Applied Evidence

Over the past several years, prolotherapy has been gaining support as an option for patients with tendinopathies and painful osteoarthritic conditions. Yet the technique lacks both a consistent definition and an abundance of evidence.

Because the prefix “prolo” is thought to refer to proliferation or regeneration, some physicians prefer the term “sclerotherapy” when injecting sclerosing agents. Others point out that “prolotherapy” refers to the proliferation of tissue that the injections provoke, which has never been proven. We believe that the material injected should dictate the term used to describe it—dextrose prolotherapy (DPT) or platelet-rich plasma therapy (PRP), for example.

In this update, we focus on DPT—the injection of a solution containing hypertonic dextrose into ligaments, tendons, and joints to promote healing. You’ll find an overview of the proposed mechanism of action and a description of the technique (see “How DPT works”^1-9), as well as a look at the evidence of its effectiveness for a variety of musculoskeletal conditions in the text and TABLE^9-19 that follow. Our review is limited by the dearth of large, definitive studies, and consists mainly of anecdotal evidence, case reports, and other low-quality studies.

Considering DPT—for which patients?

Even for conditions for which the evidence of its efficacy is unequivocal, DPT is only one part of a comprehensive treatment plan. Functional assessment and correction of any weaknesses, inflexibilities, and/or training errors are also essential.

Dextrose prolotherapy is rarely covered by health insurance and is often considered only after conservative treatment has failed.

There are a number of other considerations, as well. For one thing, DPT is rarely covered by health insurance²⁰ and is often considered only after conservative treatment has failed. What’s more, it is not suited to every patient.

Absolute contraindications include acute infections at the injection site, such as cellulitis, abscess, or septic arthritis. Relative contraindications include acute gout flare and acute fracture near the site.⁶

When DPT is a viable alternative, keep in mind that the procedure should only be done by a physician experienced in the technique—and that ultrasound guidance should be used to ensure precise anatomical delivery (FIGURE 1).²¹ Consent must be obtained and documented, and universal precautions observed.

Read on to find out whether to consider DPT for particular patients.

Achilles tendinopathy: DPT decreases pain, improves function (SOR A)

Non-insertional Achilles tendinopathy can be treated with prolotherapy to decrease pain and tendon thickness (FIGURE 2). A small, single blind randomized trial compared the effectiveness of eccentric exercise (ie, contractions performed to lengthen the muscle), DPT alone, and a combination of DPT and exercise for patients with chronic Achilles tendinopathy.¹⁰

The investigators found greater improvement in the Victorian Institute of Sport Assessment-Achilles (VISA-A) score at 12 months with the combined therapy (41.1 on a 0-100 scale) vs either eccentric exercise (23.7) or DPT (27.5) alone. The increase from baseline was greater for those who received combination therapy at 6 weeks (+11.7) compared with the eccentric-only group.¹⁰ Adding DPT (injected into the tender points of the subcutaneous tissues adjacent to the Achilles tendon) to eccentric exercise resulted in a more rapid and sustained improvement in pain, function, and stiffness.

In an earlier observational study, researchers achieved improvement in pain scores using a different DPT technique.²² Here, patients with chronic Achilles tendinosis received ultrasound-guided intratendinous dextrose injections every 6 weeks until symptoms resolved. Pain scores, calculated using a visual analogue scale (VAS), showed a mean reduction at rest (88%), during normal daily activities (84%), and during physical activity (78%). The mean number of treatment sessions was 4, and the mean time to achieve results was 30 weeks.²²

Knee osteoarthritis: Pain level and movement improve (SOR A)

In a study of patients with knee osteoarthritis (OA) and pain lasting 6 months or more, participants received bimonthly injections of either DPT with lidocaine or lidocaine alone. At 12 months, only those in the DPT group had achieved significant improvement in VAS pain score (44%), self-reported swelling (63%), and knee flexion (14%).¹¹

A more recent study randomized 90 adults with painful knee OA of at least 3 months’ duration to blinded injection (either DPT or saline) or at-home exercise.⁹ The injections involved both intra- and extra-articular techniques, performed monthly for a total of 3 to 5 injections. At 52 weeks, the DPT group had improved scores on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) by 15.3 points compared with the saline group (7.6 points) and the exercise-only group (8.2 points).

Half of those receiving DPT improved by 12 or more points, compared with less than a third of those receiving saline and a quarter of those treated with exercise alone. Knee Pain Scale (KPS)-based pain frequency and severity were also significantly reduced in the DPT group vs both comparison groups.⁹

Finger OA. One small randomized study tested the efficacy of DPT in patients with symptomatic finger OA affecting the distal or proximal interphalangeal joint or the trapeziometacarpal (thumb) joint.²³ Participants received either DPT with xylocaine or xylocaine alone. Injections were done on the medial and lateral aspects of the affected joints at baseline, 2, and 4 months. Pain (VAS score) during active finger movement improved by 45% in the DPT group vs 15% in the group treated with xylocaine alone. After 6 months, those in the xylocaine-only group received the DPT protocol, and their pain reduction scores rose, on average, from 18% to 54%.²³

Low back pain: Little help for chronic condition (SOR A)

Early studies of DPT for the treatment of low back pain had conflicting results. In 2004, the largest (N=110) and most rigorous study of DPT for chronic non-specific low back pain to date¹² found no significant improvement.

Participants received either DPT or normal saline injections into tender lumbopelvic ligaments every 2 weeks for a total of 6 treatments. They were then randomized to either core and low back strengthening exercises or normal activity for 6 months. At 12 months, VAS pain and disability scores significantly decreased from baseline in all the groups, with a decline ranging from 26% to 44% for pain and 30% to 44% for disability. However, at no point were there significant differences between injection groups or activity groups.¹²

A 2007 Cochrane review found insufficient evidence to support the use of DPT alone for the treatment of non-specific low back pain but suggested that, as an adjunct, it may improve pain and disability scores.¹³ And in 2011, a Cochrane review confirmed that there was insufficient evidence for the use of DPT in sub-acute and chronic low back pain.¹⁴ Other studies on the use of DPT for specific low back conditions, including sacroiliac joint pain,^24,25 coccydynia,²⁶ and degenerative disc disease,²⁷ have shown trends toward improvement in pain scores^24-27 and disability,²⁵ but only one of these was a randomized controlled trial (RCT).²⁵

Lateral epicondylosis: More effective than saline (SOR B)

A single RCT compared DPT to placebo in patients with 6 months of moderate to severe lateral epicondylosis who had failed conservative treatment. Patients received 3 injections of either hypertonic dextrose or saline tendon insertions every 4 weeks, with needle touching bone at the supracondylar ridge, lateral epicondyle, and annular ligament.¹⁵ Patients randomly assigned to DPT experienced significant pain relief from baseline to 16 weeks, with a Likert score decline from 5.1 to 0.5, compared with the saline group (4.5 at baseline and 3.5 at 16 weeks). Clinical improvement was maintained at 52-week follow-up.¹⁵

Osgood-Schlatter: DPT improves pain relief (SOR B)

In one of the few studies of prolotherapy for adolescents, patients with recalcitrant Osgood-Schlatter disease were randomized to either structured physical therapy or 3 monthly injections of lidocaine, with or without dextrose, over the apophysis and patellar tendon origin.¹⁶ Injections began at the most distal point of tenderness and were repeated at 1 cm intervals for a total of 3 to 4 midline injections. The proximal injections were deep to the patellar tendon, on the tibia above the tuberosity.

Pain scores, measured by the Nirschl Pain Phase Scale (0-7), improved significantly more in the DPT group (3.9) compared with either the lidocaine group (2.4) or the exercise group (1.2). Dextrose-treated knees were significantly more likely than knees treated with lidocaine (14 of 21 vs 5 of 22) to be asymptomatic with sport activity. After 3 months, patients in the lidocaine and exercise groups who had not responded adequately were given the option of receiving DPT; those who underwent the 3-month DPT protocol achieved the same level of improvement as the initial DPT group.¹⁶

When considering or recommending DPT for an adolescent with Osgood-Schlatter disease, however, it is particularly important that he or she be referred to a physician with expertise in prolotherapy.

Plantar fasciosis: A possibility when conservative treatment fails (SOR B)

An early case series showed that DPT effectively improved pain at rest and during activity in patients with chronic plantar fasciosis refractory to conservative care.¹⁷ A small RCT recently compared PRP with DPT in such patients.¹⁸

Pain, disability, and activity limitation were measured by the Foot Functional Index. The PRP group improved by 29.7%, 26.6%, and 28% in pain, disability, and activity limitation, respectively, vs improvements of 17%, 14.5%, and 12.4% in the DPT group. Although there was a trend for PRP to be superior, the results were not statistically significant.¹⁸ This suggests that DPT may be an additional treatment option for patients with plantar fasciosis when conservative treatment fails.

