The Journal of Family Practice

International travel, whether for business, pleasure, child adoption, medical tourism, or adventure, continues to grow. In 2015, more than 70 million US citizens traveled internationally.¹ Many individuals contact family physicians first about their plans for travel and questions about travel-related health advice. This article provides an overview of the vaccines recommended for travelers headed to international destinations. Because country-specific vaccination recommendations and requirements for entry and departure change over time, check the Centers for Disease Control and Prevention (CDC) Web site for up-to-date requirements and recommendations (www.cdc.gov/travel).

Vaccine schedules vary according to destination and individual risks

There is no single vaccination schedule that applies to all travelers. Each schedule should be individualized based on the traveler’s destination, risk assessment, previous immunizations, health status, and time available before departure.^2,3 Pregnant or immunocompromised travelers should seek advice from an experienced travel medicine consultant on the immunization recommendations specifically meant for them.^4,5

Travel vaccines (TABLE⁶) are generally categorized as routine, required, or recommended.

1. Routine vaccines are the standard child and adult immunizations recommended by the Advisory Committee on Immunization Practices (ACIP). These include such vaccines as diphtheria-tetanus toxoids-acellular pertussis (DTaP), inactivated polio vaccine (IPV), Haemophilus influenzae type b (Hib), hepatitis B, rotavirus and pneumococcal vaccines, and human papillomavirus (HPV).
2. Required vaccines—eg, yellow fever and meningococcal vaccines—must be documented on the International Certificate of Vaccination before entry into certain countries.
3. Recommended vaccines are advised based on the travel destination and anticipated activities. These would include vaccines for typhoid, rabies, Japanese encephalitis, and polio (adult booster).

Routine vaccinations may need to be accelerated

Pre-travel patient encounters are an opportunity to update routine vaccinations.^7,8 Immunization against childhood diseases remains suboptimal in developing countries, where vaccine-preventable illnesses occur more frequently.⁹

Routine vaccines may be administered on an accelerated basis depending on geographic destination, seasonal disease variations, anticipated exposures, and known outbreaks at the time of travel.

MMR vaccine. Measles is still common in many parts of the world, and unvaccinated or incompletely vaccinated travelers are at risk of acquiring the disease and importing it to the United States (see “Measles: Why it’s still a threat,” 2017;66:446-449.) In 2015, a large, widespread measles outbreak occurred in the United States, linked to an amusement park in California, likely originating with an infected traveler who visited the park.¹⁰

Flu vaccine is recommended for all travelers ≥6 months of age, as flu season varies internationally.

All children older than 12 months should receive 2 doses of measles-mumps-rubella (MMR) vaccine separated by at least 28 days before departure (regardless of their destination). Infants between 6 and 11 months are at risk for high morbidity and may therefore receive a single dose of MMR earlier than the routinely recommended age of 12 to 15 months. Adolescents and adults without evidence of immunity against measles should get 2 doses of MMR separated by at least 28 days.¹¹ Acceptable presumptive evidence of immunity against measles includes written documentation of adequate vaccination, laboratory evidence of immunity, laboratory confirmation of measles, or birth before 1957.

Varicella vaccine. Children, adolescents, and young adults who have received only one dose of varicella should get a second dose prior to departure. For children 7 to 12 years, the recommended minimum interval between doses is 3 months. For individuals 13 years or older, the minimum interval is 4 weeks.^7,8

Influenza vaccine is routinely recommended for all travelers 6 months of age or older, as flu season varies geographically. Flu season in the Northern Hemisphere may begin as early as October and can extend until May. In the Southern Hemisphere, it may begin in April and last through September. Travelers should be vaccinated at least 2 weeks before travel in order to develop adequate immunity.^12,13

Required vaccinations: Proof is needed before traveling

Yellow fever (YF) is a mosquito-borne viral illness characterized by fever, chills, headache, myalgia, and vomiting. The disease can progress to coagulopathy, shock, and multisystem organ failure.¹⁴ YF vaccine is recommended for individuals 9 months or older who are traveling to or living in areas of South America or Africa where YF virus transmission is common (map: http://www.cdc.gov/yellowfever/maps/).

YF vaccine is a live-attenuated virus formulation and, therefore, should not be given to individuals with primary immunodeficiencies, transplant recipients or patients on immunosuppressive and immunomodulatory therapies, or patients with human immunodeficiency virus (HIV) whose CD4 count is below 200/mL. Other contraindications to YF vaccine are age younger than 6 months, allergy to a vaccine component, and thymic disorders. Serious adverse reactions to the vaccine are rare, but include 2 syndromes: YF-associated neurotropic disease and YF vaccine-associated viscerotropic disease.¹⁵

In many YF-endemic countries, vaccination is legally required for entry, and proof of vaccination must be documented on an International Certificate of Vaccination or Prophylaxis (ICVP). Additionally, some countries may require proof of vaccination before allowing travel through an endemic region, to prevent introduction of the disease elsewhere. Travelers with a specific contraindication to YF vaccine should obtain a waiver from a physician before traveling to a country requiring vaccination.¹⁶

The vaccination certificate is valid beginning 10 days after administration of YF vaccine. Immunity after a single dose is long lasting and may provide lifetime protection. Previously, re-vaccination was required every 10 years; however, in February 2015, ACIP approved a new recommendation stating a single dose of YF vaccine is adequate for most travelers.¹⁷

Many countries in which yellow fever is endemic don't allow entry without proof of vaccination on an International Certificate of Vaccination or Prophylaxis.

Although ACIP no longer recommends booster doses of YF vaccine for most travelers, clinicians and travelers should review the entry requirements for destination countries because changes to the International Health Regulations have not yet been fully implemented. Once this change is instituted, a completed ICVP will be valid for the lifetime of the vaccine.^18,19 Country-specific requirements for YF can be found at http://www.cdc.gov/yellowfever/maps/. (Click on the link below the appropriate map.) In the United States, the YF vaccine is distributed only through approved vaccination centers. These designated clinics are listed in a registry on the CDC travel Web site at https://wwwnc.cdc.gov/travel/yellow-fever-vaccination-clinics/search.

Meningococcal disease. ACIP recommends routine vaccination against meningococcal disease for people 11 to 18 years of age and for individuals with persistent complement component deficiency, functional or anatomic asplenia, and HIV. Vaccination is recommended for travelers who visit or reside in areas where meningococcal disease is hyperendemic or epidemic, such as the meningitis belt of sub-Saharan Africa during the dry season of December to June (map: http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/meningococcal-disease). Travelers to Saudi Arabia during the annual Hajj and Umrah pilgrimages are required to have a certificate of vaccination with quadrivalent (serogroups A, C, Y, W-135) meningococcal vaccine issued within 3 years (and not less than 10 days) before entry.

Several meningococcal vaccines are available in the United States. The quadrivalent vaccines are Menactra (MenACWY-D, Sanofi Pasteur) and Menveo (MenACWY-CRM, GSK). A bivalent (serogroups C and Y) conjugate vaccine MenHibrix (Hib-MenCY-TT, GSK) is also licensed for use in the United States, but infants traveling to areas with high endemic rates of meningococcal disease who received this vaccine are not protected against serogroups A and W and should receive quadrivalent meningococcal conjugate vaccine. Serogroup B vaccination is not routinely recommended for travelers. Approximately 7 to 10 days are required after vaccination for the development of protective antibody levels.^7,8,20,21

Polio. Although polio has been nearly eradicated, as of the time this article was written, the disease has not been eliminated in Afghanistan, Guinea, Laos, Nigeria, or Pakistan. Other countries, such as Cameroon, Chad, and Ukraine remain vulnerable to international transmission.²² The CDC recommends that adults who are traveling to areas where wild polio virus (WPV) has circulated in the last 12 months and who are unvaccinated, incompletely vaccinated, or whose vaccination status is unknown should receive a series of 3 doses of IPV to prevent ongoing spread.²³ Adults who completed the polio vaccine series as children and are traveling to areas where WPV has circulated in the last 12 months should receive a one-time booster dose of IPV.²³

Infants and children in the United States should be vaccinated against polio as part of a routine age-appropriate series. If a child cannot complete the routine series before departure and is traveling to an area where WPV has circulated in the last 12 months, an accelerated schedule is recommended. Vaccination should be documented on the ICVP, as countries with active spread of poliovirus may require proof of polio vaccination upon exit. A list of the countries where the polio virus is currently circulating is available at http://polioeradication.org/polio-today/polio-now/wild-poliovirus-list/.

Both routine and accelerated vaccination schedules for children and adults are published annually by the CDC and are available at http://www.cdc.gov/vaccines/schedules/hcp/index.html.

Recommended vaccines

Japanese encephalitis (JE) is endemic throughout most of Asia and parts of the Western Pacific region (map: http://www.cdc.gov/japaneseencephalitis/maps/). JE vaccine is recommended for travelers who plan to spend more than a month in endemic areas during the JE virus transmission season. (In temperate areas of Asia, JE virus transmission is seasonal and usually peaks in the summer and fall. In the subtropics and tropics, transmission can occur year-round, often with a peak during the rainy season.)

Adults who completed the polio vaccine series as children and are traveling where wild polio virus has circulated in the last 12 months should receive a one-time booster dose of IPV.

This recommendation includes recurrent travelers or expatriates who are likely to visit endemic rural or agricultural areas during a high-risk period of JE virus transmission. Risk is low for travelers who spend less than a month in endemic areas and for those who confine their travel to urban centers. Nevertheless, vaccination should be considered if travel is planned for outside an urban area and includes such activities as camping, hiking, trekking, biking, fishing, hunting, or farming. Inactivated Vero cell culture-derived vaccine (Ixiaro) is the only JE vaccine licensed and available in the United States. Ixiaro is given as a 2-dose series, with the doses spaced 28 days apart. The last dose should be given at least one week before travel.²⁴

Typhoid fever. Vaccination against typhoid fever is recommended for travelers to highly endemic areas such as the Indian subcontinent, Africa, and Central and South America. Two typhoid vaccines are available: Vi capsular polysaccharide vaccine (ViCPS) administered intramuscularly (IM), and oral live attenuated vaccine (Ty21a). Ty21a is a live vaccine and should not be given to immunocompromised people or those taking antibiotics, as it may reduce immunogenicity. Ty21a must be kept refrigerated at 35.6° F to 46.4° F (2° C - 8° C) and administered with cool liquid no warmer than 98.6° F (37° C). Both vaccines are only 50% to 80% efficacious, making access to clean food and water essential.^3,5,25

Hepatitis A vaccine should be given to all children older than one year traveling to areas where there is an intermediate or high risk of the disease. Children younger than one year who are traveling to high-risk areas can receive a single dose of immunoglobulin (IG) 0.02 mL/kg IM, which provides protection for up to 3 months. One 0.06 mL/kg-dose IM provides protection for 3 to 5 months.

If travel continues, children should receive a second dose after 5 months. IG does not interfere with the response to YF vaccine, but can interfere with the response to other live injected vaccines (such as MMR and varicella).²⁶

Hepatitis B vaccination should be administered to all unvaccinated travelers who plan to visit an area with intermediate to high prevalence of chronic hepatitis B (HBV surface antigen prevalence ≥2%). Unvaccinated travelers who may engage in high-risk sexual activity or injection drug use should receive hepatitis B vaccine regardless of destination. Additionally, travelers who access medical care for injury or illness while abroad may also be at risk of acquiring hepatitis B via contaminated blood products or medical equipment.²⁷

Serologic testing and booster vaccination are not recommended before travel for immunocompetent adults who have been previously vaccinated. The combined hepatitis A and B vaccine provides effective and convenient dual protection for travelers and can be administered with an accelerated 0-, 7-, and 21-day schedule for last-minute travelers.^7,8

Rabies remains endemic in developing countries of Africa and Asia, where appropriate post-exposure prophylaxis is limited or non-existent.²⁸ Consider pre-exposure rabies prophylaxis for traveling patients based on the availability of rabies vaccine and immunoglobulin in their destination area, planned duration of stay, and the likelihood of animal exposure (eg, veterinarians, animal handlers, cavers, missionaries). Advise travelers who decline vaccination to avoid or minimize animal contact during travel. In the event the traveler sustains an animal bite or scratch, immediate cleansing of the wound substantially reduces the risk of infection, especially when followed by timely administration of post-exposure prophylaxis.

In the event of an animal bite or scratch, immediate cleansing of the wound significantly reduces the risk of rabies infection.

Post-exposure prophylaxis for unvaccinated individuals consists of local infiltration of rabies immunoglobulin at the site of the bite and a series of 4 injections of rabies vaccine over 14 days, or 5 doses over one month for immunosuppressed patients. The first dose of the 4-dose course should be administered as soon as possible after exposure. Two vaccines are licensed for use in the United States: human diploid cell vaccine (HDCV, Imovax Rabies, Sanofi Pasteur) and purified chick embryo cell vaccine (PCECV, RabAvert, Novartis Vaccines and Diagnostics). The vaccine should never be administered in the gluteal area, as this may result in lower antibody titers.²⁹

Additionally, promising new vaccines against malaria and dengue fever are under clinical development and may be available in the near future.

CORRESPONDENCE
Vini Vijayan, MD, Division of Infectious Diseases, Arkansas Children's Hospital, 1 Children's Way, Slot 512-11, Little Rock, AR 72202; [email protected]. 

International travel, whether for business, pleasure, child adoption, medical tourism, or adventure, continues to grow. In 2015, more than 70 million US citizens traveled internationally.¹ Many individuals contact family physicians first about their plans for travel and questions about travel-related health advice. This article provides an overview of the vaccines recommended for travelers headed to international destinations. Because country-specific vaccination recommendations and requirements for entry and departure change over time, check the Centers for Disease Control and Prevention (CDC) Web site for up-to-date requirements and recommendations (www.cdc.gov/travel).

Vaccine schedules vary according to destination and individual risks

There is no single vaccination schedule that applies to all travelers. Each schedule should be individualized based on the traveler’s destination, risk assessment, previous immunizations, health status, and time available before departure.^2,3 Pregnant or immunocompromised travelers should seek advice from an experienced travel medicine consultant on the immunization recommendations specifically meant for them.^4,5

Travel vaccines (TABLE⁶) are generally categorized as routine, required, or recommended.

1. Routine vaccines are the standard child and adult immunizations recommended by the Advisory Committee on Immunization Practices (ACIP). These include such vaccines as diphtheria-tetanus toxoids-acellular pertussis (DTaP), inactivated polio vaccine (IPV), Haemophilus influenzae type b (Hib), hepatitis B, rotavirus and pneumococcal vaccines, and human papillomavirus (HPV).
2. Required vaccines—eg, yellow fever and meningococcal vaccines—must be documented on the International Certificate of Vaccination before entry into certain countries.
3. Recommended vaccines are advised based on the travel destination and anticipated activities. These would include vaccines for typhoid, rabies, Japanese encephalitis, and polio (adult booster).

Routine vaccinations may need to be accelerated

Pre-travel patient encounters are an opportunity to update routine vaccinations.^7,8 Immunization against childhood diseases remains suboptimal in developing countries, where vaccine-preventable illnesses occur more frequently.⁹

Routine vaccines may be administered on an accelerated basis depending on geographic destination, seasonal disease variations, anticipated exposures, and known outbreaks at the time of travel.

