis and gave her intravenous antibiotics for several days.

I later submitted an essay based on this case to my malpractice insurer’s Risk Management Contest, in which I called for better communication between treating doctors and those who follow up. I placed second and got a check from my malpractice insurer. How cool is that?

I hadn’t thought about that case in years, until last month. Earvin is a late-middle-aged gent with psoriasis on his elbows and liver spots on his chest. He asked me to freeze them, as I had done before.

After lunch 2 days later, my secretary buzzed me. “The man on the phone is very unhappy,” she said. “He says he called this morning and no one called back. He says if he doesn’t hear from you, his next call will be to his attorney.”

I phoned Earvin. My apology for not having gotten the message before was met with frigid hostility. “That’s unconscionable,” he said.

“My skin swelled up like a balloon,” he told me. “I know what to expect with freezing, and this never happened before. I think this time you froze me with a heavy hand. When I didn’t hear from you, I went to an urgent care clinic down the street. They said it was infected and prescribed an antibiotic ointment. I had to wait an hour, and the ointment cost $49.”

I held my breath. “Actually,” I said, “I don’t think it’s infected.”

“They said it was infected,” said Earvin. “It is swollen. I’m afraid it is going to scar. The cream cost $49.”

Straining to keep my voice even, I replied, “Would you like me to have a look at it?”

“I live too far,” he said. “I don’t have a ride. Maybe I will come tomorrow if someone can take me.”

Later that day I called him back. “I live the next town over from you,” I said. “I will stop by on my way home.” He agreed, and told me the color of his house.

Earvin let me in looking less angry than fearful. One glance at his chest told me what I needed to know: There was no infection. His skin looked like what skin looks like after it’s been frozen. Other treated areas – the ones Earvin wasn’t worried about – looked the same to me, though clearly not to him. “This one was worse,” he said. “It’s gone down since this morning.”

After examining Earvin with my cell phone flashlight, I sat down across from him. “Let me be clear,” I said. “You are not infected. Some areas frozen at the same time in the same way blister more briskly than others. In the end they heal fine, and so will yours. You’re not going to scar.”

Earvin relaxed a little. “I was afraid I’d done something I didn’t need to. My mother had skin cancer on her chest, not far from where this one is. My skin was discolored and swollen. The doctor at urgent care said it was infected.” There was a pause, as Earvin slumped in his chair. “I feel better,” he allowed.

There it was, the whole package – thinking that was full of hopelessly muddled categories. Infection? Scarring? Skin cancer? Yes to all? And there was moral anxiety – disappointment in himself for doing something needless and now having to pay the price – as well as anger at me as the instrument of retribution. Who knows what else? There were so many strands, hopelessly coiled, impossible to disentangle.

And all wrapped up in elemental terror. What have I done? What has he done?

Earvin did not need treatment. He needed a hug. Metaphorically, that is what I gave him.

So much angst, so much anger, so much fear, so little time. To be frank, it gets tiring.

People like to quote the philosopher George Santayana. He said that those who cannot remember the past are condemned to repeat it.

I like to paraphrase the even greater philosopher Bill Murray of “Groundhog Day”: Those who do remember the past are condemned to repeat it anyway.

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years.

Early in my career, an attorney asked me to review a malpractice case. “The question,” he said, “is whether liquid nitrogen is the standard of care for treating warts.”

Come again?

A young woman had visited an academic center, where a physician froze her warts. These blistered and turned purple. Alarmed, she went to an ER, where doctors admitted her for cellulitis and gave her intravenous antibiotics for several days.

I later submitted an essay based on this case to my malpractice insurer’s Risk Management Contest, in which I called for better communication between treating doctors and those who follow up. I placed second and got a check from my malpractice insurer. How cool is that?

I hadn’t thought about that case in years, until last month. Earvin is a late-middle-aged gent with psoriasis on his elbows and liver spots on his chest. He asked me to freeze them, as I had done before.

After lunch 2 days later, my secretary buzzed me. “The man on the phone is very unhappy,” she said. “He says he called this morning and no one called back. He says if he doesn’t hear from you, his next call will be to his attorney.”

I phoned Earvin. My apology for not having gotten the message before was met with frigid hostility. “That’s unconscionable,” he said.

“My skin swelled up like a balloon,” he told me. “I know what to expect with freezing, and this never happened before. I think this time you froze me with a heavy hand. When I didn’t hear from you, I went to an urgent care clinic down the street. They said it was infected and prescribed an antibiotic ointment. I had to wait an hour, and the ointment cost $49.”

I held my breath. “Actually,” I said, “I don’t think it’s infected.”

“They said it was infected,” said Earvin. “It is swollen. I’m afraid it is going to scar. The cream cost $49.”

Straining to keep my voice even, I replied, “Would you like me to have a look at it?”

“I live too far,” he said. “I don’t have a ride. Maybe I will come tomorrow if someone can take me.”

Later that day I called him back. “I live the next town over from you,” I said. “I will stop by on my way home.” He agreed, and told me the color of his house.

Earvin let me in looking less angry than fearful. One glance at his chest told me what I needed to know: There was no infection. His skin looked like what skin looks like after it’s been frozen. Other treated areas – the ones Earvin wasn’t worried about – looked the same to me, though clearly not to him. “This one was worse,” he said. “It’s gone down since this morning.”

After examining Earvin with my cell phone flashlight, I sat down across from him. “Let me be clear,” I said. “You are not infected. Some areas frozen at the same time in the same way blister more briskly than others. In the end they heal fine, and so will yours. You’re not going to scar.”

Earvin relaxed a little. “I was afraid I’d done something I didn’t need to. My mother had skin cancer on her chest, not far from where this one is. My skin was discolored and swollen. The doctor at urgent care said it was infected.” There was a pause, as Earvin slumped in his chair. “I feel better,” he allowed.

There it was, the whole package – thinking that was full of hopelessly muddled categories. Infection? Scarring? Skin cancer? Yes to all? And there was moral anxiety – disappointment in himself for doing something needless and now having to pay the price – as well as anger at me as the instrument of retribution. Who knows what else? There were so many strands, hopelessly coiled, impossible to disentangle.

And all wrapped up in elemental terror. What have I done? What has he done?

Earvin did not need treatment. He needed a hug. Metaphorically, that is what I gave him.

So much angst, so much anger, so much fear, so little time. To be frank, it gets tiring.

People like to quote the philosopher George Santayana. He said that those who cannot remember the past are condemned to repeat it.

I like to paraphrase the even greater philosopher Bill Murray of “Groundhog Day”: Those who do remember the past are condemned to repeat it anyway.

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years.

Rheumatoid arthritis (RA) commonly affects the hand and fingers, most often at the metacarpophalangeal and proximal interphalangeal (PIP) joints. Synovitis, tendon ruptures, Boutonnière and swan-neck deformities, and joint destruction often occur. Bony ankylosis is not commonly described yet frequently occurs in patients with RA.¹

Implant arthroplasty is an established treatment for arthritis of the hand and fingers. Indications for its use include RA, osteoarthritis, and posttraumatic arthritis. Most patients treated with implant arthroplasty can expect pain relief and 40° to 65° of PIP joint motion.^2,3 Silicone arthroplasty historically has been used for pain relief but not for restoration of motion in an ankylosed joint. To our knowledge, there are no reports of using implant arthroplasty in the treatment of spontaneous ankylosis in RA. Contraindications for this procedure would include infection, irreparable flexor or extensor apparatus, and severe medical comorbidities.

In this article, we report a case of PIP joint autofusion treated with silicone PIP arthroplasty in a patient with RA. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 56-year-old woman who had had RA for more than 20 years underwent left carpometacarpal arthroplasty and thumb reconstruction. She subsequently presented with complaints of progressively worsening functioning of the left ring and small fingers. On initial evaluation, her PIP joints were fused in about 15° of flexion. Radiographs (Figures 1A, 1B) showed severe diffuse arthritis of the hands and complete bony ankylosis of the ring- and small-finger PIP joints with radial deviation of the ring-finger middle phalanx. The patient had minimal pain but wanted improved hand motion and opted for takedown of the ankylosis with silicone PIP joint arthroplasty.

Radial dorsal incisions were made over the PIP joints of the ring and small fingers. As is not the case with arthroplasty for routine PIP joint arthritis, presence of bony ankylosis made identification of the native PIP joint more difficult. The transverse retinacular ligament was identified and opened, and the collateral ligament, which was not ankylosed, was dissected off the proximal phalanx. These landmarks were useful in locating the PIP joint, and proper positioning was confirmed with fluoroscopy. The ankylosed joint space was opened with an osteotome, and about 8 to 10 mm of bone was resected to create space for the instrumentation. As the amount of scarring within the flexor tendon sheath was not significant, restoration of motion did not require extensive tenolysis. The extensor mechanism was slightly contracted, but the bony resection allowed flexion to be restored. The distal portion of the proximal phalanx was then resected. The proximal and middle phalanges were reamed, and a silicone prosthesis was placed with the finger held straight. The collateral ligament was repaired back to the proximal phalanx with 4-0 polydioxanone sutures placed through a bone tunnel created with a Kirschner wire. The skin was closed with 4-0 nylon, and a postoperative splint was applied.