Chondromalacia patella: Not enough is known (SOR C)

One study showed that DPT improved self-reported pain and function scores in patients with chronic knee pain secondary to chondromalacia patella. However, the study had no control group and no standardized injected solution; rather, the solution was tailored for each individual.¹⁹ Thus, there is insufficient data to make recommendations regarding the effectiveness of DPT in treating chondromalacia patella or other causes of patellofemoral pain syndrome.

What to tell patients about recovery and adverse effects

Injection of dextrose into ligaments, tendons, and joints carries the theoretical risks of light-headedness, allergic reaction, infection, and structural damage. However, there have been no reports of serious or significant adverse events associated with DPT when used for peripheral joint indications.

To avoid inhibiting the desired inflammatory response to prolotherapy, nonsteroidal anti-inflammatory drugs should not be used to treat post-injection pain.

The most common risks of DPT are needle trauma-induced pain, mild bleeding, and bruising. A sense of fullness, stiffness, and occasional numbness at the site at the time of injection are common, benign, and typically self-limiting.⁶ If post-procedure numbness continues, the patient should follow up in 48 to 72 hours to rule out nerve damage.

Post-injection pain flare during the first 72 hours may occur. In a study of prolotherapy for knee OA pain, 10% to 20% of patients experienced such flares.¹⁵ Most patients respond well to acetaminophen and experience resolution of pain within a week. Non-steroidal anti-inflammatory drugs should not be used to treat post-procedure pain because they may interfere with the local inflammatory response needed for healing. Regular activities can be resumed immediately after an injection into a large joint, such as the knee, or after full sensation and proprioception returns if an anesthetic was used in combination with the hypertonic dextrose.

There is a theoretical risk of tendon weakening and rupture with tenotomy/intra-substance injections into weight-bearing tendons, but there are no known published reports of this complication with DPT. Nonetheless, we recommend that patients limit ballistic weight bearing or full strength activity for 48 hours after an injection into a non-weight bearing tendon and for 5 to7 days for injection into a weight-bearing tendon.

Physical/occupational therapy is important in chronic tendinopathy, and we encourage rapid return (24-48 hours) to low-intensity rehabilitation with gradual return (5-7 days) to full rehabilitation exercises.

Ballistic weight bearing and full strength activity should be limited for 48 hours after an injection into a non-weight bearing tendon and for 5 to 7 days for a weight-bearing tendon.

The number of DPT injection sessions is variable. We recommend follow-up between 3 and 6 weeks for reevaluation. If the patient’s pain and/or function has not improved after 2 sets of injections—or DPT is initially successful but pain or dysfunction returns—another round of treatment should be offered in 3 to 6 weeks.

CORRESPONDENCE
Carlton J. Covey, MD, FAAFP, Fort Belvoir Community Hospital, Sports Medicine, Eagle Pavilion, 9300 Dewitt Loop, Fort Belvoir, VA 22060; [email protected].

Over the past several years, prolotherapy has been gaining support as an option for patients with tendinopathies and painful osteoarthritic conditions. Yet the technique lacks both a consistent definition and an abundance of evidence.

Because the prefix “prolo” is thought to refer to proliferation or regeneration, some physicians prefer the term “sclerotherapy” when injecting sclerosing agents. Others point out that “prolotherapy” refers to the proliferation of tissue that the injections provoke, which has never been proven. We believe that the material injected should dictate the term used to describe it—dextrose prolotherapy (DPT) or platelet-rich plasma therapy (PRP), for example.

In this update, we focus on DPT—the injection of a solution containing hypertonic dextrose into ligaments, tendons, and joints to promote healing. You’ll find an overview of the proposed mechanism of action and a description of the technique (see “How DPT works”^1-9), as well as a look at the evidence of its effectiveness for a variety of musculoskeletal conditions in the text and TABLE^9-19 that follow. Our review is limited by the dearth of large, definitive studies, and consists mainly of anecdotal evidence, case reports, and other low-quality studies.

Considering DPT—for which patients?

Even for conditions for which the evidence of its efficacy is unequivocal, DPT is only one part of a comprehensive treatment plan. Functional assessment and correction of any weaknesses, inflexibilities, and/or training errors are also essential.

Dextrose prolotherapy is rarely covered by health insurance and is often considered only after conservative treatment has failed.

There are a number of other considerations, as well. For one thing, DPT is rarely covered by health insurance²⁰ and is often considered only after conservative treatment has failed. What’s more, it is not suited to every patient.

Absolute contraindications include acute infections at the injection site, such as cellulitis, abscess, or septic arthritis. Relative contraindications include acute gout flare and acute fracture near the site.⁶

When DPT is a viable alternative, keep in mind that the procedure should only be done by a physician experienced in the technique—and that ultrasound guidance should be used to ensure precise anatomical delivery (FIGURE 1).²¹ Consent must be obtained and documented, and universal precautions observed.

Read on to find out whether to consider DPT for particular patients.

Achilles tendinopathy: DPT decreases pain, improves function (SOR A)

Non-insertional Achilles tendinopathy can be treated with prolotherapy to decrease pain and tendon thickness (FIGURE 2). A small, single blind randomized trial compared the effectiveness of eccentric exercise (ie, contractions performed to lengthen the muscle), DPT alone, and a combination of DPT and exercise for patients with chronic Achilles tendinopathy.¹⁰

The investigators found greater improvement in the Victorian Institute of Sport Assessment-Achilles (VISA-A) score at 12 months with the combined therapy (41.1 on a 0-100 scale) vs either eccentric exercise (23.7) or DPT (27.5) alone. The increase from baseline was greater for those who received combination therapy at 6 weeks (+11.7) compared with the eccentric-only group.¹⁰ Adding DPT (injected into the tender points of the subcutaneous tissues adjacent to the Achilles tendon) to eccentric exercise resulted in a more rapid and sustained improvement in pain, function, and stiffness.

In an earlier observational study, researchers achieved improvement in pain scores using a different DPT technique.²² Here, patients with chronic Achilles tendinosis received ultrasound-guided intratendinous dextrose injections every 6 weeks until symptoms resolved. Pain scores, calculated using a visual analogue scale (VAS), showed a mean reduction at rest (88%), during normal daily activities (84%), and during physical activity (78%). The mean number of treatment sessions was 4, and the mean time to achieve results was 30 weeks.²²

Knee osteoarthritis: Pain level and movement improve (SOR A)

In a study of patients with knee osteoarthritis (OA) and pain lasting 6 months or more, participants received bimonthly injections of either DPT with lidocaine or lidocaine alone. At 12 months, only those in the DPT group had achieved significant improvement in VAS pain score (44%), self-reported swelling (63%), and knee flexion (14%).¹¹

A more recent study randomized 90 adults with painful knee OA of at least 3 months’ duration to blinded injection (either DPT or saline) or at-home exercise.⁹ The injections involved both intra- and extra-articular techniques, performed monthly for a total of 3 to 5 injections. At 52 weeks, the DPT group had improved scores on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) by 15.3 points compared with the saline group (7.6 points) and the exercise-only group (8.2 points).

Half of those receiving DPT improved by 12 or more points, compared with less than a third of those receiving saline and a quarter of those treated with exercise alone. Knee Pain Scale (KPS)-based pain frequency and severity were also significantly reduced in the DPT group vs both comparison groups.⁹

Finger OA. One small randomized study tested the efficacy of DPT in patients with symptomatic finger OA affecting the distal or proximal interphalangeal joint or the trapeziometacarpal (thumb) joint.²³ Participants received either DPT with xylocaine or xylocaine alone. Injections were done on the medial and lateral aspects of the affected joints at baseline, 2, and 4 months. Pain (VAS score) during active finger movement improved by 45% in the DPT group vs 15% in the group treated with xylocaine alone. After 6 months, those in the xylocaine-only group received the DPT protocol, and their pain reduction scores rose, on average, from 18% to 54%.²³

Low back pain: Little help for chronic condition (SOR A)

Early studies of DPT for the treatment of low back pain had conflicting results. In 2004, the largest (N=110) and most rigorous study of DPT for chronic non-specific low back pain to date¹² found no significant improvement.