MMR vaccine. Measles is still common in many parts of the world, and unvaccinated or incompletely vaccinated travelers are at risk of acquiring the disease and importing it to the United States (see “Measles: Why it’s still a threat,” 2017;66:446-449.) In 2015, a large, widespread measles outbreak occurred in the United States, linked to an amusement park in California, likely originating with an infected traveler who visited the park.¹⁰

Flu vaccine is recommended for all travelers ≥6 months of age, as flu season varies internationally.

All children older than 12 months should receive 2 doses of measles-mumps-rubella (MMR) vaccine separated by at least 28 days before departure (regardless of their destination). Infants between 6 and 11 months are at risk for high morbidity and may therefore receive a single dose of MMR earlier than the routinely recommended age of 12 to 15 months. Adolescents and adults without evidence of immunity against measles should get 2 doses of MMR separated by at least 28 days.¹¹ Acceptable presumptive evidence of immunity against measles includes written documentation of adequate vaccination, laboratory evidence of immunity, laboratory confirmation of measles, or birth before 1957.

Varicella vaccine. Children, adolescents, and young adults who have received only one dose of varicella should get a second dose prior to departure. For children 7 to 12 years, the recommended minimum interval between doses is 3 months. For individuals 13 years or older, the minimum interval is 4 weeks.^7,8

Influenza vaccine is routinely recommended for all travelers 6 months of age or older, as flu season varies geographically. Flu season in the Northern Hemisphere may begin as early as October and can extend until May. In the Southern Hemisphere, it may begin in April and last through September. Travelers should be vaccinated at least 2 weeks before travel in order to develop adequate immunity.^12,13

Required vaccinations: Proof is needed before traveling

Yellow fever (YF) is a mosquito-borne viral illness characterized by fever, chills, headache, myalgia, and vomiting. The disease can progress to coagulopathy, shock, and multisystem organ failure.¹⁴ YF vaccine is recommended for individuals 9 months or older who are traveling to or living in areas of South America or Africa where YF virus transmission is common (map: http://www.cdc.gov/yellowfever/maps/).

YF vaccine is a live-attenuated virus formulation and, therefore, should not be given to individuals with primary immunodeficiencies, transplant recipients or patients on immunosuppressive and immunomodulatory therapies, or patients with human immunodeficiency virus (HIV) whose CD4 count is below 200/mL. Other contraindications to YF vaccine are age younger than 6 months, allergy to a vaccine component, and thymic disorders. Serious adverse reactions to the vaccine are rare, but include 2 syndromes: YF-associated neurotropic disease and YF vaccine-associated viscerotropic disease.¹⁵

In many YF-endemic countries, vaccination is legally required for entry, and proof of vaccination must be documented on an International Certificate of Vaccination or Prophylaxis (ICVP). Additionally, some countries may require proof of vaccination before allowing travel through an endemic region, to prevent introduction of the disease elsewhere. Travelers with a specific contraindication to YF vaccine should obtain a waiver from a physician before traveling to a country requiring vaccination.¹⁶

The vaccination certificate is valid beginning 10 days after administration of YF vaccine. Immunity after a single dose is long lasting and may provide lifetime protection. Previously, re-vaccination was required every 10 years; however, in February 2015, ACIP approved a new recommendation stating a single dose of YF vaccine is adequate for most travelers.¹⁷

Many countries in which yellow fever is endemic don't allow entry without proof of vaccination on an International Certificate of Vaccination or Prophylaxis.

Although ACIP no longer recommends booster doses of YF vaccine for most travelers, clinicians and travelers should review the entry requirements for destination countries because changes to the International Health Regulations have not yet been fully implemented. Once this change is instituted, a completed ICVP will be valid for the lifetime of the vaccine.^18,19 Country-specific requirements for YF can be found at http://www.cdc.gov/yellowfever/maps/. (Click on the link below the appropriate map.) In the United States, the YF vaccine is distributed only through approved vaccination centers. These designated clinics are listed in a registry on the CDC travel Web site at https://wwwnc.cdc.gov/travel/yellow-fever-vaccination-clinics/search.

Meningococcal disease. ACIP recommends routine vaccination against meningococcal disease for people 11 to 18 years of age and for individuals with persistent complement component deficiency, functional or anatomic asplenia, and HIV. Vaccination is recommended for travelers who visit or reside in areas where meningococcal disease is hyperendemic or epidemic, such as the meningitis belt of sub-Saharan Africa during the dry season of December to June (map: http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/meningococcal-disease). Travelers to Saudi Arabia during the annual Hajj and Umrah pilgrimages are required to have a certificate of vaccination with quadrivalent (serogroups A, C, Y, W-135) meningococcal vaccine issued within 3 years (and not less than 10 days) before entry.

Several meningococcal vaccines are available in the United States. The quadrivalent vaccines are Menactra (MenACWY-D, Sanofi Pasteur) and Menveo (MenACWY-CRM, GSK). A bivalent (serogroups C and Y) conjugate vaccine MenHibrix (Hib-MenCY-TT, GSK) is also licensed for use in the United States, but infants traveling to areas with high endemic rates of meningococcal disease who received this vaccine are not protected against serogroups A and W and should receive quadrivalent meningococcal conjugate vaccine. Serogroup B vaccination is not routinely recommended for travelers. Approximately 7 to 10 days are required after vaccination for the development of protective antibody levels.^7,8,20,21

Polio. Although polio has been nearly eradicated, as of the time this article was written, the disease has not been eliminated in Afghanistan, Guinea, Laos, Nigeria, or Pakistan. Other countries, such as Cameroon, Chad, and Ukraine remain vulnerable to international transmission.²² The CDC recommends that adults who are traveling to areas where wild polio virus (WPV) has circulated in the last 12 months and who are unvaccinated, incompletely vaccinated, or whose vaccination status is unknown should receive a series of 3 doses of IPV to prevent ongoing spread.²³ Adults who completed the polio vaccine series as children and are traveling to areas where WPV has circulated in the last 12 months should receive a one-time booster dose of IPV.²³

Infants and children in the United States should be vaccinated against polio as part of a routine age-appropriate series. If a child cannot complete the routine series before departure and is traveling to an area where WPV has circulated in the last 12 months, an accelerated schedule is recommended. Vaccination should be documented on the ICVP, as countries with active spread of poliovirus may require proof of polio vaccination upon exit. A list of the countries where the polio virus is currently circulating is available at http://polioeradication.org/polio-today/polio-now/wild-poliovirus-list/.

Both routine and accelerated vaccination schedules for children and adults are published annually by the CDC and are available at http://www.cdc.gov/vaccines/schedules/hcp/index.html.

Recommended vaccines

Japanese encephalitis (JE) is endemic throughout most of Asia and parts of the Western Pacific region (map: http://www.cdc.gov/japaneseencephalitis/maps/). JE vaccine is recommended for travelers who plan to spend more than a month in endemic areas during the JE virus transmission season. (In temperate areas of Asia, JE virus transmission is seasonal and usually peaks in the summer and fall. In the subtropics and tropics, transmission can occur year-round, often with a peak during the rainy season.)

Adults who completed the polio vaccine series as children and are traveling where wild polio virus has circulated in the last 12 months should receive a one-time booster dose of IPV.

This recommendation includes recurrent travelers or expatriates who are likely to visit endemic rural or agricultural areas during a high-risk period of JE virus transmission. Risk is low for travelers who spend less than a month in endemic areas and for those who confine their travel to urban centers. Nevertheless, vaccination should be considered if travel is planned for outside an urban area and includes such activities as camping, hiking, trekking, biking, fishing, hunting, or farming. Inactivated Vero cell culture-derived vaccine (Ixiaro) is the only JE vaccine licensed and available in the United States. Ixiaro is given as a 2-dose series, with the doses spaced 28 days apart. The last dose should be given at least one week before travel.²⁴

Typhoid fever. Vaccination against typhoid fever is recommended for travelers to highly endemic areas such as the Indian subcontinent, Africa, and Central and South America. Two typhoid vaccines are available: Vi capsular polysaccharide vaccine (ViCPS) administered intramuscularly (IM), and oral live attenuated vaccine (Ty21a). Ty21a is a live vaccine and should not be given to immunocompromised people or those taking antibiotics, as it may reduce immunogenicity. Ty21a must be kept refrigerated at 35.6° F to 46.4° F (2° C - 8° C) and administered with cool liquid no warmer than 98.6° F (37° C). Both vaccines are only 50% to 80% efficacious, making access to clean food and water essential.^3,5,25

Hepatitis A vaccine should be given to all children older than one year traveling to areas where there is an intermediate or high risk of the disease. Children younger than one year who are traveling to high-risk areas can receive a single dose of immunoglobulin (IG) 0.02 mL/kg IM, which provides protection for up to 3 months. One 0.06 mL/kg-dose IM provides protection for 3 to 5 months.

If travel continues, children should receive a second dose after 5 months. IG does not interfere with the response to YF vaccine, but can interfere with the response to other live injected vaccines (such as MMR and varicella).²⁶

Hepatitis B vaccination should be administered to all unvaccinated travelers who plan to visit an area with intermediate to high prevalence of chronic hepatitis B (HBV surface antigen prevalence ≥2%). Unvaccinated travelers who may engage in high-risk sexual activity or injection drug use should receive hepatitis B vaccine regardless of destination. Additionally, travelers who access medical care for injury or illness while abroad may also be at risk of acquiring hepatitis B via contaminated blood products or medical equipment.²⁷

Serologic testing and booster vaccination are not recommended before travel for immunocompetent adults who have been previously vaccinated. The combined hepatitis A and B vaccine provides effective and convenient dual protection for travelers and can be administered with an accelerated 0-, 7-, and 21-day schedule for last-minute travelers.^7,8

Rabies remains endemic in developing countries of Africa and Asia, where appropriate post-exposure prophylaxis is limited or non-existent.²⁸ Consider pre-exposure rabies prophylaxis for traveling patients based on the availability of rabies vaccine and immunoglobulin in their destination area, planned duration of stay, and the likelihood of animal exposure (eg, veterinarians, animal handlers, cavers, missionaries). Advise travelers who decline vaccination to avoid or minimize animal contact during travel. In the event the traveler sustains an animal bite or scratch, immediate cleansing of the wound substantially reduces the risk of infection, especially when followed by timely administration of post-exposure prophylaxis.

In the event of an animal bite or scratch, immediate cleansing of the wound significantly reduces the risk of rabies infection.

Post-exposure prophylaxis for unvaccinated individuals consists of local infiltration of rabies immunoglobulin at the site of the bite and a series of 4 injections of rabies vaccine over 14 days, or 5 doses over one month for immunosuppressed patients. The first dose of the 4-dose course should be administered as soon as possible after exposure. Two vaccines are licensed for use in the United States: human diploid cell vaccine (HDCV, Imovax Rabies, Sanofi Pasteur) and purified chick embryo cell vaccine (PCECV, RabAvert, Novartis Vaccines and Diagnostics). The vaccine should never be administered in the gluteal area, as this may result in lower antibody titers.²⁹

Additionally, promising new vaccines against malaria and dengue fever are under clinical development and may be available in the near future.

CORRESPONDENCE
Vini Vijayan, MD, Division of Infectious Diseases, Arkansas Children's Hospital, 1 Children's Way, Slot 512-11, Little Rock, AR 72202; [email protected]. 

International travel, whether for business, pleasure, child adoption, medical tourism, or adventure, continues to grow. In 2015, more than 70 million US citizens traveled internationally.¹ Many individuals contact family physicians first about their plans for travel and questions about travel-related health advice. This article provides an overview of the vaccines recommended for travelers headed to international destinations. Because country-specific vaccination recommendations and requirements for entry and departure change over time, check the Centers for Disease Control and Prevention (CDC) Web site for up-to-date requirements and recommendations (www.cdc.gov/travel).

Vaccine schedules vary according to destination and individual risks

There is no single vaccination schedule that applies to all travelers. Each schedule should be individualized based on the traveler’s destination, risk assessment, previous immunizations, health status, and time available before departure.^2,3 Pregnant or immunocompromised travelers should seek advice from an experienced travel medicine consultant on the immunization recommendations specifically meant for them.^4,5

Travel vaccines (TABLE⁶) are generally categorized as routine, required, or recommended.

1. Routine vaccines are the standard child and adult immunizations recommended by the Advisory Committee on Immunization Practices (ACIP). These include such vaccines as diphtheria-tetanus toxoids-acellular pertussis (DTaP), inactivated polio vaccine (IPV), Haemophilus influenzae type b (Hib), hepatitis B, rotavirus and pneumococcal vaccines, and human papillomavirus (HPV).
2. Required vaccines—eg, yellow fever and meningococcal vaccines—must be documented on the International Certificate of Vaccination before entry into certain countries.
3. Recommended vaccines are advised based on the travel destination and anticipated activities. These would include vaccines for typhoid, rabies, Japanese encephalitis, and polio (adult booster).

Routine vaccinations may need to be accelerated

Pre-travel patient encounters are an opportunity to update routine vaccinations.^7,8 Immunization against childhood diseases remains suboptimal in developing countries, where vaccine-preventable illnesses occur more frequently.⁹

Routine vaccines may be administered on an accelerated basis depending on geographic destination, seasonal disease variations, anticipated exposures, and known outbreaks at the time of travel.

MMR vaccine. Measles is still common in many parts of the world, and unvaccinated or incompletely vaccinated travelers are at risk of acquiring the disease and importing it to the United States (see “Measles: Why it’s still a threat,” 2017;66:446-449.) In 2015, a large, widespread measles outbreak occurred in the United States, linked to an amusement park in California, likely originating with an infected traveler who visited the park.¹⁰

Flu vaccine is recommended for all travelers ≥6 months of age, as flu season varies internationally.

All children older than 12 months should receive 2 doses of measles-mumps-rubella (MMR) vaccine separated by at least 28 days before departure (regardless of their destination). Infants between 6 and 11 months are at risk for high morbidity and may therefore receive a single dose of MMR earlier than the routinely recommended age of 12 to 15 months. Adolescents and adults without evidence of immunity against measles should get 2 doses of MMR separated by at least 28 days.¹¹ Acceptable presumptive evidence of immunity against measles includes written documentation of adequate vaccination, laboratory evidence of immunity, laboratory confirmation of measles, or birth before 1957.

Varicella vaccine. Children, adolescents, and young adults who have received only one dose of varicella should get a second dose prior to departure. For children 7 to 12 years, the recommended minimum interval between doses is 3 months. For individuals 13 years or older, the minimum interval is 4 weeks.^7,8

Influenza vaccine is routinely recommended for all travelers 6 months of age or older, as flu season varies geographically. Flu season in the Northern Hemisphere may begin as early as October and can extend until May. In the Southern Hemisphere, it may begin in April and last through September. Travelers should be vaccinated at least 2 weeks before travel in order to develop adequate immunity.^12,13

Required vaccinations: Proof is needed before traveling

Yellow fever (YF) is a mosquito-borne viral illness characterized by fever, chills, headache, myalgia, and vomiting. The disease can progress to coagulopathy, shock, and multisystem organ failure.¹⁴ YF vaccine is recommended for individuals 9 months or older who are traveling to or living in areas of South America or Africa where YF virus transmission is common (map: http://www.cdc.gov/yellowfever/maps/).