The initial postoperative course was unremarkable. The patient was immobilized in 10° of PIP joint flexion for 10 days, and therapy was initiated after the splint was removed. Twenty-four months after surgery, the patient was pain-free and had 60° of active PIP joint flexion, with extensor lag of only 10°. Clinically, alignment of the fingers was satisfactory; there was mild persistent radial deviation of 10° to 15° (Figures 2A, 2B). Radiographs showed good positioning of the implants (Figures 3A, 3B) and no sign of coronal instability. The patient was satisfied with her improved functioning and returned to employment as a hospital clerk, working full-time.

Discussion

RA of the hand and fingers can be painful and disabling. Although there are several treatment options for many of the most common manifestations, options are limited for bony ankylosis of the finger joints. The patient described in this case report had minimal pain, but the loss of motion of the PIP joints in her ring and small fingers created difficulties for her at work. She wanted surgery that would improve the functioning of her fingers. PIP joint arthroplasty traditionally has been the treatment of choice for PIP joint arthritis. In 1985, Swanson and colleagues² reported on more than 400 silicone PIP arthroplasties performed over 16 years. Mean range of motion (ROM) was between 45° and 60°, with 70% of patients having ROM of more than 40°. Pain relief was complete in 98% of cases. Complications included implant fracture (5%) and recurrent or new deformities (6.5%). A 10.9% revision rate was noted at minimum 1-year follow-up. Recent implants made of improved biomaterials hold promise, but longer term follow-up is still needed.

Silicone arthroplasty has also been used as an effective treatment for non-RA of the PIP joint. Bales and colleagues⁴ reviewed long-term results of silicone arthroplasty for PIP joint osteoarthritis in 22 patients. At a mean of 10 years, mean QuickDASH (Disabilities of the Arm, Shoulder, and Hand) score was 17, mean visual analog scale score for pain was 0.4, and implant survivorship was 90%. Despite unchanged ROM and considerable implant deformation or fracture, patients’ pain relief and satisfaction were consistent.

Hage and colleagues⁵ reviewed long-term results of silicone PIP arthroplasty for posttraumatic arthritis in 14 patients. Most of the patients were satisfied: Although they had notable rotational deformity, alignment deviation, and loss of pinch strength and ROM, they were pain-free. The authors concluded that silicone arthroplasty should be used for posttraumatic arthrosis cases in which associated adhesions may be corrected with simple tenolysis, and even in these cases the objective results may not be as good as the subjective outcome.

Kaye⁶ used radiographs to determine the incidence of bony ankylosis in 203 patients with RA. Hand and wrist radiographs of 48 (23.6%) of these patients showed ankylosis, and 34 of the 48 patients had 2 or more joints fused. On a questionnaire, patients with ankylosis indicated more difficulty with activities of daily living and more limited activity. The authors concluded that radiographic bony ankylosis was a relatively common feature of RA and a marker of disease that was clinically, radiographically, and functionally more severe.

The patient described in this case report had a satisfactory result after PIP joint arthroplasty. At 2-year follow-up, she remained pain-free, and her previously ankylosed PIP joint had an arc of motion of 10° to 60°. Most patients with bony ankylosis of PIP joints present with minimal pain and do not seek surgical treatment. However, patients with ankylosis that limits functioning or activities of daily living may wish to pursue intervention that could be restorative. PIP joint arthroplasty may be effective in improving motion in patients with bony ankylosis of the finger joints.

Rheumatoid arthritis (RA) commonly affects the hand and fingers, most often at the metacarpophalangeal and proximal interphalangeal (PIP) joints. Synovitis, tendon ruptures, Boutonnière and swan-neck deformities, and joint destruction often occur. Bony ankylosis is not commonly described yet frequently occurs in patients with RA.¹

Implant arthroplasty is an established treatment for arthritis of the hand and fingers. Indications for its use include RA, osteoarthritis, and posttraumatic arthritis. Most patients treated with implant arthroplasty can expect pain relief and 40° to 65° of PIP joint motion.^2,3 Silicone arthroplasty historically has been used for pain relief but not for restoration of motion in an ankylosed joint. To our knowledge, there are no reports of using implant arthroplasty in the treatment of spontaneous ankylosis in RA. Contraindications for this procedure would include infection, irreparable flexor or extensor apparatus, and severe medical comorbidities.

In this article, we report a case of PIP joint autofusion treated with silicone PIP arthroplasty in a patient with RA. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 56-year-old woman who had had RA for more than 20 years underwent left carpometacarpal arthroplasty and thumb reconstruction. She subsequently presented with complaints of progressively worsening functioning of the left ring and small fingers. On initial evaluation, her PIP joints were fused in about 15° of flexion. Radiographs (Figures 1A, 1B) showed severe diffuse arthritis of the hands and complete bony ankylosis of the ring- and small-finger PIP joints with radial deviation of the ring-finger middle phalanx. The patient had minimal pain but wanted improved hand motion and opted for takedown of the ankylosis with silicone PIP joint arthroplasty.

Radial dorsal incisions were made over the PIP joints of the ring and small fingers. As is not the case with arthroplasty for routine PIP joint arthritis, presence of bony ankylosis made identification of the native PIP joint more difficult. The transverse retinacular ligament was identified and opened, and the collateral ligament, which was not ankylosed, was dissected off the proximal phalanx. These landmarks were useful in locating the PIP joint, and proper positioning was confirmed with fluoroscopy. The ankylosed joint space was opened with an osteotome, and about 8 to 10 mm of bone was resected to create space for the instrumentation. As the amount of scarring within the flexor tendon sheath was not significant, restoration of motion did not require extensive tenolysis. The extensor mechanism was slightly contracted, but the bony resection allowed flexion to be restored. The distal portion of the proximal phalanx was then resected. The proximal and middle phalanges were reamed, and a silicone prosthesis was placed with the finger held straight. The collateral ligament was repaired back to the proximal phalanx with 4-0 polydioxanone sutures placed through a bone tunnel created with a Kirschner wire. The skin was closed with 4-0 nylon, and a postoperative splint was applied.

The initial postoperative course was unremarkable. The patient was immobilized in 10° of PIP joint flexion for 10 days, and therapy was initiated after the splint was removed. Twenty-four months after surgery, the patient was pain-free and had 60° of active PIP joint flexion, with extensor lag of only 10°. Clinically, alignment of the fingers was satisfactory; there was mild persistent radial deviation of 10° to 15° (Figures 2A, 2B). Radiographs showed good positioning of the implants (Figures 3A, 3B) and no sign of coronal instability. The patient was satisfied with her improved functioning and returned to employment as a hospital clerk, working full-time.

Discussion

RA of the hand and fingers can be painful and disabling. Although there are several treatment options for many of the most common manifestations, options are limited for bony ankylosis of the finger joints. The patient described in this case report had minimal pain, but the loss of motion of the PIP joints in her ring and small fingers created difficulties for her at work. She wanted surgery that would improve the functioning of her fingers. PIP joint arthroplasty traditionally has been the treatment of choice for PIP joint arthritis. In 1985, Swanson and colleagues² reported on more than 400 silicone PIP arthroplasties performed over 16 years. Mean range of motion (ROM) was between 45° and 60°, with 70% of patients having ROM of more than 40°. Pain relief was complete in 98% of cases. Complications included implant fracture (5%) and recurrent or new deformities (6.5%). A 10.9% revision rate was noted at minimum 1-year follow-up. Recent implants made of improved biomaterials hold promise, but longer term follow-up is still needed.

Silicone arthroplasty has also been used as an effective treatment for non-RA of the PIP joint. Bales and colleagues⁴ reviewed long-term results of silicone arthroplasty for PIP joint osteoarthritis in 22 patients. At a mean of 10 years, mean QuickDASH (Disabilities of the Arm, Shoulder, and Hand) score was 17, mean visual analog scale score for pain was 0.4, and implant survivorship was 90%. Despite unchanged ROM and considerable implant deformation or fracture, patients’ pain relief and satisfaction were consistent.

Hage and colleagues⁵ reviewed long-term results of silicone PIP arthroplasty for posttraumatic arthritis in 14 patients. Most of the patients were satisfied: Although they had notable rotational deformity, alignment deviation, and loss of pinch strength and ROM, they were pain-free. The authors concluded that silicone arthroplasty should be used for posttraumatic arthrosis cases in which associated adhesions may be corrected with simple tenolysis, and even in these cases the objective results may not be as good as the subjective outcome.

Kaye⁶ used radiographs to determine the incidence of bony ankylosis in 203 patients with RA. Hand and wrist radiographs of 48 (23.6%) of these patients showed ankylosis, and 34 of the 48 patients had 2 or more joints fused. On a questionnaire, patients with ankylosis indicated more difficulty with activities of daily living and more limited activity. The authors concluded that radiographic bony ankylosis was a relatively common feature of RA and a marker of disease that was clinically, radiographically, and functionally more severe.