Participants received either DPT or normal saline injections into tender lumbopelvic ligaments every 2 weeks for a total of 6 treatments. They were then randomized to either core and low back strengthening exercises or normal activity for 6 months. At 12 months, VAS pain and disability scores significantly decreased from baseline in all the groups, with a decline ranging from 26% to 44% for pain and 30% to 44% for disability. However, at no point were there significant differences between injection groups or activity groups.¹²

A 2007 Cochrane review found insufficient evidence to support the use of DPT alone for the treatment of non-specific low back pain but suggested that, as an adjunct, it may improve pain and disability scores.¹³ And in 2011, a Cochrane review confirmed that there was insufficient evidence for the use of DPT in sub-acute and chronic low back pain.¹⁴ Other studies on the use of DPT for specific low back conditions, including sacroiliac joint pain,^24,25 coccydynia,²⁶ and degenerative disc disease,²⁷ have shown trends toward improvement in pain scores^24-27 and disability,²⁵ but only one of these was a randomized controlled trial (RCT).²⁵

Lateral epicondylosis: More effective than saline (SOR B)

A single RCT compared DPT to placebo in patients with 6 months of moderate to severe lateral epicondylosis who had failed conservative treatment. Patients received 3 injections of either hypertonic dextrose or saline tendon insertions every 4 weeks, with needle touching bone at the supracondylar ridge, lateral epicondyle, and annular ligament.¹⁵ Patients randomly assigned to DPT experienced significant pain relief from baseline to 16 weeks, with a Likert score decline from 5.1 to 0.5, compared with the saline group (4.5 at baseline and 3.5 at 16 weeks). Clinical improvement was maintained at 52-week follow-up.¹⁵

Osgood-Schlatter: DPT improves pain relief (SOR B)

In one of the few studies of prolotherapy for adolescents, patients with recalcitrant Osgood-Schlatter disease were randomized to either structured physical therapy or 3 monthly injections of lidocaine, with or without dextrose, over the apophysis and patellar tendon origin.¹⁶ Injections began at the most distal point of tenderness and were repeated at 1 cm intervals for a total of 3 to 4 midline injections. The proximal injections were deep to the patellar tendon, on the tibia above the tuberosity.

Pain scores, measured by the Nirschl Pain Phase Scale (0-7), improved significantly more in the DPT group (3.9) compared with either the lidocaine group (2.4) or the exercise group (1.2). Dextrose-treated knees were significantly more likely than knees treated with lidocaine (14 of 21 vs 5 of 22) to be asymptomatic with sport activity. After 3 months, patients in the lidocaine and exercise groups who had not responded adequately were given the option of receiving DPT; those who underwent the 3-month DPT protocol achieved the same level of improvement as the initial DPT group.¹⁶

When considering or recommending DPT for an adolescent with Osgood-Schlatter disease, however, it is particularly important that he or she be referred to a physician with expertise in prolotherapy.

Plantar fasciosis: A possibility when conservative treatment fails (SOR B)

An early case series showed that DPT effectively improved pain at rest and during activity in patients with chronic plantar fasciosis refractory to conservative care.¹⁷ A small RCT recently compared PRP with DPT in such patients.¹⁸

Pain, disability, and activity limitation were measured by the Foot Functional Index. The PRP group improved by 29.7%, 26.6%, and 28% in pain, disability, and activity limitation, respectively, vs improvements of 17%, 14.5%, and 12.4% in the DPT group. Although there was a trend for PRP to be superior, the results were not statistically significant.¹⁸ This suggests that DPT may be an additional treatment option for patients with plantar fasciosis when conservative treatment fails.

Chondromalacia patella: Not enough is known (SOR C)

One study showed that DPT improved self-reported pain and function scores in patients with chronic knee pain secondary to chondromalacia patella. However, the study had no control group and no standardized injected solution; rather, the solution was tailored for each individual.¹⁹ Thus, there is insufficient data to make recommendations regarding the effectiveness of DPT in treating chondromalacia patella or other causes of patellofemoral pain syndrome.

What to tell patients about recovery and adverse effects

Injection of dextrose into ligaments, tendons, and joints carries the theoretical risks of light-headedness, allergic reaction, infection, and structural damage. However, there have been no reports of serious or significant adverse events associated with DPT when used for peripheral joint indications.

To avoid inhibiting the desired inflammatory response to prolotherapy, nonsteroidal anti-inflammatory drugs should not be used to treat post-injection pain.

The most common risks of DPT are needle trauma-induced pain, mild bleeding, and bruising. A sense of fullness, stiffness, and occasional numbness at the site at the time of injection are common, benign, and typically self-limiting.⁶ If post-procedure numbness continues, the patient should follow up in 48 to 72 hours to rule out nerve damage.

Post-injection pain flare during the first 72 hours may occur. In a study of prolotherapy for knee OA pain, 10% to 20% of patients experienced such flares.¹⁵ Most patients respond well to acetaminophen and experience resolution of pain within a week. Non-steroidal anti-inflammatory drugs should not be used to treat post-procedure pain because they may interfere with the local inflammatory response needed for healing. Regular activities can be resumed immediately after an injection into a large joint, such as the knee, or after full sensation and proprioception returns if an anesthetic was used in combination with the hypertonic dextrose.

There is a theoretical risk of tendon weakening and rupture with tenotomy/intra-substance injections into weight-bearing tendons, but there are no known published reports of this complication with DPT. Nonetheless, we recommend that patients limit ballistic weight bearing or full strength activity for 48 hours after an injection into a non-weight bearing tendon and for 5 to7 days for injection into a weight-bearing tendon.

Physical/occupational therapy is important in chronic tendinopathy, and we encourage rapid return (24-48 hours) to low-intensity rehabilitation with gradual return (5-7 days) to full rehabilitation exercises.

Ballistic weight bearing and full strength activity should be limited for 48 hours after an injection into a non-weight bearing tendon and for 5 to 7 days for a weight-bearing tendon.

The number of DPT injection sessions is variable. We recommend follow-up between 3 and 6 weeks for reevaluation. If the patient’s pain and/or function has not improved after 2 sets of injections—or DPT is initially successful but pain or dysfunction returns—another round of treatment should be offered in 3 to 6 weeks.

CORRESPONDENCE
Carlton J. Covey, MD, FAAFP, Fort Belvoir Community Hospital, Sports Medicine, Eagle Pavilion, 9300 Dewitt Loop, Fort Belvoir, VA 22060; [email protected].

Over the past several years, prolotherapy has been gaining support as an option for patients with tendinopathies and painful osteoarthritic conditions. Yet the technique lacks both a consistent definition and an abundance of evidence.

Because the prefix “prolo” is thought to refer to proliferation or regeneration, some physicians prefer the term “sclerotherapy” when injecting sclerosing agents. Others point out that “prolotherapy” refers to the proliferation of tissue that the injections provoke, which has never been proven. We believe that the material injected should dictate the term used to describe it—dextrose prolotherapy (DPT) or platelet-rich plasma therapy (PRP), for example.

In this update, we focus on DPT—the injection of a solution containing hypertonic dextrose into ligaments, tendons, and joints to promote healing. You’ll find an overview of the proposed mechanism of action and a description of the technique (see “How DPT works”^1-9), as well as a look at the evidence of its effectiveness for a variety of musculoskeletal conditions in the text and TABLE^9-19 that follow. Our review is limited by the dearth of large, definitive studies, and consists mainly of anecdotal evidence, case reports, and other low-quality studies.

Considering DPT—for which patients?

Even for conditions for which the evidence of its efficacy is unequivocal, DPT is only one part of a comprehensive treatment plan. Functional assessment and correction of any weaknesses, inflexibilities, and/or training errors are also essential.

Dextrose prolotherapy is rarely covered by health insurance and is often considered only after conservative treatment has failed.

There are a number of other considerations, as well. For one thing, DPT is rarely covered by health insurance²⁰ and is often considered only after conservative treatment has failed. What’s more, it is not suited to every patient.

Absolute contraindications include acute infections at the injection site, such as cellulitis, abscess, or septic arthritis. Relative contraindications include acute gout flare and acute fracture near the site.⁶

When DPT is a viable alternative, keep in mind that the procedure should only be done by a physician experienced in the technique—and that ultrasound guidance should be used to ensure precise anatomical delivery (FIGURE 1).²¹ Consent must be obtained and documented, and universal precautions observed.

Read on to find out whether to consider DPT for particular patients.