YF vaccine is a live-attenuated virus formulation and, therefore, should not be given to individuals with primary immunodeficiencies, transplant recipients or patients on immunosuppressive and immunomodulatory therapies, or patients with human immunodeficiency virus (HIV) whose CD4 count is below 200/mL. Other contraindications to YF vaccine are age younger than 6 months, allergy to a vaccine component, and thymic disorders. Serious adverse reactions to the vaccine are rare, but include 2 syndromes: YF-associated neurotropic disease and YF vaccine-associated viscerotropic disease.¹⁵

In many YF-endemic countries, vaccination is legally required for entry, and proof of vaccination must be documented on an International Certificate of Vaccination or Prophylaxis (ICVP). Additionally, some countries may require proof of vaccination before allowing travel through an endemic region, to prevent introduction of the disease elsewhere. Travelers with a specific contraindication to YF vaccine should obtain a waiver from a physician before traveling to a country requiring vaccination.¹⁶

The vaccination certificate is valid beginning 10 days after administration of YF vaccine. Immunity after a single dose is long lasting and may provide lifetime protection. Previously, re-vaccination was required every 10 years; however, in February 2015, ACIP approved a new recommendation stating a single dose of YF vaccine is adequate for most travelers.¹⁷

Many countries in which yellow fever is endemic don't allow entry without proof of vaccination on an International Certificate of Vaccination or Prophylaxis.

Although ACIP no longer recommends booster doses of YF vaccine for most travelers, clinicians and travelers should review the entry requirements for destination countries because changes to the International Health Regulations have not yet been fully implemented. Once this change is instituted, a completed ICVP will be valid for the lifetime of the vaccine.^18,19 Country-specific requirements for YF can be found at http://www.cdc.gov/yellowfever/maps/. (Click on the link below the appropriate map.) In the United States, the YF vaccine is distributed only through approved vaccination centers. These designated clinics are listed in a registry on the CDC travel Web site at https://wwwnc.cdc.gov/travel/yellow-fever-vaccination-clinics/search.

Meningococcal disease. ACIP recommends routine vaccination against meningococcal disease for people 11 to 18 years of age and for individuals with persistent complement component deficiency, functional or anatomic asplenia, and HIV. Vaccination is recommended for travelers who visit or reside in areas where meningococcal disease is hyperendemic or epidemic, such as the meningitis belt of sub-Saharan Africa during the dry season of December to June (map: http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/meningococcal-disease). Travelers to Saudi Arabia during the annual Hajj and Umrah pilgrimages are required to have a certificate of vaccination with quadrivalent (serogroups A, C, Y, W-135) meningococcal vaccine issued within 3 years (and not less than 10 days) before entry.

Several meningococcal vaccines are available in the United States. The quadrivalent vaccines are Menactra (MenACWY-D, Sanofi Pasteur) and Menveo (MenACWY-CRM, GSK). A bivalent (serogroups C and Y) conjugate vaccine MenHibrix (Hib-MenCY-TT, GSK) is also licensed for use in the United States, but infants traveling to areas with high endemic rates of meningococcal disease who received this vaccine are not protected against serogroups A and W and should receive quadrivalent meningococcal conjugate vaccine. Serogroup B vaccination is not routinely recommended for travelers. Approximately 7 to 10 days are required after vaccination for the development of protective antibody levels.^7,8,20,21

Polio. Although polio has been nearly eradicated, as of the time this article was written, the disease has not been eliminated in Afghanistan, Guinea, Laos, Nigeria, or Pakistan. Other countries, such as Cameroon, Chad, and Ukraine remain vulnerable to international transmission.²² The CDC recommends that adults who are traveling to areas where wild polio virus (WPV) has circulated in the last 12 months and who are unvaccinated, incompletely vaccinated, or whose vaccination status is unknown should receive a series of 3 doses of IPV to prevent ongoing spread.²³ Adults who completed the polio vaccine series as children and are traveling to areas where WPV has circulated in the last 12 months should receive a one-time booster dose of IPV.²³

Infants and children in the United States should be vaccinated against polio as part of a routine age-appropriate series. If a child cannot complete the routine series before departure and is traveling to an area where WPV has circulated in the last 12 months, an accelerated schedule is recommended. Vaccination should be documented on the ICVP, as countries with active spread of poliovirus may require proof of polio vaccination upon exit. A list of the countries where the polio virus is currently circulating is available at http://polioeradication.org/polio-today/polio-now/wild-poliovirus-list/.

Both routine and accelerated vaccination schedules for children and adults are published annually by the CDC and are available at http://www.cdc.gov/vaccines/schedules/hcp/index.html.

Recommended vaccines

Japanese encephalitis (JE) is endemic throughout most of Asia and parts of the Western Pacific region (map: http://www.cdc.gov/japaneseencephalitis/maps/). JE vaccine is recommended for travelers who plan to spend more than a month in endemic areas during the JE virus transmission season. (In temperate areas of Asia, JE virus transmission is seasonal and usually peaks in the summer and fall. In the subtropics and tropics, transmission can occur year-round, often with a peak during the rainy season.)

Adults who completed the polio vaccine series as children and are traveling where wild polio virus has circulated in the last 12 months should receive a one-time booster dose of IPV.

This recommendation includes recurrent travelers or expatriates who are likely to visit endemic rural or agricultural areas during a high-risk period of JE virus transmission. Risk is low for travelers who spend less than a month in endemic areas and for those who confine their travel to urban centers. Nevertheless, vaccination should be considered if travel is planned for outside an urban area and includes such activities as camping, hiking, trekking, biking, fishing, hunting, or farming. Inactivated Vero cell culture-derived vaccine (Ixiaro) is the only JE vaccine licensed and available in the United States. Ixiaro is given as a 2-dose series, with the doses spaced 28 days apart. The last dose should be given at least one week before travel.²⁴

Typhoid fever. Vaccination against typhoid fever is recommended for travelers to highly endemic areas such as the Indian subcontinent, Africa, and Central and South America. Two typhoid vaccines are available: Vi capsular polysaccharide vaccine (ViCPS) administered intramuscularly (IM), and oral live attenuated vaccine (Ty21a). Ty21a is a live vaccine and should not be given to immunocompromised people or those taking antibiotics, as it may reduce immunogenicity. Ty21a must be kept refrigerated at 35.6° F to 46.4° F (2° C - 8° C) and administered with cool liquid no warmer than 98.6° F (37° C). Both vaccines are only 50% to 80% efficacious, making access to clean food and water essential.^3,5,25

Hepatitis A vaccine should be given to all children older than one year traveling to areas where there is an intermediate or high risk of the disease. Children younger than one year who are traveling to high-risk areas can receive a single dose of immunoglobulin (IG) 0.02 mL/kg IM, which provides protection for up to 3 months. One 0.06 mL/kg-dose IM provides protection for 3 to 5 months.

If travel continues, children should receive a second dose after 5 months. IG does not interfere with the response to YF vaccine, but can interfere with the response to other live injected vaccines (such as MMR and varicella).²⁶

Hepatitis B vaccination should be administered to all unvaccinated travelers who plan to visit an area with intermediate to high prevalence of chronic hepatitis B (HBV surface antigen prevalence ≥2%). Unvaccinated travelers who may engage in high-risk sexual activity or injection drug use should receive hepatitis B vaccine regardless of destination. Additionally, travelers who access medical care for injury or illness while abroad may also be at risk of acquiring hepatitis B via contaminated blood products or medical equipment.²⁷

Serologic testing and booster vaccination are not recommended before travel for immunocompetent adults who have been previously vaccinated. The combined hepatitis A and B vaccine provides effective and convenient dual protection for travelers and can be administered with an accelerated 0-, 7-, and 21-day schedule for last-minute travelers.^7,8

Rabies remains endemic in developing countries of Africa and Asia, where appropriate post-exposure prophylaxis is limited or non-existent.²⁸ Consider pre-exposure rabies prophylaxis for traveling patients based on the availability of rabies vaccine and immunoglobulin in their destination area, planned duration of stay, and the likelihood of animal exposure (eg, veterinarians, animal handlers, cavers, missionaries). Advise travelers who decline vaccination to avoid or minimize animal contact during travel. In the event the traveler sustains an animal bite or scratch, immediate cleansing of the wound substantially reduces the risk of infection, especially when followed by timely administration of post-exposure prophylaxis.

In the event of an animal bite or scratch, immediate cleansing of the wound significantly reduces the risk of rabies infection.

Post-exposure prophylaxis for unvaccinated individuals consists of local infiltration of rabies immunoglobulin at the site of the bite and a series of 4 injections of rabies vaccine over 14 days, or 5 doses over one month for immunosuppressed patients. The first dose of the 4-dose course should be administered as soon as possible after exposure. Two vaccines are licensed for use in the United States: human diploid cell vaccine (HDCV, Imovax Rabies, Sanofi Pasteur) and purified chick embryo cell vaccine (PCECV, RabAvert, Novartis Vaccines and Diagnostics). The vaccine should never be administered in the gluteal area, as this may result in lower antibody titers.²⁹

Additionally, promising new vaccines against malaria and dengue fever are under clinical development and may be available in the near future.

CORRESPONDENCE
Vini Vijayan, MD, Division of Infectious Diseases, Arkansas Children's Hospital, 1 Children's Way, Slot 512-11, Little Rock, AR 72202; [email protected]. 

ABSTRACT

Purpose The purpose of this study was to determine the frequency of patients seen at a single institution who were diagnosed with a cervical vessel dissection related to chiropractic neck manipulation.

Methods We identified cases through a retrospective chart review of patients seen between April 2008 and March 2012 who had a diagnosis of cervical artery dissection following a recent chiropractic manipulation. Relevant imaging studies were reviewed by a board-certified neuroradiologist to confirm the findings of a cervical artery dissection and stroke. We conducted telephone interviews to ascertain the presence of residual symptoms in the affected patients.

Results Of the 141 patients with cervical artery dissection, 12 had documented chiropractic neck manipulation prior to the onset of the symptoms that led to medical presentation. The 12 patients had a total of 16 cervical artery dissections. All 12 patients developed symptoms of acute stroke. All strokes were confirmed with magnetic resonance imaging or computerized tomography. We obtained follow-up information on 9 patients, 8 of whom had residual symptoms and one of whom died as a result of his injury.

Conclusions In this case series, 12 patients with newly diagnosed cervical artery dissection(s) had recent chiropractic neck manipulation. Patients who are considering chiropractic cervical manipulation should be informed of the potential risk and be advised to seek immediate medical attention should they develop symptoms.

A prospective randomized controlled study published in 2012 showed chiropractic manipulation is beneficial in the treatment of neck pain compared with medical treatment, but it showed no significant difference between chiropractic manipulation and physical therapy exercises.¹ Although chiropractic manipulation of the cervical spine may be effective, it may also cause harm.

Cerebellar and spinal cord injuries related to cervical chiropractic manipulation were first reported in 1947.² By 1974, there were 12 reported cases.³ Noninvasive imaging has since greatly improved the diagnosis of cervical artery dissection and of stroke,⁴ and cervical artery dissection is now recognized as pathogenic of strokes occurring in association with chiropractic manipulation.⁵

A prospective series published in 2011 reported that, over 4 years, 13 patients were treated at a single institution for cervical arterial dissection following chiropractic treatment.⁶ That so many patients might be seen for this condition in that time frame at a single institution suggests the risk for such injury may be greater than thought. To explore that possibility, we performed a 4-year retrospective review to determine the experience at OSF Saint Francis Medical Center, which is affiliated with the University of Illinois College of Medicine, Peoria.

METHODS

Data sources. After receiving approval by the local institutional review board, we obtained data from the electronic medical records of OSF Saint Francis Medical Center, Peoria, Ill., using Epic (Epic Systems Corporation, Verona, Wis.) and IDX (General Electric Corporation, Fairfield, Conn.) systems. The records were queried using ICD-9 codes 443.21 and 443.24 to identify patients from April 2008 through March 2012 who had primary or secondary diagnoses of vertebral artery dissection (VAD) or carotid artery dissection (CAD). We reviewed all records of VAD and CAD to identify those that may have been associated with chiropractic manipulation.

Data collection. We abstracted data from 12 patients’ charts. Two patients were unavailable for direct contact: one was involved in ongoing litigation, and one had died (although we were able to speak with his wife). We attempted telephone contact with the 10 remaining patients and reached 8.

Data included the symptoms leading to chiropractic manipulation, symptoms following manipulation, timing of onset of symptoms relative to chiropractic manipulation, identifying information for the treating chiropractor, and residual patient symptoms. We also recorded patients’ ages, sex, locations of dissection, and locations of stroke. All dissections and strokes had been diagnosed during the patient’s initial hospitalization.

A board-certified radiologist (JRD) with a Certificate of Added Qualification in Neuroradiology (American Board of Medical Specialties) reviewed all pertinent imaging to confirm all dissections and strokes.

RESULTS

The medical record query yielded 141 patients with VAD or CAD, 15 of whom had undergone chiropractic manipulation prior to their presentation. The temporal association between chiropractic manipulation and arterial dissection was equivocal for 3 patients. In 12 patients, there was a verifiable temporal association between chiropractic manipulation and the arterial dissection. Three of the 12 patients were men and 9 were women. Ages ranged from 22 to 46 years, with a mean of 35.3 years.

Acute or chronic neck pain was the most common reason for seeking chiropractic care (TABLE 1). Immediately upon performance of cervical manipulation, 10 of the 12 developed acute symptoms different than those that caused them to seek chiropractic care. Two patients developed symptoms 2 to 3 days post-manipulation. Neither of the 2 had a history of neck trauma within the preceding year. Ten of the 12 patients sought immediate medical attention. Two of the 12 patients sought care when their symptoms became more severe, ranging from 2 days to several weeks later (TABLE 2). The treating chiropractor was identified in 7 cases and was different in each of the 7 cases.

A total of 16 cervical artery dissections, 14 VAD and 2 CAD, were confirmed by computed tomography angiography (CTA), magnetic resonance angiography (MRA), or catheter angiography (FIGURE 1). All 12 patients had acute strokes confirmed by MRA or CTA, including 9 in the cerebellum (FIGURE 2), 4 in the cerebrum, 2 in the medulla, and one in the pons.