The patient described in this case report had a satisfactory result after PIP joint arthroplasty. At 2-year follow-up, she remained pain-free, and her previously ankylosed PIP joint had an arc of motion of 10° to 60°. Most patients with bony ankylosis of PIP joints present with minimal pain and do not seek surgical treatment. However, patients with ankylosis that limits functioning or activities of daily living may wish to pursue intervention that could be restorative. PIP joint arthroplasty may be effective in improving motion in patients with bony ankylosis of the finger joints.

Rheumatoid arthritis (RA) commonly affects the hand and fingers, most often at the metacarpophalangeal and proximal interphalangeal (PIP) joints. Synovitis, tendon ruptures, Boutonnière and swan-neck deformities, and joint destruction often occur. Bony ankylosis is not commonly described yet frequently occurs in patients with RA.¹

Implant arthroplasty is an established treatment for arthritis of the hand and fingers. Indications for its use include RA, osteoarthritis, and posttraumatic arthritis. Most patients treated with implant arthroplasty can expect pain relief and 40° to 65° of PIP joint motion.^2,3 Silicone arthroplasty historically has been used for pain relief but not for restoration of motion in an ankylosed joint. To our knowledge, there are no reports of using implant arthroplasty in the treatment of spontaneous ankylosis in RA. Contraindications for this procedure would include infection, irreparable flexor or extensor apparatus, and severe medical comorbidities.

In this article, we report a case of PIP joint autofusion treated with silicone PIP arthroplasty in a patient with RA. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 56-year-old woman who had had RA for more than 20 years underwent left carpometacarpal arthroplasty and thumb reconstruction. She subsequently presented with complaints of progressively worsening functioning of the left ring and small fingers. On initial evaluation, her PIP joints were fused in about 15° of flexion. Radiographs (Figures 1A, 1B) showed severe diffuse arthritis of the hands and complete bony ankylosis of the ring- and small-finger PIP joints with radial deviation of the ring-finger middle phalanx. The patient had minimal pain but wanted improved hand motion and opted for takedown of the ankylosis with silicone PIP joint arthroplasty.

Radial dorsal incisions were made over the PIP joints of the ring and small fingers. As is not the case with arthroplasty for routine PIP joint arthritis, presence of bony ankylosis made identification of the native PIP joint more difficult. The transverse retinacular ligament was identified and opened, and the collateral ligament, which was not ankylosed, was dissected off the proximal phalanx. These landmarks were useful in locating the PIP joint, and proper positioning was confirmed with fluoroscopy. The ankylosed joint space was opened with an osteotome, and about 8 to 10 mm of bone was resected to create space for the instrumentation. As the amount of scarring within the flexor tendon sheath was not significant, restoration of motion did not require extensive tenolysis. The extensor mechanism was slightly contracted, but the bony resection allowed flexion to be restored. The distal portion of the proximal phalanx was then resected. The proximal and middle phalanges were reamed, and a silicone prosthesis was placed with the finger held straight. The collateral ligament was repaired back to the proximal phalanx with 4-0 polydioxanone sutures placed through a bone tunnel created with a Kirschner wire. The skin was closed with 4-0 nylon, and a postoperative splint was applied.

The initial postoperative course was unremarkable. The patient was immobilized in 10° of PIP joint flexion for 10 days, and therapy was initiated after the splint was removed. Twenty-four months after surgery, the patient was pain-free and had 60° of active PIP joint flexion, with extensor lag of only 10°. Clinically, alignment of the fingers was satisfactory; there was mild persistent radial deviation of 10° to 15° (Figures 2A, 2B). Radiographs showed good positioning of the implants (Figures 3A, 3B) and no sign of coronal instability. The patient was satisfied with her improved functioning and returned to employment as a hospital clerk, working full-time.

Discussion

RA of the hand and fingers can be painful and disabling. Although there are several treatment options for many of the most common manifestations, options are limited for bony ankylosis of the finger joints. The patient described in this case report had minimal pain, but the loss of motion of the PIP joints in her ring and small fingers created difficulties for her at work. She wanted surgery that would improve the functioning of her fingers. PIP joint arthroplasty traditionally has been the treatment of choice for PIP joint arthritis. In 1985, Swanson and colleagues² reported on more than 400 silicone PIP arthroplasties performed over 16 years. Mean range of motion (ROM) was between 45° and 60°, with 70% of patients having ROM of more than 40°. Pain relief was complete in 98% of cases. Complications included implant fracture (5%) and recurrent or new deformities (6.5%). A 10.9% revision rate was noted at minimum 1-year follow-up. Recent implants made of improved biomaterials hold promise, but longer term follow-up is still needed.

Silicone arthroplasty has also been used as an effective treatment for non-RA of the PIP joint. Bales and colleagues⁴ reviewed long-term results of silicone arthroplasty for PIP joint osteoarthritis in 22 patients. At a mean of 10 years, mean QuickDASH (Disabilities of the Arm, Shoulder, and Hand) score was 17, mean visual analog scale score for pain was 0.4, and implant survivorship was 90%. Despite unchanged ROM and considerable implant deformation or fracture, patients’ pain relief and satisfaction were consistent.

Hage and colleagues⁵ reviewed long-term results of silicone PIP arthroplasty for posttraumatic arthritis in 14 patients. Most of the patients were satisfied: Although they had notable rotational deformity, alignment deviation, and loss of pinch strength and ROM, they were pain-free. The authors concluded that silicone arthroplasty should be used for posttraumatic arthrosis cases in which associated adhesions may be corrected with simple tenolysis, and even in these cases the objective results may not be as good as the subjective outcome.

Kaye⁶ used radiographs to determine the incidence of bony ankylosis in 203 patients with RA. Hand and wrist radiographs of 48 (23.6%) of these patients showed ankylosis, and 34 of the 48 patients had 2 or more joints fused. On a questionnaire, patients with ankylosis indicated more difficulty with activities of daily living and more limited activity. The authors concluded that radiographic bony ankylosis was a relatively common feature of RA and a marker of disease that was clinically, radiographically, and functionally more severe.

The patient described in this case report had a satisfactory result after PIP joint arthroplasty. At 2-year follow-up, she remained pain-free, and her previously ankylosed PIP joint had an arc of motion of 10° to 60°. Most patients with bony ankylosis of PIP joints present with minimal pain and do not seek surgical treatment. However, patients with ankylosis that limits functioning or activities of daily living may wish to pursue intervention that could be restorative. PIP joint arthroplasty may be effective in improving motion in patients with bony ankylosis of the finger joints.

VANCOUVER—Prescribed rest is an important component of treating concussion, but it may not be the most appropriate intervention for all patients and may worsen symptoms in some cases, said Anthony P. Kontos, PhD, at the 68th Annual Meeting of the American Academy of Neurology (AAN).

Anthony P. Kontos, PhD

“We need to move the discussion on concussion toward more active and targeted treatments,” said Dr. Kontos, Research Director of the University of Pittsburgh Medical Center (UPMC) Sports Medicine Concussion Program.Concussion is a heterogeneous injury with varying clinical profiles and recovery trajectories. Approaches to treatment should account for these differences and involve multidisciplinary teams when necessary, he said.

In October 2015, Dr. Kontos, Michael “Micky” Collins, PhD, and David O. Okonkwo, MD, PhD, directed a meeting with 37 participants from the fields of neurology, neuropsychology, neurosurgery, primary care, athletic training, and physical therapy to create a summary agreement that can assist clinicians with concussion treatment.

Nineteen guests, including representatives from professional sports organizations, the military, and public health, also attended the Targeted Evaluation and Active Management (TEAM) Approach to Treating Concussion meeting. The National Football League and UPMC sponsored the meeting, which was held in Pittsburgh.

Consensus documents have predominantly focused on things like the various definitions of concussion, how to assess concussion, and how to manage it, said Dr. Kontos. “We really wanted to focus on more of that end point of treatment and potentially more active treatment,” he said.

The TEAM participants developed and agreed upon 17 statements, which they plan to publish. At the AAN meeting, Dr. Kontos provided a brief review of some of the statements and discussed them in the context of recent research.

Rest’s Benefits and Limitations

Physical and cognitive rest, as part of an individualized treatment plan, are currently “the foundation of sport-related concussion management,” according to National Collegiate Athletic Association interassociation concussion guidelines. Rest after concussion conserves needed energy in the brain and reduces the likelihood of second impact syndrome and other catastrophic events, Dr. Kontos said. Furthermore, some studies have suggested that rest improves recovery. Brown et al reported in 2014 that athletes who self-reported more cognitive activity after a concussion took longer to recover than those who reported less cognitive activity.