Achilles tendinopathy: DPT decreases pain, improves function (SOR A)

Non-insertional Achilles tendinopathy can be treated with prolotherapy to decrease pain and tendon thickness (FIGURE 2). A small, single blind randomized trial compared the effectiveness of eccentric exercise (ie, contractions performed to lengthen the muscle), DPT alone, and a combination of DPT and exercise for patients with chronic Achilles tendinopathy.¹⁰

The investigators found greater improvement in the Victorian Institute of Sport Assessment-Achilles (VISA-A) score at 12 months with the combined therapy (41.1 on a 0-100 scale) vs either eccentric exercise (23.7) or DPT (27.5) alone. The increase from baseline was greater for those who received combination therapy at 6 weeks (+11.7) compared with the eccentric-only group.¹⁰ Adding DPT (injected into the tender points of the subcutaneous tissues adjacent to the Achilles tendon) to eccentric exercise resulted in a more rapid and sustained improvement in pain, function, and stiffness.

In an earlier observational study, researchers achieved improvement in pain scores using a different DPT technique.²² Here, patients with chronic Achilles tendinosis received ultrasound-guided intratendinous dextrose injections every 6 weeks until symptoms resolved. Pain scores, calculated using a visual analogue scale (VAS), showed a mean reduction at rest (88%), during normal daily activities (84%), and during physical activity (78%). The mean number of treatment sessions was 4, and the mean time to achieve results was 30 weeks.²²

Knee osteoarthritis: Pain level and movement improve (SOR A)

In a study of patients with knee osteoarthritis (OA) and pain lasting 6 months or more, participants received bimonthly injections of either DPT with lidocaine or lidocaine alone. At 12 months, only those in the DPT group had achieved significant improvement in VAS pain score (44%), self-reported swelling (63%), and knee flexion (14%).¹¹

A more recent study randomized 90 adults with painful knee OA of at least 3 months’ duration to blinded injection (either DPT or saline) or at-home exercise.⁹ The injections involved both intra- and extra-articular techniques, performed monthly for a total of 3 to 5 injections. At 52 weeks, the DPT group had improved scores on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) by 15.3 points compared with the saline group (7.6 points) and the exercise-only group (8.2 points).

Half of those receiving DPT improved by 12 or more points, compared with less than a third of those receiving saline and a quarter of those treated with exercise alone. Knee Pain Scale (KPS)-based pain frequency and severity were also significantly reduced in the DPT group vs both comparison groups.⁹

Finger OA. One small randomized study tested the efficacy of DPT in patients with symptomatic finger OA affecting the distal or proximal interphalangeal joint or the trapeziometacarpal (thumb) joint.²³ Participants received either DPT with xylocaine or xylocaine alone. Injections were done on the medial and lateral aspects of the affected joints at baseline, 2, and 4 months. Pain (VAS score) during active finger movement improved by 45% in the DPT group vs 15% in the group treated with xylocaine alone. After 6 months, those in the xylocaine-only group received the DPT protocol, and their pain reduction scores rose, on average, from 18% to 54%.²³

Low back pain: Little help for chronic condition (SOR A)

Early studies of DPT for the treatment of low back pain had conflicting results. In 2004, the largest (N=110) and most rigorous study of DPT for chronic non-specific low back pain to date¹² found no significant improvement.

Participants received either DPT or normal saline injections into tender lumbopelvic ligaments every 2 weeks for a total of 6 treatments. They were then randomized to either core and low back strengthening exercises or normal activity for 6 months. At 12 months, VAS pain and disability scores significantly decreased from baseline in all the groups, with a decline ranging from 26% to 44% for pain and 30% to 44% for disability. However, at no point were there significant differences between injection groups or activity groups.¹²

A 2007 Cochrane review found insufficient evidence to support the use of DPT alone for the treatment of non-specific low back pain but suggested that, as an adjunct, it may improve pain and disability scores.¹³ And in 2011, a Cochrane review confirmed that there was insufficient evidence for the use of DPT in sub-acute and chronic low back pain.¹⁴ Other studies on the use of DPT for specific low back conditions, including sacroiliac joint pain,^24,25 coccydynia,²⁶ and degenerative disc disease,²⁷ have shown trends toward improvement in pain scores^24-27 and disability,²⁵ but only one of these was a randomized controlled trial (RCT).²⁵

Lateral epicondylosis: More effective than saline (SOR B)

A single RCT compared DPT to placebo in patients with 6 months of moderate to severe lateral epicondylosis who had failed conservative treatment. Patients received 3 injections of either hypertonic dextrose or saline tendon insertions every 4 weeks, with needle touching bone at the supracondylar ridge, lateral epicondyle, and annular ligament.¹⁵ Patients randomly assigned to DPT experienced significant pain relief from baseline to 16 weeks, with a Likert score decline from 5.1 to 0.5, compared with the saline group (4.5 at baseline and 3.5 at 16 weeks). Clinical improvement was maintained at 52-week follow-up.¹⁵

Osgood-Schlatter: DPT improves pain relief (SOR B)

In one of the few studies of prolotherapy for adolescents, patients with recalcitrant Osgood-Schlatter disease were randomized to either structured physical therapy or 3 monthly injections of lidocaine, with or without dextrose, over the apophysis and patellar tendon origin.¹⁶ Injections began at the most distal point of tenderness and were repeated at 1 cm intervals for a total of 3 to 4 midline injections. The proximal injections were deep to the patellar tendon, on the tibia above the tuberosity.

Pain scores, measured by the Nirschl Pain Phase Scale (0-7), improved significantly more in the DPT group (3.9) compared with either the lidocaine group (2.4) or the exercise group (1.2). Dextrose-treated knees were significantly more likely than knees treated with lidocaine (14 of 21 vs 5 of 22) to be asymptomatic with sport activity. After 3 months, patients in the lidocaine and exercise groups who had not responded adequately were given the option of receiving DPT; those who underwent the 3-month DPT protocol achieved the same level of improvement as the initial DPT group.¹⁶

When considering or recommending DPT for an adolescent with Osgood-Schlatter disease, however, it is particularly important that he or she be referred to a physician with expertise in prolotherapy.

Plantar fasciosis: A possibility when conservative treatment fails (SOR B)

An early case series showed that DPT effectively improved pain at rest and during activity in patients with chronic plantar fasciosis refractory to conservative care.¹⁷ A small RCT recently compared PRP with DPT in such patients.¹⁸

Pain, disability, and activity limitation were measured by the Foot Functional Index. The PRP group improved by 29.7%, 26.6%, and 28% in pain, disability, and activity limitation, respectively, vs improvements of 17%, 14.5%, and 12.4% in the DPT group. Although there was a trend for PRP to be superior, the results were not statistically significant.¹⁸ This suggests that DPT may be an additional treatment option for patients with plantar fasciosis when conservative treatment fails.

Chondromalacia patella: Not enough is known (SOR C)

One study showed that DPT improved self-reported pain and function scores in patients with chronic knee pain secondary to chondromalacia patella. However, the study had no control group and no standardized injected solution; rather, the solution was tailored for each individual.¹⁹ Thus, there is insufficient data to make recommendations regarding the effectiveness of DPT in treating chondromalacia patella or other causes of patellofemoral pain syndrome.

What to tell patients about recovery and adverse effects

Injection of dextrose into ligaments, tendons, and joints carries the theoretical risks of light-headedness, allergic reaction, infection, and structural damage. However, there have been no reports of serious or significant adverse events associated with DPT when used for peripheral joint indications.

To avoid inhibiting the desired inflammatory response to prolotherapy, nonsteroidal anti-inflammatory drugs should not be used to treat post-injection pain.

The most common risks of DPT are needle trauma-induced pain, mild bleeding, and bruising. A sense of fullness, stiffness, and occasional numbness at the site at the time of injection are common, benign, and typically self-limiting.⁶ If post-procedure numbness continues, the patient should follow up in 48 to 72 hours to rule out nerve damage.

Post-injection pain flare during the first 72 hours may occur. In a study of prolotherapy for knee OA pain, 10% to 20% of patients experienced such flares.¹⁵ Most patients respond well to acetaminophen and experience resolution of pain within a week. Non-steroidal anti-inflammatory drugs should not be used to treat post-procedure pain because they may interfere with the local inflammatory response needed for healing. Regular activities can be resumed immediately after an injection into a large joint, such as the knee, or after full sensation and proprioception returns if an anesthetic was used in combination with the hypertonic dextrose.

There is a theoretical risk of tendon weakening and rupture with tenotomy/intra-substance injections into weight-bearing tendons, but there are no known published reports of this complication with DPT. Nonetheless, we recommend that patients limit ballistic weight bearing or full strength activity for 48 hours after an injection into a non-weight bearing tendon and for 5 to7 days for injection into a weight-bearing tendon.