Long-term outcomes were determined for 9 patients (TABLE 2). One patient’s symptoms resolved. Three patients had dizziness, clumsiness, or balance problems; 3 had persistent headaches; 2 had bilateral visual field abnormalities; and one patient walked with a cane, was no longer driving a car, and was on disability. One patient died as a result of his injury. One of the 12 cases was previously described in a case report.⁷

DISCUSSION

Dissection of the cervical arteries is more common than dissection in other arteries of comparable size. This increased risk in the cervical arteries is believed to be due to their relative mobility and proximity to bony structures.⁴

Sudden neck movement, a feature of chiropractic treatment, is one of several known risk factors for ‘spontaneous’ cervical artery dissection.^8,9 Symptom onset and stroke may be delayed after a spontaneous cervical artery dissection.¹⁰ Spontaneous dissection more commonly involves the carotid arteries;⁴ however, the vertebral arteries appear more prone to dissection as a consequence of chiropractic manipulation,¹¹ likely due to their relation to the cervical spine.

The Canadian Stroke Consortium has shown a 28% incidence of chiropractic manipulation in cases of cervical artery dissection.

The vertebral artery runs through foramina in the transverse processes of vertebral bodies C1 through C6 (FIGURE 3). On exiting the C2 transverse process, the vertebral artery has a tortuous course, making several turns over and through adjacent bony structures.¹² The artery is most prone to injury between the entrance to the transverse foramen of C6 and the foramen magnum (V2 and V3 segments).¹³ (The area of highest vulnerability is the tortuous segment from the transverse foramen of C2 to the foramen magnum.)

Sudden movements of the cervical spine may cause arterial dissection, whether the maneuvers are performed by a physician, a chiropractor, or a physical therapist.¹⁴ Injuries reported in the literature, however, most commonly follow chiropractic manipulation. In our series of 141 dissections, we found no cases associated with manipulation by other health professionals.

A 2003 study revealed cervical spine manipulation to be an independent and strong risk factor for vertebral artery dissection. The authors believed the relationship was likely causal.⁵ Data from the Canadian Stroke Consortium showed a 28% incidence of chiropractic manipulation in cases of cervical artery dissection.¹⁰

A 2008 study showed an association between vertebrobasilar stroke and chiropractic visits within one month of the vascular event.¹⁵ However, the study also showed an association of similar magnitude between vertebrobasilar stroke and visits to primary care physicians within the prior month. This suggests that cervical manipulation by chiropractors poses no more risk for cervical artery dissection than visits to primary care physicians. However, it is hard to reconcile such a conclusion with other studies, including our own, in which 10 patients developed new symptoms immediately with chiropractic manipulation of their cervical spines.

Perhaps the one-month observation period of Cassidy et al was excessive. Many post-manipulation events occur within hours or at most a few days, as would be expected given the hypothesized pathogenic mechanism. Perhaps if they had shortened their interval of study to the preceding 3 days, their findings may have been different.

A recent systematic review and meta-analysis demonstrated a slight association between chiropractic neck manipulation and cervical artery dissection. It stated that the quality of the published literature was very low, and it concluded there was no convincing evidence of causation.¹⁶ The fact that 10 of the 12 patients in our case series demonstrated acute symptoms immediately upon receiving spinal manipulation suggests a possible causal link; however, we agree with the authors of the meta-analysis that the quality of the literature is low.

A recent statement from the American Heart Association/American Stroke Association (and endorsed by the American Association of Neurological Surgeons and the Congress of Neurological Surgeons) has recommended that chiropractors inform patients of the statistical association between cervical artery dissection and cervical manipulation.¹⁷ In addition, it is important for chiropractors to be aware of the signs and symptoms of cervical artery dissection and stroke and to assess for these symptoms before performing neck manipulation, as illustrated in a recent case report.¹⁸ Due to the risk of death, patients who experience symptoms consistent with cervical artery dissection after chiropractic manipulation of the cervical spine should be advised to seek medical care immediately.

Our case series has several limitations. The study was retrospective. Existing documentation of associated chiropractic care was often sparse, necessitating phone calls to supplement the information. We believe it is possible that cases may have been missed because of inaccurate medical record documentation, deficits in the interview process concerning chiropractic care at the time of hospitalization, or because information concerning chiropractic care was not recorded in the chart.

A significant portion of our information came through phone contact with several of the patients. In some cases, we relied heavily on their recollection of events that had occurred anytime from a few days to a few years earlier. The accuracy and completeness of the information supplied by patients was not verified, allowing for potential recall bias.

We do not know whether our experience is consistent with that of other areas of the United States. However, the fact that a similar-size hospital in Phoenix reported similar findings suggests the experience may be more widespread.⁶

IMPLICATIONS OF OUR FINDINGS

Over a 4-year period at our institution, 12 patients experienced cervical vessel dissection related to chiropractic neck manipulation. A similar institution in another part of the country had previously described 13 such cases. The patients at both institutions were relatively young and incurred substantial residual morbidity. A single patient at each institution died. If these findings are representative of other institutions across the United States, the incidence of stroke secondary to chiropractic manipulation may be higher than supposed.

Tell patients considering cervical spine manipulation to seek medical help if symptoms suggestive of dissection or stroke occur during or after manipulation.

To assess this problem further, a randomized prospective cohort study could establish the relative risk of chiropractic manipulation of the cervical spine resulting in a cervical artery dissection. But such a study may be methodologically prohibitive. More feasible would be a case-control study similar to one carried out by Smith et al⁵ in which patients who had experienced cervical artery dissection were matched with subjects who had not incurred such injuries. Comparing the groups’ odds of having received chiropractic manipulation demonstrated that spinal manipulative therapy is an independent risk factor for vertebral artery dissection and is highly suggestive of a causal association. Replicating this study in a different population would be valuable.

Based on our findings, all patients who visit chiropractors for cervical spine manipulation should be informed of the potential risks and of the need to seek immediate medical assistance should symptoms suggestive of dissection or stroke occur during or after manipulation. Until the actual level of risk from chiropractic manipulation is known, patients with neck pain may be better served by equally effective passive physical therapy exercises.¹

CORRESPONDENCE
Raymond E. Bertino, MD, 427 West Crestwood Drive, Peoria, IL 61614; [email protected].

ACKNOWLEDGEMENTS
We thank Deepak Nair, MD, for his assistance in reviewing the stroke neurology aspects of this study; Katie Groesch, MD, for her assistance in drafting portions of the Methods and Results sections; Rita Hermacinski for the generation of 3D images; and Stephanie Arthalony for her assistance in gathering information through patient telephone interviews.

ABSTRACT

Purpose The purpose of this study was to determine the frequency of patients seen at a single institution who were diagnosed with a cervical vessel dissection related to chiropractic neck manipulation.

Methods We identified cases through a retrospective chart review of patients seen between April 2008 and March 2012 who had a diagnosis of cervical artery dissection following a recent chiropractic manipulation. Relevant imaging studies were reviewed by a board-certified neuroradiologist to confirm the findings of a cervical artery dissection and stroke. We conducted telephone interviews to ascertain the presence of residual symptoms in the affected patients.

Results Of the 141 patients with cervical artery dissection, 12 had documented chiropractic neck manipulation prior to the onset of the symptoms that led to medical presentation. The 12 patients had a total of 16 cervical artery dissections. All 12 patients developed symptoms of acute stroke. All strokes were confirmed with magnetic resonance imaging or computerized tomography. We obtained follow-up information on 9 patients, 8 of whom had residual symptoms and one of whom died as a result of his injury.

Conclusions In this case series, 12 patients with newly diagnosed cervical artery dissection(s) had recent chiropractic neck manipulation. Patients who are considering chiropractic cervical manipulation should be informed of the potential risk and be advised to seek immediate medical attention should they develop symptoms.

A prospective randomized controlled study published in 2012 showed chiropractic manipulation is beneficial in the treatment of neck pain compared with medical treatment, but it showed no significant difference between chiropractic manipulation and physical therapy exercises.¹ Although chiropractic manipulation of the cervical spine may be effective, it may also cause harm.

Cerebellar and spinal cord injuries related to cervical chiropractic manipulation were first reported in 1947.² By 1974, there were 12 reported cases.³ Noninvasive imaging has since greatly improved the diagnosis of cervical artery dissection and of stroke,⁴ and cervical artery dissection is now recognized as pathogenic of strokes occurring in association with chiropractic manipulation.⁵

A prospective series published in 2011 reported that, over 4 years, 13 patients were treated at a single institution for cervical arterial dissection following chiropractic treatment.⁶ That so many patients might be seen for this condition in that time frame at a single institution suggests the risk for such injury may be greater than thought. To explore that possibility, we performed a 4-year retrospective review to determine the experience at OSF Saint Francis Medical Center, which is affiliated with the University of Illinois College of Medicine, Peoria.

METHODS

Data sources. After receiving approval by the local institutional review board, we obtained data from the electronic medical records of OSF Saint Francis Medical Center, Peoria, Ill., using Epic (Epic Systems Corporation, Verona, Wis.) and IDX (General Electric Corporation, Fairfield, Conn.) systems. The records were queried using ICD-9 codes 443.21 and 443.24 to identify patients from April 2008 through March 2012 who had primary or secondary diagnoses of vertebral artery dissection (VAD) or carotid artery dissection (CAD). We reviewed all records of VAD and CAD to identify those that may have been associated with chiropractic manipulation.

Data collection. We abstracted data from 12 patients’ charts. Two patients were unavailable for direct contact: one was involved in ongoing litigation, and one had died (although we were able to speak with his wife). We attempted telephone contact with the 10 remaining patients and reached 8.

Data included the symptoms leading to chiropractic manipulation, symptoms following manipulation, timing of onset of symptoms relative to chiropractic manipulation, identifying information for the treating chiropractor, and residual patient symptoms. We also recorded patients’ ages, sex, locations of dissection, and locations of stroke. All dissections and strokes had been diagnosed during the patient’s initial hospitalization.

A board-certified radiologist (JRD) with a Certificate of Added Qualification in Neuroradiology (American Board of Medical Specialties) reviewed all pertinent imaging to confirm all dissections and strokes.

RESULTS

The medical record query yielded 141 patients with VAD or CAD, 15 of whom had undergone chiropractic manipulation prior to their presentation. The temporal association between chiropractic manipulation and arterial dissection was equivocal for 3 patients. In 12 patients, there was a verifiable temporal association between chiropractic manipulation and the arterial dissection. Three of the 12 patients were men and 9 were women. Ages ranged from 22 to 46 years, with a mean of 35.3 years.

Acute or chronic neck pain was the most common reason for seeking chiropractic care (TABLE 1). Immediately upon performance of cervical manipulation, 10 of the 12 developed acute symptoms different than those that caused them to seek chiropractic care. Two patients developed symptoms 2 to 3 days post-manipulation. Neither of the 2 had a history of neck trauma within the preceding year. Ten of the 12 patients sought immediate medical attention. Two of the 12 patients sought care when their symptoms became more severe, ranging from 2 days to several weeks later (TABLE 2). The treating chiropractor was identified in 7 cases and was different in each of the 7 cases.

A total of 16 cervical artery dissections, 14 VAD and 2 CAD, were confirmed by computed tomography angiography (CTA), magnetic resonance angiography (MRA), or catheter angiography (FIGURE 1). All 12 patients had acute strokes confirmed by MRA or CTA, including 9 in the cerebellum (FIGURE 2), 4 in the cerebrum, 2 in the medulla, and one in the pons.

Long-term outcomes were determined for 9 patients (TABLE 2). One patient’s symptoms resolved. Three patients had dizziness, clumsiness, or balance problems; 3 had persistent headaches; 2 had bilateral visual field abnormalities; and one patient walked with a cane, was no longer driving a car, and was on disability. One patient died as a result of his injury. One of the 12 cases was previously described in a case report.⁷

DISCUSSION

Dissection of the cervical arteries is more common than dissection in other arteries of comparable size. This increased risk in the cervical arteries is believed to be due to their relative mobility and proximity to bony structures.⁴

Sudden neck movement, a feature of chiropractic treatment, is one of several known risk factors for ‘spontaneous’ cervical artery dissection.^8,9 Symptom onset and stroke may be delayed after a spontaneous cervical artery dissection.¹⁰ Spontaneous dissection more commonly involves the carotid arteries;⁴ however, the vertebral arteries appear more prone to dissection as a consequence of chiropractic manipulation,¹¹ likely due to their relation to the cervical spine.

The Canadian Stroke Consortium has shown a 28% incidence of chiropractic manipulation in cases of cervical artery dissection.

The vertebral artery runs through foramina in the transverse processes of vertebral bodies C1 through C6 (FIGURE 3). On exiting the C2 transverse process, the vertebral artery has a tortuous course, making several turns over and through adjacent bony structures.¹² The artery is most prone to injury between the entrance to the transverse foramen of C6 and the foramen magnum (V2 and V3 segments).¹³ (The area of highest vulnerability is the tortuous segment from the transverse foramen of C2 to the foramen magnum.)

Sudden movements of the cervical spine may cause arterial dissection, whether the maneuvers are performed by a physician, a chiropractor, or a physical therapist.¹⁴ Injuries reported in the literature, however, most commonly follow chiropractic manipulation. In our series of 141 dissections, we found no cases associated with manipulation by other health professionals.

A 2003 study revealed cervical spine manipulation to be an independent and strong risk factor for vertebral artery dissection. The authors believed the relationship was likely causal.⁵ Data from the Canadian Stroke Consortium showed a 28% incidence of chiropractic manipulation in cases of cervical artery dissection.¹⁰

A 2008 study showed an association between vertebrobasilar stroke and chiropractic visits within one month of the vascular event.¹⁵ However, the study also showed an association of similar magnitude between vertebrobasilar stroke and visits to primary care physicians within the prior month. This suggests that cervical manipulation by chiropractors poses no more risk for cervical artery dissection than visits to primary care physicians. However, it is hard to reconcile such a conclusion with other studies, including our own, in which 10 patients developed new symptoms immediately with chiropractic manipulation of their cervical spines.

Perhaps the one-month observation period of Cassidy et al was excessive. Many post-manipulation events occur within hours or at most a few days, as would be expected given the hypothesized pathogenic mechanism. Perhaps if they had shortened their interval of study to the preceding 3 days, their findings may have been different.

A recent systematic review and meta-analysis demonstrated a slight association between chiropractic neck manipulation and cervical artery dissection. It stated that the quality of the published literature was very low, and it concluded there was no convincing evidence of causation.¹⁶ The fact that 10 of the 12 patients in our case series demonstrated acute symptoms immediately upon receiving spinal manipulation suggests a possible causal link; however, we agree with the authors of the meta-analysis that the quality of the literature is low.

A recent statement from the American Heart Association/American Stroke Association (and endorsed by the American Association of Neurological Surgeons and the Congress of Neurological Surgeons) has recommended that chiropractors inform patients of the statistical association between cervical artery dissection and cervical manipulation.¹⁷ In addition, it is important for chiropractors to be aware of the signs and symptoms of cervical artery dissection and stroke and to assess for these symptoms before performing neck manipulation, as illustrated in a recent case report.¹⁸ Due to the risk of death, patients who experience symptoms consistent with cervical artery dissection after chiropractic manipulation of the cervical spine should be advised to seek medical care immediately.

Our case series has several limitations. The study was retrospective. Existing documentation of associated chiropractic care was often sparse, necessitating phone calls to supplement the information. We believe it is possible that cases may have been missed because of inaccurate medical record documentation, deficits in the interview process concerning chiropractic care at the time of hospitalization, or because information concerning chiropractic care was not recorded in the chart.