However, the evidence to support rest is limited. In 2013, the Institute of Medicine and National Research Council published a report on sports-related concussion in youth that found little evidence regarding the efficacy of rest following concussion or to inform the best timing and approach for return to activity. Their statement “still resonates now,” Dr. Kontos said. “There’s very little empirical data to support what we do with rest. It’s largely an across-the-board policy that’s not data-driven, and we need to change that.” The TEAM group agreed “there is limited empirical evidence for the effectiveness of prescribed physical and cognitive rest, with no multisite trials for prescribed rest following concussion.”

Prescribed rest can have psychologic consequences, including emotional distress, depression, and anxiety. Rest allows individuals time to ruminate on their injury, which can exacerbate symptoms in self-report. Individuals who somaticize are particularly vulnerable to this effect. Jeremy M. Root, MD, of Children’s National Medical Center in Washington, DC, Dr. Kontos, and colleagues reported in April in the Journal of Pediatrics that patients who had high somatization scores were approximately five to seven times more likely to report an increase in symptoms at two weeks and four weeks, compared with those who were not in the highest quartile of somatization.

In addition, patients who are prescribed rest may think, “Wow, I must have a really bad injury such that I can’t do anything for a week.” This contextual framing effect may also influence the outcome, said Dr. Kontos.

Thomas et al in 2015 published the results of a randomized controlled trial that found that, after a concussion, patients ages 11 to 22 who were prescribed five days’ rest reported more daily postconcussive symptoms, compared with patients who were prescribed two days’ rest with progressive return to activity. Symptoms peaked at four days, and differences between groups remained at 10 days. “They have higher symptoms when they’re told to rest longer than if they’re told to rest less,” Dr. Kontos said. Clinically, there was no significant difference between groups in neurocognitive or balance outcomes, however.

The effect of treatment on the number of postconcussive symptoms may not be that straightforward, however. When Dr. Kontos, Dr. Thomas, and colleagues reanalyzed the data to look at patients who only reported symptoms (eg, headache, nausea, dizziness) but did not otherwise have early signs of concussion (eg, loss of consciousness, posttraumatic amnesia, disorientation, confusion), the symptoms-only group reported more symptoms at 10 days when prescribed five days’ rest, compared with two days’ rest with progressive return to activity. Patients who had early signs of concussion, however, reported fewer symptoms when prescribed five days’ rest versus two days’ rest with progressive return to activity.

“We have a sort of dichotomy here. We don’t want to say rest is bad. It may be very good for these people who have a high organic level or severity to their injury, and we may need to think in terms of resting them longer, whereas these patients [with symptoms only] certainly need to get more active, probably earlier in the process,” Dr. Kontos said.

Activity and social interaction may provide benefits. Miller et al in 2013 reported that environmental enrichment, including cognitive, physical, and social activity, is associated with improved outcome and sparing of hippocampal atrophy in the chronic stages of traumatic brain injury.

The TEAM group agreed, “Active treatment strategies may be initiated early in recovery following concussion.” The group also agreed, “strict brain rest (eg, ‘cocoon’ therapy) is not indicated and may have detrimental effects on patients following concussion.”

A Heterogeneous Injury

A focal point of the TEAM meeting was the concept of various clinical profiles of concussion. The group agreed, “Concussions are characterized by diverse symptoms and impairments in function resulting in different clinical profiles and recovery trajectories.”

“We need to think in terms of what type of concussion does this individual have and is it multiple types,” such as cognitive-fatigue, vestibular, or ocular, said Dr. Kontos. “We don’t typically just see one of these.” For example, a patient may have a predominant vestibular concussion with some posttraumatic migraine and neck involvement. “Oftentimes we see misdiagnoses when people show up. They’ve been diagnosed with cognitive issues when in reality they’re having vision or oculomotor difficulties.”

There are many potential approaches to categorizing, classifying, or profiling concussion, including those that consider posttraumatic mood and migraine as modifying factors, he said.

Multidisciplinary Teams

In addition, the TEAM group stated, “thorough multidomain assessment is warranted to properly evaluate the clinical profiles of concussion.” Various experts may be needed to assess cognitive, exertional, oculomotor, vestibular, and other symptoms and impairment.

As part of a multidisciplinary team, a neurologist, neuropsychologist, or primary care physician could “serve as kind of a point guard, to use a basketball analogy,” said Dr. Kontos. When an aspect of a patient’s assessment or treatment needs to be addressed more in depth, such as with regard to medication, vestibular therapy, or imaging, the patient may be referred to experts in those areas. “We try to work as a team and work back through the point guard to coordinate that care system,” he said. Telemedicine might allow for multidisciplinary treatment in remote geographic areas where establishing multidisciplinary teams otherwise might not be feasible, Dr. Kontos noted.

“Pharmacological therapy may be indicated in selected circumstances to treat certain symptoms and impairments related to concussion,” the TEAM group agreed.There is “very little” evidence for medicine in concussion, and drugs can exacerbate symptoms in some situations, Dr. Kontos said. Randomized controlled trials will help researchers better understand medication’s role in treating concussion.

More Active Treatment

In particular, patients who do not receive appropriate management after a concussion and then go to a clinic several months later with chronic symptoms may benefit from more active approaches to treatment, such as brisk walking.

Dr. Kontos described the case of an ice hockey player who was prescribed rest following a first concussion. After resting, the athlete began a return-to-play protocol that focused on aerobic exertion with no dynamic movements. As soon as the player returned to the ice, however, dizziness and headache came flooding back.

Several months later, the athlete was referred to a concussion clinic. The patient underwent a thorough evaluation that included vestibular and oculomotor assessments. Clinicians determined that the athlete needed more active treatment, including vision training and walking with head movements. In three weeks, the athlete returned to the ice. About a week later, the athlete resumed full-contact ice hockey.

“Prescribing rest is not the only approach,” Dr. Kontos said. “We need to move the discussion in different directions. We need to be more active with certain people and we need to be more targeted with our approaches.”

—Jake Remaly

VANCOUVER—Prescribed rest is an important component of treating concussion, but it may not be the most appropriate intervention for all patients and may worsen symptoms in some cases, said Anthony P. Kontos, PhD, at the 68th Annual Meeting of the American Academy of Neurology (AAN).

Anthony P. Kontos, PhD

“We need to move the discussion on concussion toward more active and targeted treatments,” said Dr. Kontos, Research Director of the University of Pittsburgh Medical Center (UPMC) Sports Medicine Concussion Program.Concussion is a heterogeneous injury with varying clinical profiles and recovery trajectories. Approaches to treatment should account for these differences and involve multidisciplinary teams when necessary, he said.

In October 2015, Dr. Kontos, Michael “Micky” Collins, PhD, and David O. Okonkwo, MD, PhD, directed a meeting with 37 participants from the fields of neurology, neuropsychology, neurosurgery, primary care, athletic training, and physical therapy to create a summary agreement that can assist clinicians with concussion treatment.

Nineteen guests, including representatives from professional sports organizations, the military, and public health, also attended the Targeted Evaluation and Active Management (TEAM) Approach to Treating Concussion meeting. The National Football League and UPMC sponsored the meeting, which was held in Pittsburgh.

Consensus documents have predominantly focused on things like the various definitions of concussion, how to assess concussion, and how to manage it, said Dr. Kontos. “We really wanted to focus on more of that end point of treatment and potentially more active treatment,” he said.

The TEAM participants developed and agreed upon 17 statements, which they plan to publish. At the AAN meeting, Dr. Kontos provided a brief review of some of the statements and discussed them in the context of recent research.

Rest’s Benefits and Limitations

Physical and cognitive rest, as part of an individualized treatment plan, are currently “the foundation of sport-related concussion management,” according to National Collegiate Athletic Association interassociation concussion guidelines. Rest after concussion conserves needed energy in the brain and reduces the likelihood of second impact syndrome and other catastrophic events, Dr. Kontos said. Furthermore, some studies have suggested that rest improves recovery. Brown et al reported in 2014 that athletes who self-reported more cognitive activity after a concussion took longer to recover than those who reported less cognitive activity.

However, the evidence to support rest is limited. In 2013, the Institute of Medicine and National Research Council published a report on sports-related concussion in youth that found little evidence regarding the efficacy of rest following concussion or to inform the best timing and approach for return to activity. Their statement “still resonates now,” Dr. Kontos said. “There’s very little empirical data to support what we do with rest. It’s largely an across-the-board policy that’s not data-driven, and we need to change that.” The TEAM group agreed “there is limited empirical evidence for the effectiveness of prescribed physical and cognitive rest, with no multisite trials for prescribed rest following concussion.”

Prescribed rest can have psychologic consequences, including emotional distress, depression, and anxiety. Rest allows individuals time to ruminate on their injury, which can exacerbate symptoms in self-report. Individuals who somaticize are particularly vulnerable to this effect. Jeremy M. Root, MD, of Children’s National Medical Center in Washington, DC, Dr. Kontos, and colleagues reported in April in the Journal of Pediatrics that patients who had high somatization scores were approximately five to seven times more likely to report an increase in symptoms at two weeks and four weeks, compared with those who were not in the highest quartile of somatization.