Physical/occupational therapy is important in chronic tendinopathy, and we encourage rapid return (24-48 hours) to low-intensity rehabilitation with gradual return (5-7 days) to full rehabilitation exercises.

Ballistic weight bearing and full strength activity should be limited for 48 hours after an injection into a non-weight bearing tendon and for 5 to 7 days for a weight-bearing tendon.

The number of DPT injection sessions is variable. We recommend follow-up between 3 and 6 weeks for reevaluation. If the patient’s pain and/or function has not improved after 2 sets of injections—or DPT is initially successful but pain or dysfunction returns—another round of treatment should be offered in 3 to 6 weeks.

CORRESPONDENCE
Carlton J. Covey, MD, FAAFP, Fort Belvoir Community Hospital, Sports Medicine, Eagle Pavilion, 9300 Dewitt Loop, Fort Belvoir, VA 22060; [email protected].

CASE 1 › Sally G, age 46, has been experiencing paresthesias for the past 3 months. She says that when she is cycling, the air on her legs feels much cooler than normal, with a similar feeling in her hands. Whenever her hands or legs are in cool water, she says it feels as if she’s dipped them into an ice bucket. Summer heat makes her skin feel as if it's on fire, and she’s noticed increased sweating on her lower legs. She complains of itching (although she has no rash) and she’s had intermittent tingling and burning in her toes. On neurologic exam, she demonstrates normal strength, sensation, reflexes, coordination, and cranial nerve function.

Case 2 › Jessica T, age 25, comes in to see her family physician because she’s been experiencing numbness in her right leg. It had begun with numbness of the right great toe about a year ago. Subsequently, the numbness extended up her foot to the lateral aspect of the lower leg with an accompanying burning sensation. Three months prior to this visit, she developed weakness in her right foot and toes. She denies any symptoms in her left leg, upper extremities, or face.

A neurologic exam of the upper extremities is normal. Ms. T also has normal cranial nerve function, and normal strength, sensation, and reflexes in the left leg. A motor exam of the right leg reveals normal strength in the hip flexors, hip adductors, hip abductors, and quadriceps. On the Medical Research Council scale, she has 4/5 strength in the hamstrings, 0/5 in the ankle dorsiflexors, 1/5 in the posterior tibialis, and 3/5 in the gastrocnemius. She has a normal right patellar reflex, and an ankle jerk reflex and Babinski sign are absent. She has reduced sensation on the posterior and lateral portions of the right leg and the entire foot. Sensation is preserved on the medial side of the right lower leg and anterior thigh. She has right-sided steppage gait.

Look for positive neuropathic symptoms such as cramping and tingling, negative symptoms such as numbness and weakness, and autonomic symptoms such as constipation, diarrhea, and sweating.

If these 2 women were your patients, how would you proceed with their care?

Paresthesias such as numbness and tingling in the lower extremities are common complaints in family medicine. These symptoms can be challenging to evaluate because they have multiple potential etiologies with varied clinical presentations.¹

A well-honed understanding of lower extremity anatomy and the location and characteristics of common complaints is essential to making an accurate diagnosis and treatment plan. This article discusses the tests to use when evaluating a patient who presents with lower extremity numbness and pain. It also describes the typical presentation and findings of several types of peripheral neuropathy, and how to manage them.

Parasthesias are often the result of peripheral neuropathy

While paresthesias can arise from disorders of the central or peripheral nervous system, this article focuses on paresthesias that are the result of peripheral neuropathy. Peripheral neuropathy can be classified as mononeuropathy, multiple mononeuropathy, or polyneuropathy:

• Mononeuropathy is focal involvement of a single nerve resulting from a localized process such as compression or entrapment, as in carpal tunnel syndrome.¹
• Multiple mononeuropathy (mononeuritis multiplex) results from damage to multiple noncontiguous nerves that can occur simultaneously or sequentially, as in vasculitic causes of neuropathy.¹
• Polyneuropathy involves 2 or more contiguous nerves, usually symmetric and length-dependent, creating a “stocking-glove” pattern of paresthesias.¹ Polyneuropathy affects longer nerves first, and thus, patients will initially complain of symptoms in their feet and legs, and later their hands. Polyneuropathy is most commonly seen in diabetes.

Possible causes of peripheral neuropathy include numerous anatomic, systemic, metabolic, and toxic conditions (TABLE 1).^1,2

What's causing the neuropathy? The search for telltale clues

While obtaining the history, ask the patient about the presence of positive, negative, or autonomic neuropathic symptoms. Positive symptoms, which usually present first, are due to excess or inappropriate nerve activity and include cramping, twitching, burning, and tingling.³ Negative symptoms are due to reduced nerve activity and include numbness, weakness, decreased balance, and poor sensation. Autonomic symptoms include early satiety, constipation or diarrhea, impotence, sweating abnormalities, and orthostasis.³ The timing of onset, progression, and duration of such symptoms can give important diagnostic clues. For example, an acute onset of painful foot drop may indicate an inflammatory cause such as vasculitis, whereas slowly progressive numbness in both feet points toward a distal sensorimotor polyneuropathy, likely from a metabolic cause. Symmetry or asymmetry at presentation, as well as speed of progression of symptoms, can also significantly narrow the differential (TABLE 2).

Determining the exact location of symptoms is important and usually requires prompting. For example, when a patient refers to “the legs,” he could mean anywhere from the foot to the hip. The presence of radiating pain can also help localize the lesion, generally pointing to a radiculopathy (disease at the root of a nerve). Bowel or bladder involvement could suggest involvement of the spinal cord or autonomic nervous system.

A thorough social history can help identify potentially treatable causes of neuropathy. The probability of a toxic, infectious, or vitamin deficiency etiology can be ascertained by inquiring about a patient’s occupation, sexual history, dietary habits, and drug, alcohol, and tobacco history.³ Personal and family medical history can suggest possible genetic or endocrine causes of neuropathy. A personal or family history of childhood “clumsiness” (suggestive of a hereditary neuropathy, such as Charcot-Marie-Tooth disease), diabetes mellitus, or thyroid, renal, hepatic, or autoimmune diseases would be significant. A personal or family history of cancer is also an important diagnostic clue.³

These tests help narrow the diagnostic possibilities

An acute onset of painful foot drop may indicate an inflammatory cause of neuropathic symptoms, such as vasculitis.

Motor and sensory testing are essential, as is testing of coordination and reflexes. Motor examination involves manual muscle testing. In many patients, pain can limit effort, so encourage patients to try hard during testing so you can determine the true severity of weakness. Sensory testing should include pinprick, temperature differentiation, vibration, and proprioception. Also examine the cranial nerves and upper extremities because abnormal findings could suggest a central nervous system (CNS) lesion or proximal progression of disease, with the patient unaware of subtle symptom worsening or spreading. The pattern of deficits as well as predominance of motor vs sensory nerve involvement can further narrow the differential. For example, unilateral symptoms typically suggest either a structural lesion or inflammatory lesion as the cause, while unilateral weakness without numbness could be significant for the onset of amyotrophic lateral sclerosis.¹ A careful skin, hair, and mucous membrane exam is useful because many infectious, toxic, autoimmune, and genetic causes of peripheral neuropathy also cause changes in these areas. High arches, hammer toes, and inverted champagne bottle legs suggest a hereditary neuropathy.³

In addition to the history and examination, electrodiagnostic testing (EDX) is often helpful, and judicious laboratory testing can further narrow diagnostic possibilities. (See “How best to use EDX and lab testing to evaluate peripheral neuropathy”.^1-3)

So what type of neuropathy are you dealing with?

The details of your patient’s history and findings from the exam and testing will point you toward any one of a number of different types of neuropathies. The list below covers a range—from the common (distal sensorimotor polyneuropathy) to the more rare (paraneoplastic neuropathies).

Distal sensorimotor polyneuropathy (DSP)

DSP is the most common type of neuropathy.⁴ The typical presentation of DSP is chronic, distal, symmetric, and predominantly sensory.⁵ Any variation on this suggests an atypical neuropathy.⁵ Patients with DSP present with loss of function (loss of sensation to pinprick, temperature, vibration, proprioception) and/or tingling, burning, and pain starting symmetrically in the lower extremities. Over the course of years, paresthesias move up the legs to the knees before symptoms begin in the arms.

While the disorder can be quite painful, it is not usually functionally limiting unless the loss of sensation is severe enough to cause falls from sensory ataxia. Weakness is rare. When it occurs, it is usually a mild weakness of the distal leg with foot atrophy.