A significant portion of our information came through phone contact with several of the patients. In some cases, we relied heavily on their recollection of events that had occurred anytime from a few days to a few years earlier. The accuracy and completeness of the information supplied by patients was not verified, allowing for potential recall bias.

We do not know whether our experience is consistent with that of other areas of the United States. However, the fact that a similar-size hospital in Phoenix reported similar findings suggests the experience may be more widespread.⁶

IMPLICATIONS OF OUR FINDINGS

Over a 4-year period at our institution, 12 patients experienced cervical vessel dissection related to chiropractic neck manipulation. A similar institution in another part of the country had previously described 13 such cases. The patients at both institutions were relatively young and incurred substantial residual morbidity. A single patient at each institution died. If these findings are representative of other institutions across the United States, the incidence of stroke secondary to chiropractic manipulation may be higher than supposed.

Tell patients considering cervical spine manipulation to seek medical help if symptoms suggestive of dissection or stroke occur during or after manipulation.

To assess this problem further, a randomized prospective cohort study could establish the relative risk of chiropractic manipulation of the cervical spine resulting in a cervical artery dissection. But such a study may be methodologically prohibitive. More feasible would be a case-control study similar to one carried out by Smith et al⁵ in which patients who had experienced cervical artery dissection were matched with subjects who had not incurred such injuries. Comparing the groups’ odds of having received chiropractic manipulation demonstrated that spinal manipulative therapy is an independent risk factor for vertebral artery dissection and is highly suggestive of a causal association. Replicating this study in a different population would be valuable.

Based on our findings, all patients who visit chiropractors for cervical spine manipulation should be informed of the potential risks and of the need to seek immediate medical assistance should symptoms suggestive of dissection or stroke occur during or after manipulation. Until the actual level of risk from chiropractic manipulation is known, patients with neck pain may be better served by equally effective passive physical therapy exercises.¹

CORRESPONDENCE
Raymond E. Bertino, MD, 427 West Crestwood Drive, Peoria, IL 61614; [email protected].

ACKNOWLEDGEMENTS
We thank Deepak Nair, MD, for his assistance in reviewing the stroke neurology aspects of this study; Katie Groesch, MD, for her assistance in drafting portions of the Methods and Results sections; Rita Hermacinski for the generation of 3D images; and Stephanie Arthalony for her assistance in gathering information through patient telephone interviews.

ABSTRACT

Purpose The purpose of this study was to determine the frequency of patients seen at a single institution who were diagnosed with a cervical vessel dissection related to chiropractic neck manipulation.

Methods We identified cases through a retrospective chart review of patients seen between April 2008 and March 2012 who had a diagnosis of cervical artery dissection following a recent chiropractic manipulation. Relevant imaging studies were reviewed by a board-certified neuroradiologist to confirm the findings of a cervical artery dissection and stroke. We conducted telephone interviews to ascertain the presence of residual symptoms in the affected patients.

Results Of the 141 patients with cervical artery dissection, 12 had documented chiropractic neck manipulation prior to the onset of the symptoms that led to medical presentation. The 12 patients had a total of 16 cervical artery dissections. All 12 patients developed symptoms of acute stroke. All strokes were confirmed with magnetic resonance imaging or computerized tomography. We obtained follow-up information on 9 patients, 8 of whom had residual symptoms and one of whom died as a result of his injury.

Conclusions In this case series, 12 patients with newly diagnosed cervical artery dissection(s) had recent chiropractic neck manipulation. Patients who are considering chiropractic cervical manipulation should be informed of the potential risk and be advised to seek immediate medical attention should they develop symptoms.

A prospective randomized controlled study published in 2012 showed chiropractic manipulation is beneficial in the treatment of neck pain compared with medical treatment, but it showed no significant difference between chiropractic manipulation and physical therapy exercises.¹ Although chiropractic manipulation of the cervical spine may be effective, it may also cause harm.

Cerebellar and spinal cord injuries related to cervical chiropractic manipulation were first reported in 1947.² By 1974, there were 12 reported cases.³ Noninvasive imaging has since greatly improved the diagnosis of cervical artery dissection and of stroke,⁴ and cervical artery dissection is now recognized as pathogenic of strokes occurring in association with chiropractic manipulation.⁵

A prospective series published in 2011 reported that, over 4 years, 13 patients were treated at a single institution for cervical arterial dissection following chiropractic treatment.⁶ That so many patients might be seen for this condition in that time frame at a single institution suggests the risk for such injury may be greater than thought. To explore that possibility, we performed a 4-year retrospective review to determine the experience at OSF Saint Francis Medical Center, which is affiliated with the University of Illinois College of Medicine, Peoria.

METHODS

Data sources. After receiving approval by the local institutional review board, we obtained data from the electronic medical records of OSF Saint Francis Medical Center, Peoria, Ill., using Epic (Epic Systems Corporation, Verona, Wis.) and IDX (General Electric Corporation, Fairfield, Conn.) systems. The records were queried using ICD-9 codes 443.21 and 443.24 to identify patients from April 2008 through March 2012 who had primary or secondary diagnoses of vertebral artery dissection (VAD) or carotid artery dissection (CAD). We reviewed all records of VAD and CAD to identify those that may have been associated with chiropractic manipulation.

Data collection. We abstracted data from 12 patients’ charts. Two patients were unavailable for direct contact: one was involved in ongoing litigation, and one had died (although we were able to speak with his wife). We attempted telephone contact with the 10 remaining patients and reached 8.

Data included the symptoms leading to chiropractic manipulation, symptoms following manipulation, timing of onset of symptoms relative to chiropractic manipulation, identifying information for the treating chiropractor, and residual patient symptoms. We also recorded patients’ ages, sex, locations of dissection, and locations of stroke. All dissections and strokes had been diagnosed during the patient’s initial hospitalization.

A board-certified radiologist (JRD) with a Certificate of Added Qualification in Neuroradiology (American Board of Medical Specialties) reviewed all pertinent imaging to confirm all dissections and strokes.

RESULTS

The medical record query yielded 141 patients with VAD or CAD, 15 of whom had undergone chiropractic manipulation prior to their presentation. The temporal association between chiropractic manipulation and arterial dissection was equivocal for 3 patients. In 12 patients, there was a verifiable temporal association between chiropractic manipulation and the arterial dissection. Three of the 12 patients were men and 9 were women. Ages ranged from 22 to 46 years, with a mean of 35.3 years.

Acute or chronic neck pain was the most common reason for seeking chiropractic care (TABLE 1). Immediately upon performance of cervical manipulation, 10 of the 12 developed acute symptoms different than those that caused them to seek chiropractic care. Two patients developed symptoms 2 to 3 days post-manipulation. Neither of the 2 had a history of neck trauma within the preceding year. Ten of the 12 patients sought immediate medical attention. Two of the 12 patients sought care when their symptoms became more severe, ranging from 2 days to several weeks later (TABLE 2). The treating chiropractor was identified in 7 cases and was different in each of the 7 cases.

A total of 16 cervical artery dissections, 14 VAD and 2 CAD, were confirmed by computed tomography angiography (CTA), magnetic resonance angiography (MRA), or catheter angiography (FIGURE 1). All 12 patients had acute strokes confirmed by MRA or CTA, including 9 in the cerebellum (FIGURE 2), 4 in the cerebrum, 2 in the medulla, and one in the pons.

Long-term outcomes were determined for 9 patients (TABLE 2). One patient’s symptoms resolved. Three patients had dizziness, clumsiness, or balance problems; 3 had persistent headaches; 2 had bilateral visual field abnormalities; and one patient walked with a cane, was no longer driving a car, and was on disability. One patient died as a result of his injury. One of the 12 cases was previously described in a case report.⁷

DISCUSSION

Dissection of the cervical arteries is more common than dissection in other arteries of comparable size. This increased risk in the cervical arteries is believed to be due to their relative mobility and proximity to bony structures.⁴

Sudden neck movement, a feature of chiropractic treatment, is one of several known risk factors for ‘spontaneous’ cervical artery dissection.^8,9 Symptom onset and stroke may be delayed after a spontaneous cervical artery dissection.¹⁰ Spontaneous dissection more commonly involves the carotid arteries;⁴ however, the vertebral arteries appear more prone to dissection as a consequence of chiropractic manipulation,¹¹ likely due to their relation to the cervical spine.

The Canadian Stroke Consortium has shown a 28% incidence of chiropractic manipulation in cases of cervical artery dissection.

The vertebral artery runs through foramina in the transverse processes of vertebral bodies C1 through C6 (FIGURE 3). On exiting the C2 transverse process, the vertebral artery has a tortuous course, making several turns over and through adjacent bony structures.¹² The artery is most prone to injury between the entrance to the transverse foramen of C6 and the foramen magnum (V2 and V3 segments).¹³ (The area of highest vulnerability is the tortuous segment from the transverse foramen of C2 to the foramen magnum.)

Sudden movements of the cervical spine may cause arterial dissection, whether the maneuvers are performed by a physician, a chiropractor, or a physical therapist.¹⁴ Injuries reported in the literature, however, most commonly follow chiropractic manipulation. In our series of 141 dissections, we found no cases associated with manipulation by other health professionals.

A 2003 study revealed cervical spine manipulation to be an independent and strong risk factor for vertebral artery dissection. The authors believed the relationship was likely causal.⁵ Data from the Canadian Stroke Consortium showed a 28% incidence of chiropractic manipulation in cases of cervical artery dissection.¹⁰

A 2008 study showed an association between vertebrobasilar stroke and chiropractic visits within one month of the vascular event.¹⁵ However, the study also showed an association of similar magnitude between vertebrobasilar stroke and visits to primary care physicians within the prior month. This suggests that cervical manipulation by chiropractors poses no more risk for cervical artery dissection than visits to primary care physicians. However, it is hard to reconcile such a conclusion with other studies, including our own, in which 10 patients developed new symptoms immediately with chiropractic manipulation of their cervical spines.

Perhaps the one-month observation period of Cassidy et al was excessive. Many post-manipulation events occur within hours or at most a few days, as would be expected given the hypothesized pathogenic mechanism. Perhaps if they had shortened their interval of study to the preceding 3 days, their findings may have been different.

A recent systematic review and meta-analysis demonstrated a slight association between chiropractic neck manipulation and cervical artery dissection. It stated that the quality of the published literature was very low, and it concluded there was no convincing evidence of causation.¹⁶ The fact that 10 of the 12 patients in our case series demonstrated acute symptoms immediately upon receiving spinal manipulation suggests a possible causal link; however, we agree with the authors of the meta-analysis that the quality of the literature is low.

A recent statement from the American Heart Association/American Stroke Association (and endorsed by the American Association of Neurological Surgeons and the Congress of Neurological Surgeons) has recommended that chiropractors inform patients of the statistical association between cervical artery dissection and cervical manipulation.¹⁷ In addition, it is important for chiropractors to be aware of the signs and symptoms of cervical artery dissection and stroke and to assess for these symptoms before performing neck manipulation, as illustrated in a recent case report.¹⁸ Due to the risk of death, patients who experience symptoms consistent with cervical artery dissection after chiropractic manipulation of the cervical spine should be advised to seek medical care immediately.

Our case series has several limitations. The study was retrospective. Existing documentation of associated chiropractic care was often sparse, necessitating phone calls to supplement the information. We believe it is possible that cases may have been missed because of inaccurate medical record documentation, deficits in the interview process concerning chiropractic care at the time of hospitalization, or because information concerning chiropractic care was not recorded in the chart.

A significant portion of our information came through phone contact with several of the patients. In some cases, we relied heavily on their recollection of events that had occurred anytime from a few days to a few years earlier. The accuracy and completeness of the information supplied by patients was not verified, allowing for potential recall bias.

We do not know whether our experience is consistent with that of other areas of the United States. However, the fact that a similar-size hospital in Phoenix reported similar findings suggests the experience may be more widespread.⁶

IMPLICATIONS OF OUR FINDINGS

Over a 4-year period at our institution, 12 patients experienced cervical vessel dissection related to chiropractic neck manipulation. A similar institution in another part of the country had previously described 13 such cases. The patients at both institutions were relatively young and incurred substantial residual morbidity. A single patient at each institution died. If these findings are representative of other institutions across the United States, the incidence of stroke secondary to chiropractic manipulation may be higher than supposed.

Tell patients considering cervical spine manipulation to seek medical help if symptoms suggestive of dissection or stroke occur during or after manipulation.

To assess this problem further, a randomized prospective cohort study could establish the relative risk of chiropractic manipulation of the cervical spine resulting in a cervical artery dissection. But such a study may be methodologically prohibitive. More feasible would be a case-control study similar to one carried out by Smith et al⁵ in which patients who had experienced cervical artery dissection were matched with subjects who had not incurred such injuries. Comparing the groups’ odds of having received chiropractic manipulation demonstrated that spinal manipulative therapy is an independent risk factor for vertebral artery dissection and is highly suggestive of a causal association. Replicating this study in a different population would be valuable.

Based on our findings, all patients who visit chiropractors for cervical spine manipulation should be informed of the potential risks and of the need to seek immediate medical assistance should symptoms suggestive of dissection or stroke occur during or after manipulation. Until the actual level of risk from chiropractic manipulation is known, patients with neck pain may be better served by equally effective passive physical therapy exercises.¹

CORRESPONDENCE
Raymond E. Bertino, MD, 427 West Crestwood Drive, Peoria, IL 61614; [email protected].

ACKNOWLEDGEMENTS
We thank Deepak Nair, MD, for his assistance in reviewing the stroke neurology aspects of this study; Katie Groesch, MD, for her assistance in drafting portions of the Methods and Results sections; Rita Hermacinski for the generation of 3D images; and Stephanie Arthalony for her assistance in gathering information through patient telephone interviews.

Signs and symptoms of autonomic dysfunction commonly present in the primary care setting. Potential causes of dysfunction include certain medications and age-related changes in physiology, as well as conditions such as diabetes mellitus, multiple sclerosis, and Parkinson’s disease (TABLE¹). This evidence-based review details common manifestations of autonomic dysfunction, provides a streamlined approach to patients presenting with symptoms, and reviews appropriate step-wise management.

When a delicate balance is disrupted

The autonomic nervous system provides brisk physiologic adjustments necessary to maintain homeostasis. Physiologic functions impacted by the central nervous system include: heart rate, blood pressure (BP), tone of the bladder sphincter and detrusor muscle, bowel motility, bronchodilation and constriction, pupillary dilation and constriction, sweating, catecholamine release, erection, ejaculation and orgasm, tearing, and salivation.¹

Disorders of the autonomic system may result from pathologies of the central or peripheral nervous system or from medications including some antihypertensives, selective serotonin-reuptake inhibitors (SSRIs), and opioids.¹ Such disorders tend to be grouped into one of 3 categories: those involving the brain, those involving the spinal cord, and autonomic neuropathies.¹

The source of dysautonomia can often be determined by clinical context, coexisting neurologic abnormalities, targeted testing of the autonomic nervous system, and neuroimaging.¹

Worrisome symptoms prompt a visit

A thorough history is critical to zeroing in on a patient’s complaints and ultimately providing treatment that will help manage symptoms.