In addition, patients who are prescribed rest may think, “Wow, I must have a really bad injury such that I can’t do anything for a week.” This contextual framing effect may also influence the outcome, said Dr. Kontos.

Thomas et al in 2015 published the results of a randomized controlled trial that found that, after a concussion, patients ages 11 to 22 who were prescribed five days’ rest reported more daily postconcussive symptoms, compared with patients who were prescribed two days’ rest with progressive return to activity. Symptoms peaked at four days, and differences between groups remained at 10 days. “They have higher symptoms when they’re told to rest longer than if they’re told to rest less,” Dr. Kontos said. Clinically, there was no significant difference between groups in neurocognitive or balance outcomes, however.

The effect of treatment on the number of postconcussive symptoms may not be that straightforward, however. When Dr. Kontos, Dr. Thomas, and colleagues reanalyzed the data to look at patients who only reported symptoms (eg, headache, nausea, dizziness) but did not otherwise have early signs of concussion (eg, loss of consciousness, posttraumatic amnesia, disorientation, confusion), the symptoms-only group reported more symptoms at 10 days when prescribed five days’ rest, compared with two days’ rest with progressive return to activity. Patients who had early signs of concussion, however, reported fewer symptoms when prescribed five days’ rest versus two days’ rest with progressive return to activity.

“We have a sort of dichotomy here. We don’t want to say rest is bad. It may be very good for these people who have a high organic level or severity to their injury, and we may need to think in terms of resting them longer, whereas these patients [with symptoms only] certainly need to get more active, probably earlier in the process,” Dr. Kontos said.

Activity and social interaction may provide benefits. Miller et al in 2013 reported that environmental enrichment, including cognitive, physical, and social activity, is associated with improved outcome and sparing of hippocampal atrophy in the chronic stages of traumatic brain injury.

The TEAM group agreed, “Active treatment strategies may be initiated early in recovery following concussion.” The group also agreed, “strict brain rest (eg, ‘cocoon’ therapy) is not indicated and may have detrimental effects on patients following concussion.”

A Heterogeneous Injury

A focal point of the TEAM meeting was the concept of various clinical profiles of concussion. The group agreed, “Concussions are characterized by diverse symptoms and impairments in function resulting in different clinical profiles and recovery trajectories.”

“We need to think in terms of what type of concussion does this individual have and is it multiple types,” such as cognitive-fatigue, vestibular, or ocular, said Dr. Kontos. “We don’t typically just see one of these.” For example, a patient may have a predominant vestibular concussion with some posttraumatic migraine and neck involvement. “Oftentimes we see misdiagnoses when people show up. They’ve been diagnosed with cognitive issues when in reality they’re having vision or oculomotor difficulties.”

There are many potential approaches to categorizing, classifying, or profiling concussion, including those that consider posttraumatic mood and migraine as modifying factors, he said.

Multidisciplinary Teams

In addition, the TEAM group stated, “thorough multidomain assessment is warranted to properly evaluate the clinical profiles of concussion.” Various experts may be needed to assess cognitive, exertional, oculomotor, vestibular, and other symptoms and impairment.

As part of a multidisciplinary team, a neurologist, neuropsychologist, or primary care physician could “serve as kind of a point guard, to use a basketball analogy,” said Dr. Kontos. When an aspect of a patient’s assessment or treatment needs to be addressed more in depth, such as with regard to medication, vestibular therapy, or imaging, the patient may be referred to experts in those areas. “We try to work as a team and work back through the point guard to coordinate that care system,” he said. Telemedicine might allow for multidisciplinary treatment in remote geographic areas where establishing multidisciplinary teams otherwise might not be feasible, Dr. Kontos noted.

“Pharmacological therapy may be indicated in selected circumstances to treat certain symptoms and impairments related to concussion,” the TEAM group agreed.There is “very little” evidence for medicine in concussion, and drugs can exacerbate symptoms in some situations, Dr. Kontos said. Randomized controlled trials will help researchers better understand medication’s role in treating concussion.

More Active Treatment

In particular, patients who do not receive appropriate management after a concussion and then go to a clinic several months later with chronic symptoms may benefit from more active approaches to treatment, such as brisk walking.

Dr. Kontos described the case of an ice hockey player who was prescribed rest following a first concussion. After resting, the athlete began a return-to-play protocol that focused on aerobic exertion with no dynamic movements. As soon as the player returned to the ice, however, dizziness and headache came flooding back.

Several months later, the athlete was referred to a concussion clinic. The patient underwent a thorough evaluation that included vestibular and oculomotor assessments. Clinicians determined that the athlete needed more active treatment, including vision training and walking with head movements. In three weeks, the athlete returned to the ice. About a week later, the athlete resumed full-contact ice hockey.

“Prescribing rest is not the only approach,” Dr. Kontos said. “We need to move the discussion in different directions. We need to be more active with certain people and we need to be more targeted with our approaches.”

—Jake Remaly

VANCOUVER—Prescribed rest is an important component of treating concussion, but it may not be the most appropriate intervention for all patients and may worsen symptoms in some cases, said Anthony P. Kontos, PhD, at the 68th Annual Meeting of the American Academy of Neurology (AAN).

Anthony P. Kontos, PhD

“We need to move the discussion on concussion toward more active and targeted treatments,” said Dr. Kontos, Research Director of the University of Pittsburgh Medical Center (UPMC) Sports Medicine Concussion Program.Concussion is a heterogeneous injury with varying clinical profiles and recovery trajectories. Approaches to treatment should account for these differences and involve multidisciplinary teams when necessary, he said.

In October 2015, Dr. Kontos, Michael “Micky” Collins, PhD, and David O. Okonkwo, MD, PhD, directed a meeting with 37 participants from the fields of neurology, neuropsychology, neurosurgery, primary care, athletic training, and physical therapy to create a summary agreement that can assist clinicians with concussion treatment.

Nineteen guests, including representatives from professional sports organizations, the military, and public health, also attended the Targeted Evaluation and Active Management (TEAM) Approach to Treating Concussion meeting. The National Football League and UPMC sponsored the meeting, which was held in Pittsburgh.

Consensus documents have predominantly focused on things like the various definitions of concussion, how to assess concussion, and how to manage it, said Dr. Kontos. “We really wanted to focus on more of that end point of treatment and potentially more active treatment,” he said.

The TEAM participants developed and agreed upon 17 statements, which they plan to publish. At the AAN meeting, Dr. Kontos provided a brief review of some of the statements and discussed them in the context of recent research.

Rest’s Benefits and Limitations

Physical and cognitive rest, as part of an individualized treatment plan, are currently “the foundation of sport-related concussion management,” according to National Collegiate Athletic Association interassociation concussion guidelines. Rest after concussion conserves needed energy in the brain and reduces the likelihood of second impact syndrome and other catastrophic events, Dr. Kontos said. Furthermore, some studies have suggested that rest improves recovery. Brown et al reported in 2014 that athletes who self-reported more cognitive activity after a concussion took longer to recover than those who reported less cognitive activity.

However, the evidence to support rest is limited. In 2013, the Institute of Medicine and National Research Council published a report on sports-related concussion in youth that found little evidence regarding the efficacy of rest following concussion or to inform the best timing and approach for return to activity. Their statement “still resonates now,” Dr. Kontos said. “There’s very little empirical data to support what we do with rest. It’s largely an across-the-board policy that’s not data-driven, and we need to change that.” The TEAM group agreed “there is limited empirical evidence for the effectiveness of prescribed physical and cognitive rest, with no multisite trials for prescribed rest following concussion.”

Prescribed rest can have psychologic consequences, including emotional distress, depression, and anxiety. Rest allows individuals time to ruminate on their injury, which can exacerbate symptoms in self-report. Individuals who somaticize are particularly vulnerable to this effect. Jeremy M. Root, MD, of Children’s National Medical Center in Washington, DC, Dr. Kontos, and colleagues reported in April in the Journal of Pediatrics that patients who had high somatization scores were approximately five to seven times more likely to report an increase in symptoms at two weeks and four weeks, compared with those who were not in the highest quartile of somatization.

In addition, patients who are prescribed rest may think, “Wow, I must have a really bad injury such that I can’t do anything for a week.” This contextual framing effect may also influence the outcome, said Dr. Kontos.

Thomas et al in 2015 published the results of a randomized controlled trial that found that, after a concussion, patients ages 11 to 22 who were prescribed five days’ rest reported more daily postconcussive symptoms, compared with patients who were prescribed two days’ rest with progressive return to activity. Symptoms peaked at four days, and differences between groups remained at 10 days. “They have higher symptoms when they’re told to rest longer than if they’re told to rest less,” Dr. Kontos said. Clinically, there was no significant difference between groups in neurocognitive or balance outcomes, however.