The most common cause of DSP is diabetes or impaired glucose tolerance. Other common causes are vitamin deficiencies (vitamin B1, B6, B12), folate deficiency, paraproteinemia, and hypo/hyperthyroidism. Also consider alcohol abuse, human immunodeficiency virus (HIV) infection, gastric bypass, chemotherapy, chronic kidney disease, and autoimmune conditions such as Sjögren’s syndrome, lupus, and rheumatoid arthritis.¹

Testing. EDX can help confirm a diagnosis of DSP. A 2009 American Academy of Neurology review of lab testing for DSP found the tests with the highest diagnostic yield were fasting blood glucose, vitamin B12 level with methylmalonic acid, and serum protein electrophoresis and immunofixation electrophoresis (IFE).⁴ If the initial screen with a fasting blood sugar or hemoglobin A1c (HbA1c) is negative, further testing with a glucose tolerance test is recommended.

Treatment of DSP depends on the underlying etiology. Vitamin deficiencies should be corrected and metabolic or autoimmune etiologies addressed as appropriate. There are multiple pharmacologic options for treating persistent pain or discomfort. Best evidence (Level A) exists for pregabalin.⁶ Moderate evidence of effectiveness (Level B) exists for gabapentin, sodium valproate, amitriptyline, venlafaxine, and duloxetine.⁶

Small fiber neuropathy

Small fiber neuropathy can present similarly to DSP, with distal painful paresthesias, but can spread to the upper extremities within a few weeks or months from onset, while DSP spreads to the hands years after onset. Small fiber neuropathy is also associated with early autonomic dysfunction. Examination usually reveals decreased sensation distally, but reflexes and strength are normal.

Common causes of small fiber neuropathy are diabetes, glucose intolerance, metabolic syndrome, hypo/hyperthyroidism, monoclonal gammopathy, alcohol abuse, vitamin B12 deficiency, and hypertriglyceridemia.⁷ Less common causes include Sjögren’s syndrome, HIV, Lyme disease, sarcoidosis, heavy metal toxicity, amyloidosis, and celiac disease.⁷

Testing and treatment. Skin biopsy is used to confirm the diagnosis of small fiber neuropathy.⁷ (EDX results are normal.⁷) Persistent pain can be treated with the same agents discussed above for treating DSP.

Acquired demyelinating neuropathy

Acquired demyelinating neuropathy is a rare condition, but one in which prompt recognition and treatment can prevent significant neurologic decline. There are both acute and chronic types of acquired demyelinating neuropathies.

Guillain-Barré syndrome (GBS) is an acute inflammatory demyelinating polyradiculoneuropathy. Nearly two-thirds of patients with GBS report a previous respiratory or gastrointestinal illness; cytomegalovirus and Campylobacter jejuni are the most frequently associated infections.⁸

Small fiber neuropathy can look like distal sensorimotor polyneuropathy, but can spread to the upper extremities quicker and can cause autonomic dysfunction.

The onset of GBS often involves pain in the back or limbs, followed by a rapid progression of sensory loss and weakness (over days to a few weeks) that typically starts in the feet and moves upward.⁸ Though the typical presentation of GBS is “ascending,” there are frequent exceptions to this pattern.⁸ Physical exam shows weakness, sensory loss, and absent reflexes. Severe cases can result in complete paralysis, even of extraocular movements. Autonomic dysfunction is common.

Testing. EDX and lumbar puncture are needed to accurately diagnose GBS.⁸ EDX initially may be unremarkable, but over time, areas of demyelination become apparent. Lumbar puncture shows albuminocytologic dissociation (no white cells, elevated protein).

Treatment. Patients with GBS are initially managed as inpatients because 33% of cases lead to respiratory failure.⁹ Treatments include intravenous immunoglobulin (IVIg) or plasmapheresis; both have similar outcomes, speeding neurologic recovery time but not affecting overall long-term prognosis.¹⁰ Response to treatment is often not immediate, and some patients continue to worsen after treatment.⁸ Still, long-term prognosis is good, even for severely affected patients, as long as they receive good supportive care. The relapse rate is between 2% and 6%.⁸

In chronic inflammatory demyelinating polyneuropathy (CIDP), patients develop stepwise nerve dysfunction over many weeks to months. One nerve is affected, then another, usually in a different limb. There is generally no antecedent illness, and pain is infrequent.⁸ Progressive limb weakness is by far the most common presentation, and manifests as a foot drop or wrist drop. Patients may report difficulty getting up from a chair, walking up stairs, or opening jars.⁸ Facial or extraocular nerve involvement is uncommon, as is respiratory involvement.⁸ Neurologic exam shows absent reflexes, weakness, and loss of sensation in the distribution of a particular nerve or nerves.

Testing and treatment. Diagnosis of CIDP is made by a combination of EDX that shows demyelination and lumbar puncture that demonstrates albuminocytologic dissociation. Treatments include long-term immunosuppression with oral prednisone, IVIg, plasmapheresis, and rarely, agents such as mycophenolate mofetil, azathioprine, cyclosporine, and rituximab.⁹

Entrapment neuropathy

This is the result of compression or entrapment of a nerve by another anatomic structure. It can be caused by internal or external factors, including fluid retention.¹¹ Damage from compression or entrapment progresses in stages and, over time, can result in demyelination and distal degeneration of the nerve.¹¹ More interior nerve fibers, such as pain nerve fibers, are often the last to be affected.¹¹ Therefore, patients often first experience loss of motor function or loss of sensation to light touch.

Common fibular nerve (formerly known as common peroneal nerve) entrapment at the fibular head is the most common entrapment neuropathy in the lower extremities. It’s usually the result of direct trauma, such as prolonged positioning in debilitated patients or surgical patients, habitual leg-crossing, tight boots, or tight casts.^11,12 Uncoordinated gait due to poor dorsiflexion of the foot at the ankle (foot drop) is common while plantar flexion is preserved. Pain and sensory loss depend on the degree of compression and the exact location of compression.

Testing and treatment. EDX is useful for identifying the location of compression or entrapment and can guide further imaging, if needed. Conservative treatments aimed at modifying or correcting the underlying etiology, such as removing a tight-fitting cast or brace or instructing a patient to stop leg crossing, can be effective. Occasionally, surgery is required.

Anterior tarsal tunnel syndrome is compression of the deep fibular nerve as it passes through the inferior extensor retinaculum of the distal lower leg. Characteristic symptoms include pain and burning over the dorsum of the foot.¹¹ Paresthesias in the first dorsal web space are also common.¹¹ This can be seen in athletes who perform repetitive ankle plantar flexion, such as ballet dancers, soccer players, and runners.¹² It can also be caused by recurrent ankle sprains, ganglion cysts, and tight-fitting shoes or boots.^11,12 Chronic cases can result in toe extensor weakness or atrophy of the extensor digitorum brevis muscle.

Testing and treatment. Again, EDX is very useful in identifying the exact area of compression and involved nerve segments. Management requires correcting the underlying etiology, which can usually be done conservatively. Surgical decompression may be needed.

Suspect a paraneoplastic process if a patient presents with subacute progressive onset of neuropathic symptoms in the upper extremities.

Paraneoplastic neuropathies

Paraneoplastic neuropathies are exceptionally rare but often develop before cancer is diagnosed. Therefore, early suspicion and recognition can greatly affect cancer prognosis.¹³ Certain characteristics should increase suspicion of a paraneoplastic process. For example, symptoms with a subacute progressive onset that involve the upper extremities early in the disease are characteristic of a paraneoplastic process.¹³

Coexisting CNS symptoms and/or constitutional symptoms of malignancy should also increase suspicion.¹³ Consider a paraneo­plastic process in patients who have a past history of cancer or significant cancer risk factors, such as smoking.

Testing. When you suspect a paraneoplastic process, the work-up should include antibody testing for the most common or likely cancers according to patient characteristics. Panels of the most common paraneoplastic antibodies are available from many commercial labs. Obtain imaging to identify a possible underlying malignancy.

That said, it’s also important to perform a basic work-up for the more common causes of neuropathy in patients you suspect may have cancer. The reason: Paraneoplastic neuropathies are rare, and not all neuropathies in patients with cancer are paraneoplastic.¹³

CASE 1 › Ms. G describes diffuse paresthesias that are worse in her lower extremities, but she has a normal neurologic exam. Her physician suspects a neuropathic cause, and a normal exam makes small fiber neuropathy more likely. EDX is normal. The initial work-up includes an HbA1c, thyroid-stimulating hormone, vitamin B12 level, antinuclear antibody, erythrocyte sedimentation rate, IFE, and free light chain assay.