When patient complaints are suggestive of autonomic dysfunction, a review of systems should include inquiry about lightheadedness, abnormal salivation, temperature changes of the extremities, gastrointestinal issues (vomiting, constipation, or diarrhea), and symptoms of presyncope/syncope or urinary or sexual dysfunction.¹ The physical exam should include recordings of BP and heart rate in the supine and standing positions and a complete neurologic examination.¹ Findings will typically point to one or more common complications.

Common complications of autonomic dysfunction

Complications of autonomic dysfunction include impotence, bladder dysfunction, gastrointestinal (GI) dysfunction, and orthostatic hypotension and vasomotor abnormalities. A less common condition—autonomic dysreflexia, which is a distinct type of autonomic dysfunction, and a true medical emergency—is also important to keep in mind.

Impotence

Autonomic neuropathy is a common cause of impotence and retrograde ejaculation. Loss of early morning erections and complete loss of nocturnal erections often have an etiology related to vascular disease and/or autonomic neuropathy. In addition, poor glycemic control and vascular risk factors appear to be associated with the development of diabetic autonomic neuropathy.²

If diabetic autonomic neuropathy is the suspected etiology of impotence, consider prescribing a phosphodiesterase inhibitor.

Development of an erection requires an increase in parasympathetic activity and a decrease in sympathetic output. Nocturnal penile tumescence testing has been used to infer parasympathetic damage to the penis in men with diabetes who do not have vascular disease.³

First- and second-line agents. Phosphodiesterase-5 inhibitors (eg, sildenafil, tadalafil, vardenafil) have demonstrated efficacy in improving the ability to achieve and maintain erections in patients with autonomic dysfunction, including diabetic autonomic neuropathy.^4-6 Second-line therapies with proven efficacy include intraurethral application and intracavernosal injections of alprostadil.^7,8

Bladder dysfunction

Sympathetic activity increases bladder sphincter tone and inhibits detrusor activity, while the parasympathetic nervous system increases detrusor activity and decreases sphincter tone to aid in voiding.¹ Disrupted autonomic activity can lead to urinary frequency, retention, and hesitancy; overactive bladder; and incontinence.¹ Brain and spinal cord disease above the level of the lumbar spine results in urinary frequency and small bladder volumes, whereas diseases involving autonomic nerve fibers to and from the bladder result in large bladder volumes and overflow incontinence.⁹

Botulinum toxin type A, injected directly into the detrusor muscle, can be as effective as medication in patients with urinary urge incontinence.

Patients presenting with lower urinary tract symptoms require a comprehensive evaluation to rule out other pathologies, as the differential for such symptoms is broad and includes infection, malignancies, interstitial cystitis, and bladder stones. The initial evaluation of lower urinary tract symptoms should include a history and physical exam including that of the abdomen, pelvis, and neurologic system. Lab work should assess renal function and blood glucose, and should include urinalysis and culture to rule out infection and/or hematuria. A prostate-specific antigen (PSA) test may be appropriate in men with a life expectancy >10 years, after counseling regarding the risks and benefits of screening.

Anticholinergic drugs with antimuscarinic effects, such as oxybutynin, may be used to treat symptoms of urge incontinence and overactive bladder. They work to suppress involuntary contractions of the bladder’s smooth muscle by blocking the release of acetylcholine. These medications relax the bladder’s outer layer of muscle—the detrusor. Such medications often have a number of anticholinergic adverse effects, such as dry mouth and constipation, sometimes leading to discontinuation. A post-void residual (PVR) test may be helpful in guiding management. For example, caution should be used in patients with elevated PVRs, as anticholinergics can worsen urinary retention.

Beta-3 agonists (eg, mirabegron) are a novel class of medications used to treat overactive bladder. These medications act to increase sympathetic tone in the bladder. Because they have the potential to raise BP, monitor BP in patients taking these agents. In addition, monitor patients taking antimuscarinics or beta-3 agonists for the development of urinary retention.

Other tests, treatments. Urodynamic testing is recommended for patients who fail to respond to treatment. Combining behavioral therapy with medication has been shown to be effective in patients with urge incontinence.¹⁰ Botulinum toxin type A, injected directly into the detrusor muscle, can be as effective as medication in patients with urinary urge incontinence.¹¹

Detrusor underactivity is defined as contraction of reduced strength and/or duration, resulting in prolonged bladder emptying and/or a failure to achieve complete bladder emptying within a normal timespan.¹² This diagnosis is typically made using urodynamic testing.¹³ PVRs ≥150 mL are considered evidence of urinary retention. Overflow incontinence can result from detrusor underactivity.

Consider a trial of a cholinergic agonist, such as bethanechol, in patients with urinary retention. Some patients will require intermittent straight catheterization or chronic indwelling foley or suprapubic catheters to void.

Gastrointestinal dysfunction

In patients with diabetes, GI autonomic neuropathy can result in altered esophageal motility leading to gastroesophageal reflux disease (GERD) or dysphagia, gastroparesis, or diabetic enteropathy.¹⁴ Gastroparesis often presents as nausea, vomiting, and bloating.¹ It may be diagnosed via gastric emptying studies (scintigraphy), and often requires a multidimensional approach to treatment.

Management. Food may be chopped or pureed to aid in digestion. Metoclopramide is the most commonly used prokinetic agent, but avoid its use in patients with parkinsonism. In more severe cases, consider adding domperidone and erythromycin as prokinetic agents. Recommend antiemetics, such as diphenhydramine, ondansetron, and prochlorperazine for management of nausea and vomiting. Severe cases of gastroparesis may merit a venting gastrostomy tube for decompression and/or feeding via a jejunostomy tube.¹⁵ Impaired intestinal mobility may lead to stasis syndrome, causing diarrhea.

Hypermobility caused by decreased sympathetic inhibition can also contribute to diarrhea. Altered anal sphincter function tone may contribute to fecal incontinence. Management should focus on balancing electrolytes, maintaining adequate fluid intake, and relieving symptoms. Consider antidiarrheals such as loperamide, but use them with caution to avoid toxic megacolon.¹⁶

Constipation. Another common manifestation of autonomic dysfunction in the GI tract is severe constipation.¹ This may be managed conservatively with hydration, increased activity, and increased fiber intake. If such measures prove inadequate, consider stool softeners and laxatives.

Patients with constipation due to spinal cord lesions may benefit from a routine bowel regimen. To provide predictable defecation, advise patients to begin by inserting a stimulant rectal suppository. Follow with gentle digital stimulation of the distal rectum for one minute or less. They’ll need to repeat the process every 5 to 10 minutes until stool evacuation is complete. A forward-leaning position may assist with evacuation. It is helpful to perform this routine at the same time each day.¹⁷

Orthostatic (postural) hypotension

The autonomic nervous system plays an important role in maintaining BP during positional changes. The sympathetic nervous system adjusts the tone in arteries, veins, and the heart. Baroreceptors located primarily in the carotid arteries and aorta, are highly sensitive to changes in BP. When the baroreceptors sense the slightest drop in pressure, a coordinated increase in sympathetic outflow occurs. Arteries constrict to increase peripheral resistance and BP, and heart rate and contractility increase, all in an attempt to maintain BP and perfusion.¹⁸

The most common causes of orthostatic hypotension are not neurologic in origin,⁹ but rather involve medications, hypovolemia, and impaired autonomic reflexes. The condition is common in the elderly, with one study demonstrating a prevalence of 18.2% in those ≥65 years.¹⁹

Orthostatic hypotension may present with dimming or loss of vision, lightheadedness, diaphoresis, diminished hearing, pallor, and weakness. As a result, it is a risk factor for falls. Syncope results when the drop in BP impairs cerebral perfusion. Signs of impaired baroreflexes are supine hypertension, a heart rate that is fixed regardless of posture (the heart rate should increase upon standing), postprandial hypotension, and an excessively high nocturnal BP.¹

Orthostatic hypotension is diagnosed when, within 3 minutes of quiet standing after a 5-minute period of supine rest, one or both of the following is present: at least a 20 mm Hg-fall in systolic pressure or at least a 10 mm Hg-fall in diastolic pressure.²⁰ Soysal et al demonstrated that such a drop in BP, measured one minute after standing, is adequate and effective for diagnosing orthostatic hypotension in the elderly.²¹

Nonpharmacologic management. Recognition and removal of medications that can exacerbate orthostatic hypotension is the first step in managing the condition. Such medications include diuretics, beta-blockers, alpha adrenergic blockers, vasodilators, antipsychotics, antidepressants (SSRIs, trazodone, monoamine oxidase inhibitors, and tricyclic antidepressants), phosphodiesterase inhibitors, narcotics, and antiparkinsonian medications.²²

The most common causes of orthostatic hypotension are not neurologic in origin, but rather involve medications, hypovolemia, and impaired autonomic reflexes.

Lifestyle interventions, such as having the patient arise slowly and maintain good hydration, can be helpful. Eating smaller, more frequent meals may also help if the orthostatic hypotension is triggered postprandially. Compressive stockings can help limit venous pooling in the lower extremities and improve venous return. Tensing the legs by crossing them while standing on both feet has been shown to increase cardiac output and BP.²³ An aerobic exercise regimen of walking or stair climbing 30 to 45 minutes/day 3 days/week for 6 months was shown to eliminate symptoms of orthostasis on tilt table testing in elderly patients with cardiac deconditioning, as opposed to chronic autonomic failure.²⁴

The reduction in central blood volume associated with autonomic insufficiency (due to increased urinary sodium and water excretion) can be lessened by increasing sodium and water intake.^25-27

Pharmacotherapy. Fludrocortisone acetate, a synthetic mineralocorticoid, is the medication of first choice for most patients with orthostatic hypotension whose symptoms are not adequately controlled using nonpharmacologic measures,²⁸ but keep in mind that treating orthostatic hypotension with fludrocortisones is an off-label use of the medication.

Monitor patients taking fludrocortisone for worsened supine hypertension and edema. Also, check their serum potassium levels one to 2 weeks after initiation of therapy and after dose increases. Frequent home monitoring of BP in sitting, standing, and supine positions may be helpful in assessing response to therapy.

If the patient remains symptomatic despite therapy with fludrocortisone, consider adding an alpha-1 adrenergic agonist, such as midodrine. Avoid prescribing midodrine, however, for patients with advanced cardiovascular disease, urinary retention, or uncontrolled hypertension.²⁹

Autonomic dysreflexia: A medical emergency

Autonomic dysreflexia, a medical emergency that must be recognized immediately, is a distinct type of autonomic dysfunction seen in patients with spinal cord injury at or above the T6 level.³⁰ It is a condition of uncontrolled sympathetic response secondary to an underlying condition such as infection, urinary retention, or rectal distention.³⁰

Common symptoms include headache, significant hypertension, flushing of the skin, and diaphoresis above the level of injury.² In addition, a review of systems should screen for fever, visual changes, abnormalities of the cardiovascular system, syncope, bowel and bladder symptoms, and sexual dysfunction.

When nonpharmacologic measures don't control orthostatic hypotension, consider the off-label use of fludrocortisone.

Patients demonstrating autonomic dysreflexia should be placed in the upright position to produce an orthostatic decrease in BP.³⁰ Patients should be evaluated to identify any reversible precipitants, such as urinary retention or fecal impaction. Severe attacks involving hypertensive crisis require prompt transfer to the emergency department. Sublingual nifedipine or an intravenous agent, such as hydralazine, may be used to lower BP.³¹

CORRESPONDENCE
Kristen Thornton, MD, 777 South Clinton Ave., Rochester, NY 14620; [email protected]

Signs and symptoms of autonomic dysfunction commonly present in the primary care setting. Potential causes of dysfunction include certain medications and age-related changes in physiology, as well as conditions such as diabetes mellitus, multiple sclerosis, and Parkinson’s disease (TABLE¹). This evidence-based review details common manifestations of autonomic dysfunction, provides a streamlined approach to patients presenting with symptoms, and reviews appropriate step-wise management.

When a delicate balance is disrupted

The autonomic nervous system provides brisk physiologic adjustments necessary to maintain homeostasis. Physiologic functions impacted by the central nervous system include: heart rate, blood pressure (BP), tone of the bladder sphincter and detrusor muscle, bowel motility, bronchodilation and constriction, pupillary dilation and constriction, sweating, catecholamine release, erection, ejaculation and orgasm, tearing, and salivation.¹

Disorders of the autonomic system may result from pathologies of the central or peripheral nervous system or from medications including some antihypertensives, selective serotonin-reuptake inhibitors (SSRIs), and opioids.¹ Such disorders tend to be grouped into one of 3 categories: those involving the brain, those involving the spinal cord, and autonomic neuropathies.¹

The source of dysautonomia can often be determined by clinical context, coexisting neurologic abnormalities, targeted testing of the autonomic nervous system, and neuroimaging.¹

Worrisome symptoms prompt a visit

A thorough history is critical to zeroing in on a patient’s complaints and ultimately providing treatment that will help manage symptoms.

When patient complaints are suggestive of autonomic dysfunction, a review of systems should include inquiry about lightheadedness, abnormal salivation, temperature changes of the extremities, gastrointestinal issues (vomiting, constipation, or diarrhea), and symptoms of presyncope/syncope or urinary or sexual dysfunction.¹ The physical exam should include recordings of BP and heart rate in the supine and standing positions and a complete neurologic examination.¹ Findings will typically point to one or more common complications.

Common complications of autonomic dysfunction

Complications of autonomic dysfunction include impotence, bladder dysfunction, gastrointestinal (GI) dysfunction, and orthostatic hypotension and vasomotor abnormalities. A less common condition—autonomic dysreflexia, which is a distinct type of autonomic dysfunction, and a true medical emergency—is also important to keep in mind.

Impotence

Autonomic neuropathy is a common cause of impotence and retrograde ejaculation. Loss of early morning erections and complete loss of nocturnal erections often have an etiology related to vascular disease and/or autonomic neuropathy. In addition, poor glycemic control and vascular risk factors appear to be associated with the development of diabetic autonomic neuropathy.²

If diabetic autonomic neuropathy is the suspected etiology of impotence, consider prescribing a phosphodiesterase inhibitor.

Development of an erection requires an increase in parasympathetic activity and a decrease in sympathetic output. Nocturnal penile tumescence testing has been used to infer parasympathetic damage to the penis in men with diabetes who do not have vascular disease.³

First- and second-line agents. Phosphodiesterase-5 inhibitors (eg, sildenafil, tadalafil, vardenafil) have demonstrated efficacy in improving the ability to achieve and maintain erections in patients with autonomic dysfunction, including diabetic autonomic neuropathy.^4-6 Second-line therapies with proven efficacy include intraurethral application and intracavernosal injections of alprostadil.^7,8

Bladder dysfunction

Sympathetic activity increases bladder sphincter tone and inhibits detrusor activity, while the parasympathetic nervous system increases detrusor activity and decreases sphincter tone to aid in voiding.¹ Disrupted autonomic activity can lead to urinary frequency, retention, and hesitancy; overactive bladder; and incontinence.¹ Brain and spinal cord disease above the level of the lumbar spine results in urinary frequency and small bladder volumes, whereas diseases involving autonomic nerve fibers to and from the bladder result in large bladder volumes and overflow incontinence.⁹

Botulinum toxin type A, injected directly into the detrusor muscle, can be as effective as medication in patients with urinary urge incontinence.