The effect of treatment on the number of postconcussive symptoms may not be that straightforward, however. When Dr. Kontos, Dr. Thomas, and colleagues reanalyzed the data to look at patients who only reported symptoms (eg, headache, nausea, dizziness) but did not otherwise have early signs of concussion (eg, loss of consciousness, posttraumatic amnesia, disorientation, confusion), the symptoms-only group reported more symptoms at 10 days when prescribed five days’ rest, compared with two days’ rest with progressive return to activity. Patients who had early signs of concussion, however, reported fewer symptoms when prescribed five days’ rest versus two days’ rest with progressive return to activity.

“We have a sort of dichotomy here. We don’t want to say rest is bad. It may be very good for these people who have a high organic level or severity to their injury, and we may need to think in terms of resting them longer, whereas these patients [with symptoms only] certainly need to get more active, probably earlier in the process,” Dr. Kontos said.

Activity and social interaction may provide benefits. Miller et al in 2013 reported that environmental enrichment, including cognitive, physical, and social activity, is associated with improved outcome and sparing of hippocampal atrophy in the chronic stages of traumatic brain injury.

The TEAM group agreed, “Active treatment strategies may be initiated early in recovery following concussion.” The group also agreed, “strict brain rest (eg, ‘cocoon’ therapy) is not indicated and may have detrimental effects on patients following concussion.”

A Heterogeneous Injury

A focal point of the TEAM meeting was the concept of various clinical profiles of concussion. The group agreed, “Concussions are characterized by diverse symptoms and impairments in function resulting in different clinical profiles and recovery trajectories.”

“We need to think in terms of what type of concussion does this individual have and is it multiple types,” such as cognitive-fatigue, vestibular, or ocular, said Dr. Kontos. “We don’t typically just see one of these.” For example, a patient may have a predominant vestibular concussion with some posttraumatic migraine and neck involvement. “Oftentimes we see misdiagnoses when people show up. They’ve been diagnosed with cognitive issues when in reality they’re having vision or oculomotor difficulties.”

There are many potential approaches to categorizing, classifying, or profiling concussion, including those that consider posttraumatic mood and migraine as modifying factors, he said.

Multidisciplinary Teams

In addition, the TEAM group stated, “thorough multidomain assessment is warranted to properly evaluate the clinical profiles of concussion.” Various experts may be needed to assess cognitive, exertional, oculomotor, vestibular, and other symptoms and impairment.

As part of a multidisciplinary team, a neurologist, neuropsychologist, or primary care physician could “serve as kind of a point guard, to use a basketball analogy,” said Dr. Kontos. When an aspect of a patient’s assessment or treatment needs to be addressed more in depth, such as with regard to medication, vestibular therapy, or imaging, the patient may be referred to experts in those areas. “We try to work as a team and work back through the point guard to coordinate that care system,” he said. Telemedicine might allow for multidisciplinary treatment in remote geographic areas where establishing multidisciplinary teams otherwise might not be feasible, Dr. Kontos noted.

“Pharmacological therapy may be indicated in selected circumstances to treat certain symptoms and impairments related to concussion,” the TEAM group agreed.There is “very little” evidence for medicine in concussion, and drugs can exacerbate symptoms in some situations, Dr. Kontos said. Randomized controlled trials will help researchers better understand medication’s role in treating concussion.

More Active Treatment

In particular, patients who do not receive appropriate management after a concussion and then go to a clinic several months later with chronic symptoms may benefit from more active approaches to treatment, such as brisk walking.

Dr. Kontos described the case of an ice hockey player who was prescribed rest following a first concussion. After resting, the athlete began a return-to-play protocol that focused on aerobic exertion with no dynamic movements. As soon as the player returned to the ice, however, dizziness and headache came flooding back.

Several months later, the athlete was referred to a concussion clinic. The patient underwent a thorough evaluation that included vestibular and oculomotor assessments. Clinicians determined that the athlete needed more active treatment, including vision training and walking with head movements. In three weeks, the athlete returned to the ice. About a week later, the athlete resumed full-contact ice hockey.

“Prescribing rest is not the only approach,” Dr. Kontos said. “We need to move the discussion in different directions. We need to be more active with certain people and we need to be more targeted with our approaches.”

—Jake Remaly

VANCOUVER—Methylphenidate, a therapy approved for the treatment of attention deficit hyperactivity disorder (ADHD), lessens cognitive deficits associated with epilepsy, according to the results of a double-blind, placebo-controlled trial. Although the trial was small, the benefit was observed in multiple cognitive domains and persisted among patients who participated in an open-label extension after the double-blind portion of the study was completed.

“To the best of our knowledge, this is the first epilepsy study in adults using this type of established objective and standardized measures to evaluate multiple cognitive domains,” reported Jesse Adams, MD, who is completing a neuropsychiatry fellowship at Stanford University School of Medicine in California. The results of the trial, which was conducted with immediate-release methylphenidate, were presented by Dr. Adams at the 68th Annual Meeting of the American Academy of Neurology.

Thirty-five patients were enrolled and 31 completed the double-blind portion. Of those completing, 24 had focal seizure types, six had generalized seizure activity, and one had unclassified seizure activity. A broad array of seizure subtypes was represented. The age range of participants was 20 to 60 (median age, 35.3). The median duration of epilepsy was 12.5 years.

The study was conducted with a crossover design in three periods. Each patient received single dose placebo, 10 mg of methylphenidate, and 20 mg of methylphenidate in a random order one week apart. The primary cognitive measures were the Connors Continuous Performance Task (CPT), the Symbol-Digit Modalities Test (SDMT), and Medical College of Georgia Paragraph Memory Test (MCGPMT). These, along with additional cognitive tests employed as secondary measures, were administered at baseline and at the end of each period of treatment. Although not all differences reached statistical significance, cognitive performance on either dose of methylphenidate was consistently better than on placebo. The greatest difference was observed for the SDMT. Dr. Adams characterized the effect size in this measure as “moderate to large.” While other differences were more modest, the direction of benefit was consistently in favor of methylphenidate.

For example, an advantage was observed for CPT variables of hits, omissions, and detectability. No significant difference in cognitive performance could be detected when the two doses of methylphenidate were compared with each other.

Of the four patients who did not complete the double-blind portion of the study, one taking the 20-mg dose withdrew for cognitive problems, another taking the 20-mg was lost to follow-up, and one taking the 10-mg dose withdrew for agitation and tachycardia. A fourth participant who received 40 mg withdrew for tachycardia. However, the same patient participated in the open-label study on a lower dose without further complaints. Methylphenidate was otherwise well tolerated, although several patients, including those taking placebo, reported agitation.

At the end of the double-blind portion of the study, 30 participants elected to enter a four-week open-label extension. Patients were started on 5 mg or 10 mg with upward titration permitted as tolerated. Two patients left the extension before completion due to anxiety. However, testing at the end of this period continued to show improvements in cognitive function for those who remained on methylphenidate. In addition, improvement in a validated epilepsy quality-of-life instrument on methylphenidate was characterized as having “a large effect size.” Of the 28 patients who completed the open-label extension, 22 elected to continue taking methylphenidate.

Concern has been expressed about the potential for methylphenidate to trigger seizures, but this effect was not observed in this study. The seizure rate was not statistically different during the double-blind trial, compared with baseline.

—Theodore Bosworth

VANCOUVER—Methylphenidate, a therapy approved for the treatment of attention deficit hyperactivity disorder (ADHD), lessens cognitive deficits associated with epilepsy, according to the results of a double-blind, placebo-controlled trial. Although the trial was small, the benefit was observed in multiple cognitive domains and persisted among patients who participated in an open-label extension after the double-blind portion of the study was completed.

“To the best of our knowledge, this is the first epilepsy study in adults using this type of established objective and standardized measures to evaluate multiple cognitive domains,” reported Jesse Adams, MD, who is completing a neuropsychiatry fellowship at Stanford University School of Medicine in California. The results of the trial, which was conducted with immediate-release methylphenidate, were presented by Dr. Adams at the 68th Annual Meeting of the American Academy of Neurology.

Thirty-five patients were enrolled and 31 completed the double-blind portion. Of those completing, 24 had focal seizure types, six had generalized seizure activity, and one had unclassified seizure activity. A broad array of seizure subtypes was represented. The age range of participants was 20 to 60 (median age, 35.3). The median duration of epilepsy was 12.5 years.

The study was conducted with a crossover design in three periods. Each patient received single dose placebo, 10 mg of methylphenidate, and 20 mg of methylphenidate in a random order one week apart. The primary cognitive measures were the Connors Continuous Performance Task (CPT), the Symbol-Digit Modalities Test (SDMT), and Medical College of Georgia Paragraph Memory Test (MCGPMT). These, along with additional cognitive tests employed as secondary measures, were administered at baseline and at the end of each period of treatment. Although not all differences reached statistical significance, cognitive performance on either dose of methylphenidate was consistently better than on placebo. The greatest difference was observed for the SDMT. Dr. Adams characterized the effect size in this measure as “moderate to large.” While other differences were more modest, the direction of benefit was consistently in favor of methylphenidate.