Testing reveals that Ms. G has a high free light chain ratio, which suggests a monoclonal gammopathy is the most likely etiology. Skin biopsy demonstrates decreased nerve fiber density consistent with a small fiber neuropathy. Her physician refers her to Hematology for bone marrow biopsy, and also prescribes gabapentin 300 mg/d at bedtime for symptomatic relief. Ms. G is currently being closely monitored for conversion to multiple myeloma.

CASE 2 › In Ms. T’s case, the exam helps localize the lesion. Areas supplied by the common fibular nerve, tibial nerve, and sural nerve are affected, while the area innervated by the femoral nerve and saphenous nerve and the proximal hip muscles are spared. This localizes a lesion to the sciatic nerve. EDX confirms a proximal sciatic lesion, but not the underlying etiology. Since the lesion had been precisely localized, her physician orders imaging.

Magnetic resonance imaging of Ms. T’s hip and upper leg shows a 10.7 cm x 7.8 cm x 13 cm heterogeneously enhancing mass in the expected location of the right sciatic nerve (FIGURE). Biopsy reveals a high grade, poorly differentiated synovial sarcoma. Her physician refers her to an oncologist for initiation of chemotherapy, radiation, and debulking surgery.

CORRESPONDENCE
Laura C. Mayans, MD, Department of Family and Community Medicine, University of Kansas School of Medicine-Wichita, 1010 N. Kansas, Wichita, KS 67214; [email protected].

CASE 1 › Sally G, age 46, has been experiencing paresthesias for the past 3 months. She says that when she is cycling, the air on her legs feels much cooler than normal, with a similar feeling in her hands. Whenever her hands or legs are in cool water, she says it feels as if she’s dipped them into an ice bucket. Summer heat makes her skin feel as if it's on fire, and she’s noticed increased sweating on her lower legs. She complains of itching (although she has no rash) and she’s had intermittent tingling and burning in her toes. On neurologic exam, she demonstrates normal strength, sensation, reflexes, coordination, and cranial nerve function.

Case 2 › Jessica T, age 25, comes in to see her family physician because she’s been experiencing numbness in her right leg. It had begun with numbness of the right great toe about a year ago. Subsequently, the numbness extended up her foot to the lateral aspect of the lower leg with an accompanying burning sensation. Three months prior to this visit, she developed weakness in her right foot and toes. She denies any symptoms in her left leg, upper extremities, or face.

A neurologic exam of the upper extremities is normal. Ms. T also has normal cranial nerve function, and normal strength, sensation, and reflexes in the left leg. A motor exam of the right leg reveals normal strength in the hip flexors, hip adductors, hip abductors, and quadriceps. On the Medical Research Council scale, she has 4/5 strength in the hamstrings, 0/5 in the ankle dorsiflexors, 1/5 in the posterior tibialis, and 3/5 in the gastrocnemius. She has a normal right patellar reflex, and an ankle jerk reflex and Babinski sign are absent. She has reduced sensation on the posterior and lateral portions of the right leg and the entire foot. Sensation is preserved on the medial side of the right lower leg and anterior thigh. She has right-sided steppage gait.

Look for positive neuropathic symptoms such as cramping and tingling, negative symptoms such as numbness and weakness, and autonomic symptoms such as constipation, diarrhea, and sweating.

If these 2 women were your patients, how would you proceed with their care?

Paresthesias such as numbness and tingling in the lower extremities are common complaints in family medicine. These symptoms can be challenging to evaluate because they have multiple potential etiologies with varied clinical presentations.¹

A well-honed understanding of lower extremity anatomy and the location and characteristics of common complaints is essential to making an accurate diagnosis and treatment plan. This article discusses the tests to use when evaluating a patient who presents with lower extremity numbness and pain. It also describes the typical presentation and findings of several types of peripheral neuropathy, and how to manage them.

Parasthesias are often the result of peripheral neuropathy

While paresthesias can arise from disorders of the central or peripheral nervous system, this article focuses on paresthesias that are the result of peripheral neuropathy. Peripheral neuropathy can be classified as mononeuropathy, multiple mononeuropathy, or polyneuropathy:

• Mononeuropathy is focal involvement of a single nerve resulting from a localized process such as compression or entrapment, as in carpal tunnel syndrome.¹
• Multiple mononeuropathy (mononeuritis multiplex) results from damage to multiple noncontiguous nerves that can occur simultaneously or sequentially, as in vasculitic causes of neuropathy.¹
• Polyneuropathy involves 2 or more contiguous nerves, usually symmetric and length-dependent, creating a “stocking-glove” pattern of paresthesias.¹ Polyneuropathy affects longer nerves first, and thus, patients will initially complain of symptoms in their feet and legs, and later their hands. Polyneuropathy is most commonly seen in diabetes.

Possible causes of peripheral neuropathy include numerous anatomic, systemic, metabolic, and toxic conditions (TABLE 1).^1,2

What's causing the neuropathy? The search for telltale clues

While obtaining the history, ask the patient about the presence of positive, negative, or autonomic neuropathic symptoms. Positive symptoms, which usually present first, are due to excess or inappropriate nerve activity and include cramping, twitching, burning, and tingling.³ Negative symptoms are due to reduced nerve activity and include numbness, weakness, decreased balance, and poor sensation. Autonomic symptoms include early satiety, constipation or diarrhea, impotence, sweating abnormalities, and orthostasis.³ The timing of onset, progression, and duration of such symptoms can give important diagnostic clues. For example, an acute onset of painful foot drop may indicate an inflammatory cause such as vasculitis, whereas slowly progressive numbness in both feet points toward a distal sensorimotor polyneuropathy, likely from a metabolic cause. Symmetry or asymmetry at presentation, as well as speed of progression of symptoms, can also significantly narrow the differential (TABLE 2).

Determining the exact location of symptoms is important and usually requires prompting. For example, when a patient refers to “the legs,” he could mean anywhere from the foot to the hip. The presence of radiating pain can also help localize the lesion, generally pointing to a radiculopathy (disease at the root of a nerve). Bowel or bladder involvement could suggest involvement of the spinal cord or autonomic nervous system.

A thorough social history can help identify potentially treatable causes of neuropathy. The probability of a toxic, infectious, or vitamin deficiency etiology can be ascertained by inquiring about a patient’s occupation, sexual history, dietary habits, and drug, alcohol, and tobacco history.³ Personal and family medical history can suggest possible genetic or endocrine causes of neuropathy. A personal or family history of childhood “clumsiness” (suggestive of a hereditary neuropathy, such as Charcot-Marie-Tooth disease), diabetes mellitus, or thyroid, renal, hepatic, or autoimmune diseases would be significant. A personal or family history of cancer is also an important diagnostic clue.³

These tests help narrow the diagnostic possibilities

An acute onset of painful foot drop may indicate an inflammatory cause of neuropathic symptoms, such as vasculitis.

Motor and sensory testing are essential, as is testing of coordination and reflexes. Motor examination involves manual muscle testing. In many patients, pain can limit effort, so encourage patients to try hard during testing so you can determine the true severity of weakness. Sensory testing should include pinprick, temperature differentiation, vibration, and proprioception. Also examine the cranial nerves and upper extremities because abnormal findings could suggest a central nervous system (CNS) lesion or proximal progression of disease, with the patient unaware of subtle symptom worsening or spreading. The pattern of deficits as well as predominance of motor vs sensory nerve involvement can further narrow the differential. For example, unilateral symptoms typically suggest either a structural lesion or inflammatory lesion as the cause, while unilateral weakness without numbness could be significant for the onset of amyotrophic lateral sclerosis.¹ A careful skin, hair, and mucous membrane exam is useful because many infectious, toxic, autoimmune, and genetic causes of peripheral neuropathy also cause changes in these areas. High arches, hammer toes, and inverted champagne bottle legs suggest a hereditary neuropathy.³

In addition to the history and examination, electrodiagnostic testing (EDX) is often helpful, and judicious laboratory testing can further narrow diagnostic possibilities. (See “How best to use EDX and lab testing to evaluate peripheral neuropathy”.^1-3)

So what type of neuropathy are you dealing with?

The details of your patient’s history and findings from the exam and testing will point you toward any one of a number of different types of neuropathies. The list below covers a range—from the common (distal sensorimotor polyneuropathy) to the more rare (paraneoplastic neuropathies).