Patients presenting with lower urinary tract symptoms require a comprehensive evaluation to rule out other pathologies, as the differential for such symptoms is broad and includes infection, malignancies, interstitial cystitis, and bladder stones. The initial evaluation of lower urinary tract symptoms should include a history and physical exam including that of the abdomen, pelvis, and neurologic system. Lab work should assess renal function and blood glucose, and should include urinalysis and culture to rule out infection and/or hematuria. A prostate-specific antigen (PSA) test may be appropriate in men with a life expectancy >10 years, after counseling regarding the risks and benefits of screening.

Anticholinergic drugs with antimuscarinic effects, such as oxybutynin, may be used to treat symptoms of urge incontinence and overactive bladder. They work to suppress involuntary contractions of the bladder’s smooth muscle by blocking the release of acetylcholine. These medications relax the bladder’s outer layer of muscle—the detrusor. Such medications often have a number of anticholinergic adverse effects, such as dry mouth and constipation, sometimes leading to discontinuation. A post-void residual (PVR) test may be helpful in guiding management. For example, caution should be used in patients with elevated PVRs, as anticholinergics can worsen urinary retention.

Beta-3 agonists (eg, mirabegron) are a novel class of medications used to treat overactive bladder. These medications act to increase sympathetic tone in the bladder. Because they have the potential to raise BP, monitor BP in patients taking these agents. In addition, monitor patients taking antimuscarinics or beta-3 agonists for the development of urinary retention.

Other tests, treatments. Urodynamic testing is recommended for patients who fail to respond to treatment. Combining behavioral therapy with medication has been shown to be effective in patients with urge incontinence.¹⁰ Botulinum toxin type A, injected directly into the detrusor muscle, can be as effective as medication in patients with urinary urge incontinence.¹¹

Detrusor underactivity is defined as contraction of reduced strength and/or duration, resulting in prolonged bladder emptying and/or a failure to achieve complete bladder emptying within a normal timespan.¹² This diagnosis is typically made using urodynamic testing.¹³ PVRs ≥150 mL are considered evidence of urinary retention. Overflow incontinence can result from detrusor underactivity.

Consider a trial of a cholinergic agonist, such as bethanechol, in patients with urinary retention. Some patients will require intermittent straight catheterization or chronic indwelling foley or suprapubic catheters to void.

Gastrointestinal dysfunction

In patients with diabetes, GI autonomic neuropathy can result in altered esophageal motility leading to gastroesophageal reflux disease (GERD) or dysphagia, gastroparesis, or diabetic enteropathy.¹⁴ Gastroparesis often presents as nausea, vomiting, and bloating.¹ It may be diagnosed via gastric emptying studies (scintigraphy), and often requires a multidimensional approach to treatment.

Management. Food may be chopped or pureed to aid in digestion. Metoclopramide is the most commonly used prokinetic agent, but avoid its use in patients with parkinsonism. In more severe cases, consider adding domperidone and erythromycin as prokinetic agents. Recommend antiemetics, such as diphenhydramine, ondansetron, and prochlorperazine for management of nausea and vomiting. Severe cases of gastroparesis may merit a venting gastrostomy tube for decompression and/or feeding via a jejunostomy tube.¹⁵ Impaired intestinal mobility may lead to stasis syndrome, causing diarrhea.

Hypermobility caused by decreased sympathetic inhibition can also contribute to diarrhea. Altered anal sphincter function tone may contribute to fecal incontinence. Management should focus on balancing electrolytes, maintaining adequate fluid intake, and relieving symptoms. Consider antidiarrheals such as loperamide, but use them with caution to avoid toxic megacolon.¹⁶

Constipation. Another common manifestation of autonomic dysfunction in the GI tract is severe constipation.¹ This may be managed conservatively with hydration, increased activity, and increased fiber intake. If such measures prove inadequate, consider stool softeners and laxatives.

Patients with constipation due to spinal cord lesions may benefit from a routine bowel regimen. To provide predictable defecation, advise patients to begin by inserting a stimulant rectal suppository. Follow with gentle digital stimulation of the distal rectum for one minute or less. They’ll need to repeat the process every 5 to 10 minutes until stool evacuation is complete. A forward-leaning position may assist with evacuation. It is helpful to perform this routine at the same time each day.¹⁷

Orthostatic (postural) hypotension

The autonomic nervous system plays an important role in maintaining BP during positional changes. The sympathetic nervous system adjusts the tone in arteries, veins, and the heart. Baroreceptors located primarily in the carotid arteries and aorta, are highly sensitive to changes in BP. When the baroreceptors sense the slightest drop in pressure, a coordinated increase in sympathetic outflow occurs. Arteries constrict to increase peripheral resistance and BP, and heart rate and contractility increase, all in an attempt to maintain BP and perfusion.¹⁸

The most common causes of orthostatic hypotension are not neurologic in origin,⁹ but rather involve medications, hypovolemia, and impaired autonomic reflexes. The condition is common in the elderly, with one study demonstrating a prevalence of 18.2% in those ≥65 years.¹⁹

Orthostatic hypotension may present with dimming or loss of vision, lightheadedness, diaphoresis, diminished hearing, pallor, and weakness. As a result, it is a risk factor for falls. Syncope results when the drop in BP impairs cerebral perfusion. Signs of impaired baroreflexes are supine hypertension, a heart rate that is fixed regardless of posture (the heart rate should increase upon standing), postprandial hypotension, and an excessively high nocturnal BP.¹

Orthostatic hypotension is diagnosed when, within 3 minutes of quiet standing after a 5-minute period of supine rest, one or both of the following is present: at least a 20 mm Hg-fall in systolic pressure or at least a 10 mm Hg-fall in diastolic pressure.²⁰ Soysal et al demonstrated that such a drop in BP, measured one minute after standing, is adequate and effective for diagnosing orthostatic hypotension in the elderly.²¹

Nonpharmacologic management. Recognition and removal of medications that can exacerbate orthostatic hypotension is the first step in managing the condition. Such medications include diuretics, beta-blockers, alpha adrenergic blockers, vasodilators, antipsychotics, antidepressants (SSRIs, trazodone, monoamine oxidase inhibitors, and tricyclic antidepressants), phosphodiesterase inhibitors, narcotics, and antiparkinsonian medications.²²

The most common causes of orthostatic hypotension are not neurologic in origin, but rather involve medications, hypovolemia, and impaired autonomic reflexes.

Lifestyle interventions, such as having the patient arise slowly and maintain good hydration, can be helpful. Eating smaller, more frequent meals may also help if the orthostatic hypotension is triggered postprandially. Compressive stockings can help limit venous pooling in the lower extremities and improve venous return. Tensing the legs by crossing them while standing on both feet has been shown to increase cardiac output and BP.²³ An aerobic exercise regimen of walking or stair climbing 30 to 45 minutes/day 3 days/week for 6 months was shown to eliminate symptoms of orthostasis on tilt table testing in elderly patients with cardiac deconditioning, as opposed to chronic autonomic failure.²⁴

The reduction in central blood volume associated with autonomic insufficiency (due to increased urinary sodium and water excretion) can be lessened by increasing sodium and water intake.^25-27

Pharmacotherapy. Fludrocortisone acetate, a synthetic mineralocorticoid, is the medication of first choice for most patients with orthostatic hypotension whose symptoms are not adequately controlled using nonpharmacologic measures,²⁸ but keep in mind that treating orthostatic hypotension with fludrocortisones is an off-label use of the medication.

Monitor patients taking fludrocortisone for worsened supine hypertension and edema. Also, check their serum potassium levels one to 2 weeks after initiation of therapy and after dose increases. Frequent home monitoring of BP in sitting, standing, and supine positions may be helpful in assessing response to therapy.

If the patient remains symptomatic despite therapy with fludrocortisone, consider adding an alpha-1 adrenergic agonist, such as midodrine. Avoid prescribing midodrine, however, for patients with advanced cardiovascular disease, urinary retention, or uncontrolled hypertension.²⁹

Autonomic dysreflexia: A medical emergency

Autonomic dysreflexia, a medical emergency that must be recognized immediately, is a distinct type of autonomic dysfunction seen in patients with spinal cord injury at or above the T6 level.³⁰ It is a condition of uncontrolled sympathetic response secondary to an underlying condition such as infection, urinary retention, or rectal distention.³⁰

Common symptoms include headache, significant hypertension, flushing of the skin, and diaphoresis above the level of injury.² In addition, a review of systems should screen for fever, visual changes, abnormalities of the cardiovascular system, syncope, bowel and bladder symptoms, and sexual dysfunction.

When nonpharmacologic measures don't control orthostatic hypotension, consider the off-label use of fludrocortisone.

Patients demonstrating autonomic dysreflexia should be placed in the upright position to produce an orthostatic decrease in BP.³⁰ Patients should be evaluated to identify any reversible precipitants, such as urinary retention or fecal impaction. Severe attacks involving hypertensive crisis require prompt transfer to the emergency department. Sublingual nifedipine or an intravenous agent, such as hydralazine, may be used to lower BP.³¹

CORRESPONDENCE
Kristen Thornton, MD, 777 South Clinton Ave., Rochester, NY 14620; [email protected]

Signs and symptoms of autonomic dysfunction commonly present in the primary care setting. Potential causes of dysfunction include certain medications and age-related changes in physiology, as well as conditions such as diabetes mellitus, multiple sclerosis, and Parkinson’s disease (TABLE¹). This evidence-based review details common manifestations of autonomic dysfunction, provides a streamlined approach to patients presenting with symptoms, and reviews appropriate step-wise management.

When a delicate balance is disrupted

The autonomic nervous system provides brisk physiologic adjustments necessary to maintain homeostasis. Physiologic functions impacted by the central nervous system include: heart rate, blood pressure (BP), tone of the bladder sphincter and detrusor muscle, bowel motility, bronchodilation and constriction, pupillary dilation and constriction, sweating, catecholamine release, erection, ejaculation and orgasm, tearing, and salivation.¹

Disorders of the autonomic system may result from pathologies of the central or peripheral nervous system or from medications including some antihypertensives, selective serotonin-reuptake inhibitors (SSRIs), and opioids.¹ Such disorders tend to be grouped into one of 3 categories: those involving the brain, those involving the spinal cord, and autonomic neuropathies.¹

The source of dysautonomia can often be determined by clinical context, coexisting neurologic abnormalities, targeted testing of the autonomic nervous system, and neuroimaging.¹

Worrisome symptoms prompt a visit

A thorough history is critical to zeroing in on a patient’s complaints and ultimately providing treatment that will help manage symptoms.

When patient complaints are suggestive of autonomic dysfunction, a review of systems should include inquiry about lightheadedness, abnormal salivation, temperature changes of the extremities, gastrointestinal issues (vomiting, constipation, or diarrhea), and symptoms of presyncope/syncope or urinary or sexual dysfunction.¹ The physical exam should include recordings of BP and heart rate in the supine and standing positions and a complete neurologic examination.¹ Findings will typically point to one or more common complications.

Common complications of autonomic dysfunction

Complications of autonomic dysfunction include impotence, bladder dysfunction, gastrointestinal (GI) dysfunction, and orthostatic hypotension and vasomotor abnormalities. A less common condition—autonomic dysreflexia, which is a distinct type of autonomic dysfunction, and a true medical emergency—is also important to keep in mind.

Impotence

Autonomic neuropathy is a common cause of impotence and retrograde ejaculation. Loss of early morning erections and complete loss of nocturnal erections often have an etiology related to vascular disease and/or autonomic neuropathy. In addition, poor glycemic control and vascular risk factors appear to be associated with the development of diabetic autonomic neuropathy.²

If diabetic autonomic neuropathy is the suspected etiology of impotence, consider prescribing a phosphodiesterase inhibitor.

Development of an erection requires an increase in parasympathetic activity and a decrease in sympathetic output. Nocturnal penile tumescence testing has been used to infer parasympathetic damage to the penis in men with diabetes who do not have vascular disease.³

First- and second-line agents. Phosphodiesterase-5 inhibitors (eg, sildenafil, tadalafil, vardenafil) have demonstrated efficacy in improving the ability to achieve and maintain erections in patients with autonomic dysfunction, including diabetic autonomic neuropathy.^4-6 Second-line therapies with proven efficacy include intraurethral application and intracavernosal injections of alprostadil.^7,8

Bladder dysfunction

Sympathetic activity increases bladder sphincter tone and inhibits detrusor activity, while the parasympathetic nervous system increases detrusor activity and decreases sphincter tone to aid in voiding.¹ Disrupted autonomic activity can lead to urinary frequency, retention, and hesitancy; overactive bladder; and incontinence.¹ Brain and spinal cord disease above the level of the lumbar spine results in urinary frequency and small bladder volumes, whereas diseases involving autonomic nerve fibers to and from the bladder result in large bladder volumes and overflow incontinence.⁹

Botulinum toxin type A, injected directly into the detrusor muscle, can be as effective as medication in patients with urinary urge incontinence.

Patients presenting with lower urinary tract symptoms require a comprehensive evaluation to rule out other pathologies, as the differential for such symptoms is broad and includes infection, malignancies, interstitial cystitis, and bladder stones. The initial evaluation of lower urinary tract symptoms should include a history and physical exam including that of the abdomen, pelvis, and neurologic system. Lab work should assess renal function and blood glucose, and should include urinalysis and culture to rule out infection and/or hematuria. A prostate-specific antigen (PSA) test may be appropriate in men with a life expectancy >10 years, after counseling regarding the risks and benefits of screening.

Anticholinergic drugs with antimuscarinic effects, such as oxybutynin, may be used to treat symptoms of urge incontinence and overactive bladder. They work to suppress involuntary contractions of the bladder’s smooth muscle by blocking the release of acetylcholine. These medications relax the bladder’s outer layer of muscle—the detrusor. Such medications often have a number of anticholinergic adverse effects, such as dry mouth and constipation, sometimes leading to discontinuation. A post-void residual (PVR) test may be helpful in guiding management. For example, caution should be used in patients with elevated PVRs, as anticholinergics can worsen urinary retention.

Beta-3 agonists (eg, mirabegron) are a novel class of medications used to treat overactive bladder. These medications act to increase sympathetic tone in the bladder. Because they have the potential to raise BP, monitor BP in patients taking these agents. In addition, monitor patients taking antimuscarinics or beta-3 agonists for the development of urinary retention.

Other tests, treatments. Urodynamic testing is recommended for patients who fail to respond to treatment. Combining behavioral therapy with medication has been shown to be effective in patients with urge incontinence.¹⁰ Botulinum toxin type A, injected directly into the detrusor muscle, can be as effective as medication in patients with urinary urge incontinence.¹¹

Detrusor underactivity is defined as contraction of reduced strength and/or duration, resulting in prolonged bladder emptying and/or a failure to achieve complete bladder emptying within a normal timespan.¹² This diagnosis is typically made using urodynamic testing.¹³ PVRs ≥150 mL are considered evidence of urinary retention. Overflow incontinence can result from detrusor underactivity.