For example, an advantage was observed for CPT variables of hits, omissions, and detectability. No significant difference in cognitive performance could be detected when the two doses of methylphenidate were compared with each other.

Of the four patients who did not complete the double-blind portion of the study, one taking the 20-mg dose withdrew for cognitive problems, another taking the 20-mg was lost to follow-up, and one taking the 10-mg dose withdrew for agitation and tachycardia. A fourth participant who received 40 mg withdrew for tachycardia. However, the same patient participated in the open-label study on a lower dose without further complaints. Methylphenidate was otherwise well tolerated, although several patients, including those taking placebo, reported agitation.

At the end of the double-blind portion of the study, 30 participants elected to enter a four-week open-label extension. Patients were started on 5 mg or 10 mg with upward titration permitted as tolerated. Two patients left the extension before completion due to anxiety. However, testing at the end of this period continued to show improvements in cognitive function for those who remained on methylphenidate. In addition, improvement in a validated epilepsy quality-of-life instrument on methylphenidate was characterized as having “a large effect size.” Of the 28 patients who completed the open-label extension, 22 elected to continue taking methylphenidate.

Concern has been expressed about the potential for methylphenidate to trigger seizures, but this effect was not observed in this study. The seizure rate was not statistically different during the double-blind trial, compared with baseline.

—Theodore Bosworth

VANCOUVER—Methylphenidate, a therapy approved for the treatment of attention deficit hyperactivity disorder (ADHD), lessens cognitive deficits associated with epilepsy, according to the results of a double-blind, placebo-controlled trial. Although the trial was small, the benefit was observed in multiple cognitive domains and persisted among patients who participated in an open-label extension after the double-blind portion of the study was completed.

“To the best of our knowledge, this is the first epilepsy study in adults using this type of established objective and standardized measures to evaluate multiple cognitive domains,” reported Jesse Adams, MD, who is completing a neuropsychiatry fellowship at Stanford University School of Medicine in California. The results of the trial, which was conducted with immediate-release methylphenidate, were presented by Dr. Adams at the 68th Annual Meeting of the American Academy of Neurology.

Thirty-five patients were enrolled and 31 completed the double-blind portion. Of those completing, 24 had focal seizure types, six had generalized seizure activity, and one had unclassified seizure activity. A broad array of seizure subtypes was represented. The age range of participants was 20 to 60 (median age, 35.3). The median duration of epilepsy was 12.5 years.

The study was conducted with a crossover design in three periods. Each patient received single dose placebo, 10 mg of methylphenidate, and 20 mg of methylphenidate in a random order one week apart. The primary cognitive measures were the Connors Continuous Performance Task (CPT), the Symbol-Digit Modalities Test (SDMT), and Medical College of Georgia Paragraph Memory Test (MCGPMT). These, along with additional cognitive tests employed as secondary measures, were administered at baseline and at the end of each period of treatment. Although not all differences reached statistical significance, cognitive performance on either dose of methylphenidate was consistently better than on placebo. The greatest difference was observed for the SDMT. Dr. Adams characterized the effect size in this measure as “moderate to large.” While other differences were more modest, the direction of benefit was consistently in favor of methylphenidate.

For example, an advantage was observed for CPT variables of hits, omissions, and detectability. No significant difference in cognitive performance could be detected when the two doses of methylphenidate were compared with each other.

Of the four patients who did not complete the double-blind portion of the study, one taking the 20-mg dose withdrew for cognitive problems, another taking the 20-mg was lost to follow-up, and one taking the 10-mg dose withdrew for agitation and tachycardia. A fourth participant who received 40 mg withdrew for tachycardia. However, the same patient participated in the open-label study on a lower dose without further complaints. Methylphenidate was otherwise well tolerated, although several patients, including those taking placebo, reported agitation.

At the end of the double-blind portion of the study, 30 participants elected to enter a four-week open-label extension. Patients were started on 5 mg or 10 mg with upward titration permitted as tolerated. Two patients left the extension before completion due to anxiety. However, testing at the end of this period continued to show improvements in cognitive function for those who remained on methylphenidate. In addition, improvement in a validated epilepsy quality-of-life instrument on methylphenidate was characterized as having “a large effect size.” Of the 28 patients who completed the open-label extension, 22 elected to continue taking methylphenidate.

Concern has been expressed about the potential for methylphenidate to trigger seizures, but this effect was not observed in this study. The seizure rate was not statistically different during the double-blind trial, compared with baseline.

—Theodore Bosworth

VANCOUVER—Among patients with Parkinson’s disease, the lowest level of olfactory function is associated with subjective cognitive impairment and more rapid decline in global cognition, compared with higher levels of olfactory function, according to an analysis described at the 68th Annual Meeting of the American Academy of Neurology. Furthermore, a combination of CSF biomarkers and olfactory testing may increase neurologists’ ability to identify patients at highest risk for cognitive decline and progression to mild cognitive impairment (MCI).

These two biomarkers may reflect the dual pathology of Lewy bodies and amyloid plaques observed in Parkinson’s disease–related MCI and Parkinson’s disease dementia and come together to give a more complete clinical picture, said Michelle Fullard, MD, a fellow at the Parkinson’s Disease Research, Education, and Clinical Center at the Philadelphia Veterans Affairs Medical Center.

Michelle Fullard, MD

The rate and risk of cognitive decline in Parkinson’s disease vary from person to person, and biomarkers could help identify patients at highest risk for this outcome. Data suggest that olfaction reflects the Lewy pathology present in Parkinson’s disease. In addition, approximately one-third of patients with Parkinson’s disease dementia meet the pathologic criteria for Alzheimer’s disease. Increased levels of CSF tau and decreased levels of CSF amyloid beta are associated with cognitive impairment in this population.

The Parkinson’s Progression Markers Initiative

Dr. Fullard and colleagues sought to examine the association between baseline olfaction and measures of cognition in a cohort of 423 patients with early Parkinson’s disease. The researchers investigated whether olfaction alone or in combination with CSF biomarkers predicts cognitive decline and conversion to MCI. They analyzed data from the Parkinson’s Progression Markers Initiative, an observational cohort study of patients with Parkinson’s disease. Eligible participants were untreated at enrollment, had been diagnosed within two years of enrollment, and had dopamine transporter deficit on imaging.

All participants underwent various assessments at predetermined time points. Dr. Fullard and colleagues specifically examined the University of Pennsylvania Smell Identification Test (UPSIT), which was administered at baseline, and the Montreal Cognitive Assessment (MOCA), which was administered at baseline and annually thereafter. The investigators also analyzed CSF tau and CSF beta amyloid levels at baseline.

For the data analysis, the researchers grouped the cohort into tertiles according to olfactory function. They performed a cross-sectional analysis to investigate the association between olfaction and measures of cognition. A linear mixed-effects model was used to identify predictors of cognitive decline. Finally, the investigators used Cox proportional hazards models to investigate conversion to MCI.

UPSIT Predicted Cognitive Decline

Approximately 91% of participants had olfactory impairment. About 35% of patients were anosmic, and these patients constituted the lowest tertile of olfaction. This group tended to be older and had a higher proportion of males, compared with the other tertiles. Dr. Fullard and colleagues adjusted for age and gender in subsequent analyses. Education and disease duration were similar among the three tertiles. Average disease duration was between six to seven months for the population.

Participants in the lowest tertile were more likely to report subjective nonmotor symptoms than participants in the other tertiles, as measured by Part 1A of the Unified Parkinson’s Disease Rating Scale. Patients in the lowest tertile also were more likely to report subjective cognitive impairment, compared with the rest of the cohort. After the researchers adjusted the data for age and sex, they found that MOCA scores were similar among the three tertiles.

When Dr. Fullard and colleagues considered the UPSIT and the CSF biomarkers as continuous variables, they found that each was significantly associated with decline in MOCA score. For every one-point decrease in UPSIT score, the MOCA score declined by 0.02 points per year. Using a separate linear mixed-effects model, the investigators noted that patients in the lowest amyloid beta tertile tended to have more cognitive decline, but the result was not statistically significant. Participants with the highest tau–amyloid beta ratios, however, had significantly more cognitive decline than other participants.

Next, Dr. Fullard’s group categorized the patients as having low-, medium-, or high-risk profiles based on olfaction and CSF biomarkers. When they analyzed the composite of olfaction and amyloid beta, as well as the composite for olfaction and tau–amyloid beta ratio, they noted that patients with the highest risk profiles had significantly more cognitive decline, as measured by the MOCA.

Furthermore, the researchers observed that patients with the worst olfaction, as measured by the UPSIT, appeared to have a higher rate of conversion to MCI, but the result did not reach statistical significance. Similarly, participants with the highest tau–amyloid beta ratio appeared to have a higher rate of conversion to MCI, but the finding was not significant. When the investigators combined the biomarkers using the risk profiles, participants with the highest risk profiles were 79% more likely to develop MCI during the three-year study period than other participants.