Consider a trial of a cholinergic agonist, such as bethanechol, in patients with urinary retention. Some patients will require intermittent straight catheterization or chronic indwelling foley or suprapubic catheters to void.

Gastrointestinal dysfunction

In patients with diabetes, GI autonomic neuropathy can result in altered esophageal motility leading to gastroesophageal reflux disease (GERD) or dysphagia, gastroparesis, or diabetic enteropathy.¹⁴ Gastroparesis often presents as nausea, vomiting, and bloating.¹ It may be diagnosed via gastric emptying studies (scintigraphy), and often requires a multidimensional approach to treatment.

Management. Food may be chopped or pureed to aid in digestion. Metoclopramide is the most commonly used prokinetic agent, but avoid its use in patients with parkinsonism. In more severe cases, consider adding domperidone and erythromycin as prokinetic agents. Recommend antiemetics, such as diphenhydramine, ondansetron, and prochlorperazine for management of nausea and vomiting. Severe cases of gastroparesis may merit a venting gastrostomy tube for decompression and/or feeding via a jejunostomy tube.¹⁵ Impaired intestinal mobility may lead to stasis syndrome, causing diarrhea.

Hypermobility caused by decreased sympathetic inhibition can also contribute to diarrhea. Altered anal sphincter function tone may contribute to fecal incontinence. Management should focus on balancing electrolytes, maintaining adequate fluid intake, and relieving symptoms. Consider antidiarrheals such as loperamide, but use them with caution to avoid toxic megacolon.¹⁶

Constipation. Another common manifestation of autonomic dysfunction in the GI tract is severe constipation.¹ This may be managed conservatively with hydration, increased activity, and increased fiber intake. If such measures prove inadequate, consider stool softeners and laxatives.

Patients with constipation due to spinal cord lesions may benefit from a routine bowel regimen. To provide predictable defecation, advise patients to begin by inserting a stimulant rectal suppository. Follow with gentle digital stimulation of the distal rectum for one minute or less. They’ll need to repeat the process every 5 to 10 minutes until stool evacuation is complete. A forward-leaning position may assist with evacuation. It is helpful to perform this routine at the same time each day.¹⁷

Orthostatic (postural) hypotension

The autonomic nervous system plays an important role in maintaining BP during positional changes. The sympathetic nervous system adjusts the tone in arteries, veins, and the heart. Baroreceptors located primarily in the carotid arteries and aorta, are highly sensitive to changes in BP. When the baroreceptors sense the slightest drop in pressure, a coordinated increase in sympathetic outflow occurs. Arteries constrict to increase peripheral resistance and BP, and heart rate and contractility increase, all in an attempt to maintain BP and perfusion.¹⁸

The most common causes of orthostatic hypotension are not neurologic in origin,⁹ but rather involve medications, hypovolemia, and impaired autonomic reflexes. The condition is common in the elderly, with one study demonstrating a prevalence of 18.2% in those ≥65 years.¹⁹

Orthostatic hypotension may present with dimming or loss of vision, lightheadedness, diaphoresis, diminished hearing, pallor, and weakness. As a result, it is a risk factor for falls. Syncope results when the drop in BP impairs cerebral perfusion. Signs of impaired baroreflexes are supine hypertension, a heart rate that is fixed regardless of posture (the heart rate should increase upon standing), postprandial hypotension, and an excessively high nocturnal BP.¹

Orthostatic hypotension is diagnosed when, within 3 minutes of quiet standing after a 5-minute period of supine rest, one or both of the following is present: at least a 20 mm Hg-fall in systolic pressure or at least a 10 mm Hg-fall in diastolic pressure.²⁰ Soysal et al demonstrated that such a drop in BP, measured one minute after standing, is adequate and effective for diagnosing orthostatic hypotension in the elderly.²¹

Nonpharmacologic management. Recognition and removal of medications that can exacerbate orthostatic hypotension is the first step in managing the condition. Such medications include diuretics, beta-blockers, alpha adrenergic blockers, vasodilators, antipsychotics, antidepressants (SSRIs, trazodone, monoamine oxidase inhibitors, and tricyclic antidepressants), phosphodiesterase inhibitors, narcotics, and antiparkinsonian medications.²²

The most common causes of orthostatic hypotension are not neurologic in origin, but rather involve medications, hypovolemia, and impaired autonomic reflexes.

Lifestyle interventions, such as having the patient arise slowly and maintain good hydration, can be helpful. Eating smaller, more frequent meals may also help if the orthostatic hypotension is triggered postprandially. Compressive stockings can help limit venous pooling in the lower extremities and improve venous return. Tensing the legs by crossing them while standing on both feet has been shown to increase cardiac output and BP.²³ An aerobic exercise regimen of walking or stair climbing 30 to 45 minutes/day 3 days/week for 6 months was shown to eliminate symptoms of orthostasis on tilt table testing in elderly patients with cardiac deconditioning, as opposed to chronic autonomic failure.²⁴

The reduction in central blood volume associated with autonomic insufficiency (due to increased urinary sodium and water excretion) can be lessened by increasing sodium and water intake.^25-27

Pharmacotherapy. Fludrocortisone acetate, a synthetic mineralocorticoid, is the medication of first choice for most patients with orthostatic hypotension whose symptoms are not adequately controlled using nonpharmacologic measures,²⁸ but keep in mind that treating orthostatic hypotension with fludrocortisones is an off-label use of the medication.

Monitor patients taking fludrocortisone for worsened supine hypertension and edema. Also, check their serum potassium levels one to 2 weeks after initiation of therapy and after dose increases. Frequent home monitoring of BP in sitting, standing, and supine positions may be helpful in assessing response to therapy.

If the patient remains symptomatic despite therapy with fludrocortisone, consider adding an alpha-1 adrenergic agonist, such as midodrine. Avoid prescribing midodrine, however, for patients with advanced cardiovascular disease, urinary retention, or uncontrolled hypertension.²⁹

Autonomic dysreflexia: A medical emergency

Autonomic dysreflexia, a medical emergency that must be recognized immediately, is a distinct type of autonomic dysfunction seen in patients with spinal cord injury at or above the T6 level.³⁰ It is a condition of uncontrolled sympathetic response secondary to an underlying condition such as infection, urinary retention, or rectal distention.³⁰

Common symptoms include headache, significant hypertension, flushing of the skin, and diaphoresis above the level of injury.² In addition, a review of systems should screen for fever, visual changes, abnormalities of the cardiovascular system, syncope, bowel and bladder symptoms, and sexual dysfunction.

When nonpharmacologic measures don't control orthostatic hypotension, consider the off-label use of fludrocortisone.

Patients demonstrating autonomic dysreflexia should be placed in the upright position to produce an orthostatic decrease in BP.³⁰ Patients should be evaluated to identify any reversible precipitants, such as urinary retention or fecal impaction. Severe attacks involving hypertensive crisis require prompt transfer to the emergency department. Sublingual nifedipine or an intravenous agent, such as hydralazine, may be used to lower BP.³¹

CORRESPONDENCE
Kristen Thornton, MD, 777 South Clinton Ave., Rochester, NY 14620; [email protected]

The FP suspected pustular psoriasis, which was confirmed by a dermatologist the patient saw the following day. The dermatologist confirmed this diagnosis by performing a 4-mm punch biopsy, which included an area of new pustules on the patient’s arm. When a rash is extensive, it’s best to biopsy new lesions from the upper body, rather than old lesions below the waist.

Pustular psoriasis can lead to confluent pustules, a condition in which the skin peels off in sheets, resulting in dehydration and a risk of sepsis. This is why you shouldn’t prescribe oral prednisone for any rash before you know that it’s not psoriasis. While oral prednisone may be an effective treatment for many types of dermatitis, it can exacerbate psoriasis (as it did with this patient), and is therefore not an effective or safe treatment for it.

Knowing that pustular psoriasis can become a dermatologic emergency, the FP prescribed oral cyclosporine for the most rapid result. The patient’s blood pressure and kidney function were normal, so it was only necessary for the FP to order baseline laboratory tests. At the follow-up appointment 2 days later, the patient’s condition was already improving and there were no new pustules. Her vital signs remained stable and the pathology report confirmed pustular psoriasis.

The dermatologist planned to transition the patient from cyclosporine to acitretin, determining it was safe to prescribe an oral retinoid. The patient’s hysterectomy 2 years earlier also eliminated concerns about acitretin’s teratogenic potency. The dermatologist prescribed acitretin with directions for the patient to begin taking it in one week, tapering off the cyclosporine once the pustular psoriasis was significantly better.

After a month, the patient was off of cyclosporine completely. Her skin was clear while using daily acitretin. Monitoring of lab tests did not show any adverse effects of the patient using these 2 potentially toxic medications.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Psoriasis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013: 878-895.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The FP suspected pustular psoriasis, which was confirmed by a dermatologist the patient saw the following day. The dermatologist confirmed this diagnosis by performing a 4-mm punch biopsy, which included an area of new pustules on the patient’s arm. When a rash is extensive, it’s best to biopsy new lesions from the upper body, rather than old lesions below the waist.

Pustular psoriasis can lead to confluent pustules, a condition in which the skin peels off in sheets, resulting in dehydration and a risk of sepsis. This is why you shouldn’t prescribe oral prednisone for any rash before you know that it’s not psoriasis. While oral prednisone may be an effective treatment for many types of dermatitis, it can exacerbate psoriasis (as it did with this patient), and is therefore not an effective or safe treatment for it.

Knowing that pustular psoriasis can become a dermatologic emergency, the FP prescribed oral cyclosporine for the most rapid result. The patient’s blood pressure and kidney function were normal, so it was only necessary for the FP to order baseline laboratory tests. At the follow-up appointment 2 days later, the patient’s condition was already improving and there were no new pustules. Her vital signs remained stable and the pathology report confirmed pustular psoriasis.

The dermatologist planned to transition the patient from cyclosporine to acitretin, determining it was safe to prescribe an oral retinoid. The patient’s hysterectomy 2 years earlier also eliminated concerns about acitretin’s teratogenic potency. The dermatologist prescribed acitretin with directions for the patient to begin taking it in one week, tapering off the cyclosporine once the pustular psoriasis was significantly better.

After a month, the patient was off of cyclosporine completely. Her skin was clear while using daily acitretin. Monitoring of lab tests did not show any adverse effects of the patient using these 2 potentially toxic medications.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Psoriasis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013: 878-895.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The FP suspected pustular psoriasis, which was confirmed by a dermatologist the patient saw the following day. The dermatologist confirmed this diagnosis by performing a 4-mm punch biopsy, which included an area of new pustules on the patient’s arm. When a rash is extensive, it’s best to biopsy new lesions from the upper body, rather than old lesions below the waist.

Pustular psoriasis can lead to confluent pustules, a condition in which the skin peels off in sheets, resulting in dehydration and a risk of sepsis. This is why you shouldn’t prescribe oral prednisone for any rash before you know that it’s not psoriasis. While oral prednisone may be an effective treatment for many types of dermatitis, it can exacerbate psoriasis (as it did with this patient), and is therefore not an effective or safe treatment for it.

Knowing that pustular psoriasis can become a dermatologic emergency, the FP prescribed oral cyclosporine for the most rapid result. The patient’s blood pressure and kidney function were normal, so it was only necessary for the FP to order baseline laboratory tests. At the follow-up appointment 2 days later, the patient’s condition was already improving and there were no new pustules. Her vital signs remained stable and the pathology report confirmed pustular psoriasis.

The dermatologist planned to transition the patient from cyclosporine to acitretin, determining it was safe to prescribe an oral retinoid. The patient’s hysterectomy 2 years earlier also eliminated concerns about acitretin’s teratogenic potency. The dermatologist prescribed acitretin with directions for the patient to begin taking it in one week, tapering off the cyclosporine once the pustular psoriasis was significantly better.

After a month, the patient was off of cyclosporine completely. Her skin was clear while using daily acitretin. Monitoring of lab tests did not show any adverse effects of the patient using these 2 potentially toxic medications.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Psoriasis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013: 878-895.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

Based on the negative KOH and the nail pits, the FP made a diagnosis of plaque psoriasis. This condition can present in an annular pattern resembling tinea corporis. The combination of negative KOH and nail pits are enough to diagnose plaque psoriasis without a biopsy. Otherwise, a 4-mm punch biopsy of the area with erythema and scale would confirm the diagnosis.

Plaque psoriasis is typically treated using a mid- to high-potency topical steroid. Although repeated use of steroids in cases of atopic dermatitis can lead to skin atrophy, this is less common when treating psoriasis. If skin atrophy is still a concern, an alternative to topical steroids is a topical vitamin D preparation.

Vitamin D preparations are typically more expensive than steroids and require prior authorization, but there is one generic preparation (calcipotriene) that is more affordable than its brand-name counterparts. Another nonsystemic treatment to consider when treating plaque psoriasis without psoriatic arthritis is narrowband ultraviolet B therapy.

One risk factor for psoriasis is being overweight. In this case, the FP counseled the patient on weight loss. The FP then prescribed 0.1% triamcinolone ointment to be applied twice daily (especially after bathing).

At a follow-up appointment a month later, there was about 70% clearance of the lesions. For the stubborn areas, the FP prescribed a higher-potency steroid, 0.05% clobetasol ointment, to be applied twice daily. As the cost of clobetasol has risen over the past 2 years, alternatives that may be covered by insurance include augmented betamethasone and halobetasol.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Psoriasis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013: 878-895.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

Based on the negative KOH and the nail pits, the FP made a diagnosis of plaque psoriasis. This condition can present in an annular pattern resembling tinea corporis. The combination of negative KOH and nail pits are enough to diagnose plaque psoriasis without a biopsy. Otherwise, a 4-mm punch biopsy of the area with erythema and scale would confirm the diagnosis.

Plaque psoriasis is typically treated using a mid- to high-potency topical steroid. Although repeated use of steroids in cases of atopic dermatitis can lead to skin atrophy, this is less common when treating psoriasis. If skin atrophy is still a concern, an alternative to topical steroids is a topical vitamin D preparation.

Vitamin D preparations are typically more expensive than steroids and require prior authorization, but there is one generic preparation (calcipotriene) that is more affordable than its brand-name counterparts. Another nonsystemic treatment to consider when treating plaque psoriasis without psoriatic arthritis is narrowband ultraviolet B therapy.

One risk factor for psoriasis is being overweight. In this case, the FP counseled the patient on weight loss. The FP then prescribed 0.1% triamcinolone ointment to be applied twice daily (especially after bathing).

At a follow-up appointment a month later, there was about 70% clearance of the lesions. For the stubborn areas, the FP prescribed a higher-potency steroid, 0.05% clobetasol ointment, to be applied twice daily. As the cost of clobetasol has risen over the past 2 years, alternatives that may be covered by insurance include augmented betamethasone and halobetasol.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Psoriasis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013: 878-895.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com