—Erik Greb

VANCOUVER—Among patients with Parkinson’s disease, the lowest level of olfactory function is associated with subjective cognitive impairment and more rapid decline in global cognition, compared with higher levels of olfactory function, according to an analysis described at the 68th Annual Meeting of the American Academy of Neurology. Furthermore, a combination of CSF biomarkers and olfactory testing may increase neurologists’ ability to identify patients at highest risk for cognitive decline and progression to mild cognitive impairment (MCI).

These two biomarkers may reflect the dual pathology of Lewy bodies and amyloid plaques observed in Parkinson’s disease–related MCI and Parkinson’s disease dementia and come together to give a more complete clinical picture, said Michelle Fullard, MD, a fellow at the Parkinson’s Disease Research, Education, and Clinical Center at the Philadelphia Veterans Affairs Medical Center.

Michelle Fullard, MD

The rate and risk of cognitive decline in Parkinson’s disease vary from person to person, and biomarkers could help identify patients at highest risk for this outcome. Data suggest that olfaction reflects the Lewy pathology present in Parkinson’s disease. In addition, approximately one-third of patients with Parkinson’s disease dementia meet the pathologic criteria for Alzheimer’s disease. Increased levels of CSF tau and decreased levels of CSF amyloid beta are associated with cognitive impairment in this population.

The Parkinson’s Progression Markers Initiative

Dr. Fullard and colleagues sought to examine the association between baseline olfaction and measures of cognition in a cohort of 423 patients with early Parkinson’s disease. The researchers investigated whether olfaction alone or in combination with CSF biomarkers predicts cognitive decline and conversion to MCI. They analyzed data from the Parkinson’s Progression Markers Initiative, an observational cohort study of patients with Parkinson’s disease. Eligible participants were untreated at enrollment, had been diagnosed within two years of enrollment, and had dopamine transporter deficit on imaging.

All participants underwent various assessments at predetermined time points. Dr. Fullard and colleagues specifically examined the University of Pennsylvania Smell Identification Test (UPSIT), which was administered at baseline, and the Montreal Cognitive Assessment (MOCA), which was administered at baseline and annually thereafter. The investigators also analyzed CSF tau and CSF beta amyloid levels at baseline.

For the data analysis, the researchers grouped the cohort into tertiles according to olfactory function. They performed a cross-sectional analysis to investigate the association between olfaction and measures of cognition. A linear mixed-effects model was used to identify predictors of cognitive decline. Finally, the investigators used Cox proportional hazards models to investigate conversion to MCI.

UPSIT Predicted Cognitive Decline

Approximately 91% of participants had olfactory impairment. About 35% of patients were anosmic, and these patients constituted the lowest tertile of olfaction. This group tended to be older and had a higher proportion of males, compared with the other tertiles. Dr. Fullard and colleagues adjusted for age and gender in subsequent analyses. Education and disease duration were similar among the three tertiles. Average disease duration was between six to seven months for the population.

Participants in the lowest tertile were more likely to report subjective nonmotor symptoms than participants in the other tertiles, as measured by Part 1A of the Unified Parkinson’s Disease Rating Scale. Patients in the lowest tertile also were more likely to report subjective cognitive impairment, compared with the rest of the cohort. After the researchers adjusted the data for age and sex, they found that MOCA scores were similar among the three tertiles.

When Dr. Fullard and colleagues considered the UPSIT and the CSF biomarkers as continuous variables, they found that each was significantly associated with decline in MOCA score. For every one-point decrease in UPSIT score, the MOCA score declined by 0.02 points per year. Using a separate linear mixed-effects model, the investigators noted that patients in the lowest amyloid beta tertile tended to have more cognitive decline, but the result was not statistically significant. Participants with the highest tau–amyloid beta ratios, however, had significantly more cognitive decline than other participants.

Next, Dr. Fullard’s group categorized the patients as having low-, medium-, or high-risk profiles based on olfaction and CSF biomarkers. When they analyzed the composite of olfaction and amyloid beta, as well as the composite for olfaction and tau–amyloid beta ratio, they noted that patients with the highest risk profiles had significantly more cognitive decline, as measured by the MOCA.

Furthermore, the researchers observed that patients with the worst olfaction, as measured by the UPSIT, appeared to have a higher rate of conversion to MCI, but the result did not reach statistical significance. Similarly, participants with the highest tau–amyloid beta ratio appeared to have a higher rate of conversion to MCI, but the finding was not significant. When the investigators combined the biomarkers using the risk profiles, participants with the highest risk profiles were 79% more likely to develop MCI during the three-year study period than other participants.

—Erik Greb

VANCOUVER—Among patients with Parkinson’s disease, the lowest level of olfactory function is associated with subjective cognitive impairment and more rapid decline in global cognition, compared with higher levels of olfactory function, according to an analysis described at the 68th Annual Meeting of the American Academy of Neurology. Furthermore, a combination of CSF biomarkers and olfactory testing may increase neurologists’ ability to identify patients at highest risk for cognitive decline and progression to mild cognitive impairment (MCI).

These two biomarkers may reflect the dual pathology of Lewy bodies and amyloid plaques observed in Parkinson’s disease–related MCI and Parkinson’s disease dementia and come together to give a more complete clinical picture, said Michelle Fullard, MD, a fellow at the Parkinson’s Disease Research, Education, and Clinical Center at the Philadelphia Veterans Affairs Medical Center.

Michelle Fullard, MD

The rate and risk of cognitive decline in Parkinson’s disease vary from person to person, and biomarkers could help identify patients at highest risk for this outcome. Data suggest that olfaction reflects the Lewy pathology present in Parkinson’s disease. In addition, approximately one-third of patients with Parkinson’s disease dementia meet the pathologic criteria for Alzheimer’s disease. Increased levels of CSF tau and decreased levels of CSF amyloid beta are associated with cognitive impairment in this population.

The Parkinson’s Progression Markers Initiative

Dr. Fullard and colleagues sought to examine the association between baseline olfaction and measures of cognition in a cohort of 423 patients with early Parkinson’s disease. The researchers investigated whether olfaction alone or in combination with CSF biomarkers predicts cognitive decline and conversion to MCI. They analyzed data from the Parkinson’s Progression Markers Initiative, an observational cohort study of patients with Parkinson’s disease. Eligible participants were untreated at enrollment, had been diagnosed within two years of enrollment, and had dopamine transporter deficit on imaging.

All participants underwent various assessments at predetermined time points. Dr. Fullard and colleagues specifically examined the University of Pennsylvania Smell Identification Test (UPSIT), which was administered at baseline, and the Montreal Cognitive Assessment (MOCA), which was administered at baseline and annually thereafter. The investigators also analyzed CSF tau and CSF beta amyloid levels at baseline.

For the data analysis, the researchers grouped the cohort into tertiles according to olfactory function. They performed a cross-sectional analysis to investigate the association between olfaction and measures of cognition. A linear mixed-effects model was used to identify predictors of cognitive decline. Finally, the investigators used Cox proportional hazards models to investigate conversion to MCI.

UPSIT Predicted Cognitive Decline

Approximately 91% of participants had olfactory impairment. About 35% of patients were anosmic, and these patients constituted the lowest tertile of olfaction. This group tended to be older and had a higher proportion of males, compared with the other tertiles. Dr. Fullard and colleagues adjusted for age and gender in subsequent analyses. Education and disease duration were similar among the three tertiles. Average disease duration was between six to seven months for the population.

Participants in the lowest tertile were more likely to report subjective nonmotor symptoms than participants in the other tertiles, as measured by Part 1A of the Unified Parkinson’s Disease Rating Scale. Patients in the lowest tertile also were more likely to report subjective cognitive impairment, compared with the rest of the cohort. After the researchers adjusted the data for age and sex, they found that MOCA scores were similar among the three tertiles.

When Dr. Fullard and colleagues considered the UPSIT and the CSF biomarkers as continuous variables, they found that each was significantly associated with decline in MOCA score. For every one-point decrease in UPSIT score, the MOCA score declined by 0.02 points per year. Using a separate linear mixed-effects model, the investigators noted that patients in the lowest amyloid beta tertile tended to have more cognitive decline, but the result was not statistically significant. Participants with the highest tau–amyloid beta ratios, however, had significantly more cognitive decline than other participants.

Next, Dr. Fullard’s group categorized the patients as having low-, medium-, or high-risk profiles based on olfaction and CSF biomarkers. When they analyzed the composite of olfaction and amyloid beta, as well as the composite for olfaction and tau–amyloid beta ratio, they noted that patients with the highest risk profiles had significantly more cognitive decline, as measured by the MOCA.

Furthermore, the researchers observed that patients with the worst olfaction, as measured by the UPSIT, appeared to have a higher rate of conversion to MCI, but the result did not reach statistical significance. Similarly, participants with the highest tau–amyloid beta ratio appeared to have a higher rate of conversion to MCI, but the finding was not significant. When the investigators combined the biomarkers using the risk profiles, participants with the highest risk profiles were 79% more likely to develop MCI during the three-year study period than other participants.

—Erik Greb