Distal sensorimotor polyneuropathy (DSP)

DSP is the most common type of neuropathy.⁴ The typical presentation of DSP is chronic, distal, symmetric, and predominantly sensory.⁵ Any variation on this suggests an atypical neuropathy.⁵ Patients with DSP present with loss of function (loss of sensation to pinprick, temperature, vibration, proprioception) and/or tingling, burning, and pain starting symmetrically in the lower extremities. Over the course of years, paresthesias move up the legs to the knees before symptoms begin in the arms.

While the disorder can be quite painful, it is not usually functionally limiting unless the loss of sensation is severe enough to cause falls from sensory ataxia. Weakness is rare. When it occurs, it is usually a mild weakness of the distal leg with foot atrophy.

The most common cause of DSP is diabetes or impaired glucose tolerance. Other common causes are vitamin deficiencies (vitamin B1, B6, B12), folate deficiency, paraproteinemia, and hypo/hyperthyroidism. Also consider alcohol abuse, human immunodeficiency virus (HIV) infection, gastric bypass, chemotherapy, chronic kidney disease, and autoimmune conditions such as Sjögren’s syndrome, lupus, and rheumatoid arthritis.¹

Testing. EDX can help confirm a diagnosis of DSP. A 2009 American Academy of Neurology review of lab testing for DSP found the tests with the highest diagnostic yield were fasting blood glucose, vitamin B12 level with methylmalonic acid, and serum protein electrophoresis and immunofixation electrophoresis (IFE).⁴ If the initial screen with a fasting blood sugar or hemoglobin A1c (HbA1c) is negative, further testing with a glucose tolerance test is recommended.

Treatment of DSP depends on the underlying etiology. Vitamin deficiencies should be corrected and metabolic or autoimmune etiologies addressed as appropriate. There are multiple pharmacologic options for treating persistent pain or discomfort. Best evidence (Level A) exists for pregabalin.⁶ Moderate evidence of effectiveness (Level B) exists for gabapentin, sodium valproate, amitriptyline, venlafaxine, and duloxetine.⁶

Small fiber neuropathy

Small fiber neuropathy can present similarly to DSP, with distal painful paresthesias, but can spread to the upper extremities within a few weeks or months from onset, while DSP spreads to the hands years after onset. Small fiber neuropathy is also associated with early autonomic dysfunction. Examination usually reveals decreased sensation distally, but reflexes and strength are normal.

Common causes of small fiber neuropathy are diabetes, glucose intolerance, metabolic syndrome, hypo/hyperthyroidism, monoclonal gammopathy, alcohol abuse, vitamin B12 deficiency, and hypertriglyceridemia.⁷ Less common causes include Sjögren’s syndrome, HIV, Lyme disease, sarcoidosis, heavy metal toxicity, amyloidosis, and celiac disease.⁷

Testing and treatment. Skin biopsy is used to confirm the diagnosis of small fiber neuropathy.⁷ (EDX results are normal.⁷) Persistent pain can be treated with the same agents discussed above for treating DSP.

Acquired demyelinating neuropathy

Acquired demyelinating neuropathy is a rare condition, but one in which prompt recognition and treatment can prevent significant neurologic decline. There are both acute and chronic types of acquired demyelinating neuropathies.

Guillain-Barré syndrome (GBS) is an acute inflammatory demyelinating polyradiculoneuropathy. Nearly two-thirds of patients with GBS report a previous respiratory or gastrointestinal illness; cytomegalovirus and Campylobacter jejuni are the most frequently associated infections.⁸

Small fiber neuropathy can look like distal sensorimotor polyneuropathy, but can spread to the upper extremities quicker and can cause autonomic dysfunction.

The onset of GBS often involves pain in the back or limbs, followed by a rapid progression of sensory loss and weakness (over days to a few weeks) that typically starts in the feet and moves upward.⁸ Though the typical presentation of GBS is “ascending,” there are frequent exceptions to this pattern.⁸ Physical exam shows weakness, sensory loss, and absent reflexes. Severe cases can result in complete paralysis, even of extraocular movements. Autonomic dysfunction is common.

Testing. EDX and lumbar puncture are needed to accurately diagnose GBS.⁸ EDX initially may be unremarkable, but over time, areas of demyelination become apparent. Lumbar puncture shows albuminocytologic dissociation (no white cells, elevated protein).

Treatment. Patients with GBS are initially managed as inpatients because 33% of cases lead to respiratory failure.⁹ Treatments include intravenous immunoglobulin (IVIg) or plasmapheresis; both have similar outcomes, speeding neurologic recovery time but not affecting overall long-term prognosis.¹⁰ Response to treatment is often not immediate, and some patients continue to worsen after treatment.⁸ Still, long-term prognosis is good, even for severely affected patients, as long as they receive good supportive care. The relapse rate is between 2% and 6%.⁸

In chronic inflammatory demyelinating polyneuropathy (CIDP), patients develop stepwise nerve dysfunction over many weeks to months. One nerve is affected, then another, usually in a different limb. There is generally no antecedent illness, and pain is infrequent.⁸ Progressive limb weakness is by far the most common presentation, and manifests as a foot drop or wrist drop. Patients may report difficulty getting up from a chair, walking up stairs, or opening jars.⁸ Facial or extraocular nerve involvement is uncommon, as is respiratory involvement.⁸ Neurologic exam shows absent reflexes, weakness, and loss of sensation in the distribution of a particular nerve or nerves.

Testing and treatment. Diagnosis of CIDP is made by a combination of EDX that shows demyelination and lumbar puncture that demonstrates albuminocytologic dissociation. Treatments include long-term immunosuppression with oral prednisone, IVIg, plasmapheresis, and rarely, agents such as mycophenolate mofetil, azathioprine, cyclosporine, and rituximab.⁹

Entrapment neuropathy

This is the result of compression or entrapment of a nerve by another anatomic structure. It can be caused by internal or external factors, including fluid retention.¹¹ Damage from compression or entrapment progresses in stages and, over time, can result in demyelination and distal degeneration of the nerve.¹¹ More interior nerve fibers, such as pain nerve fibers, are often the last to be affected.¹¹ Therefore, patients often first experience loss of motor function or loss of sensation to light touch.

Common fibular nerve (formerly known as common peroneal nerve) entrapment at the fibular head is the most common entrapment neuropathy in the lower extremities. It’s usually the result of direct trauma, such as prolonged positioning in debilitated patients or surgical patients, habitual leg-crossing, tight boots, or tight casts.^11,12 Uncoordinated gait due to poor dorsiflexion of the foot at the ankle (foot drop) is common while plantar flexion is preserved. Pain and sensory loss depend on the degree of compression and the exact location of compression.

Testing and treatment. EDX is useful for identifying the location of compression or entrapment and can guide further imaging, if needed. Conservative treatments aimed at modifying or correcting the underlying etiology, such as removing a tight-fitting cast or brace or instructing a patient to stop leg crossing, can be effective. Occasionally, surgery is required.

Anterior tarsal tunnel syndrome is compression of the deep fibular nerve as it passes through the inferior extensor retinaculum of the distal lower leg. Characteristic symptoms include pain and burning over the dorsum of the foot.¹¹ Paresthesias in the first dorsal web space are also common.¹¹ This can be seen in athletes who perform repetitive ankle plantar flexion, such as ballet dancers, soccer players, and runners.¹² It can also be caused by recurrent ankle sprains, ganglion cysts, and tight-fitting shoes or boots.^11,12 Chronic cases can result in toe extensor weakness or atrophy of the extensor digitorum brevis muscle.

Testing and treatment. Again, EDX is very useful in identifying the exact area of compression and involved nerve segments. Management requires correcting the underlying etiology, which can usually be done conservatively. Surgical decompression may be needed.

Suspect a paraneoplastic process if a patient presents with subacute progressive onset of neuropathic symptoms in the upper extremities.

Paraneoplastic neuropathies

Paraneoplastic neuropathies are exceptionally rare but often develop before cancer is diagnosed. Therefore, early suspicion and recognition can greatly affect cancer prognosis.¹³ Certain characteristics should increase suspicion of a paraneoplastic process. For example, symptoms with a subacute progressive onset that involve the upper extremities early in the disease are characteristic of a paraneoplastic process.¹³

Coexisting CNS symptoms and/or constitutional symptoms of malignancy should also increase suspicion.¹³ Consider a paraneo­plastic process in patients who have a past history of cancer or significant cancer risk factors, such as smoking.

Testing. When you suspect a paraneoplastic process, the work-up should include antibody testing for the most common or likely cancers according to patient characteristics. Panels of the most common paraneoplastic antibodies are available from many commercial labs. Obtain imaging to identify a possible underlying malignancy.

That said, it’s also important to perform a basic work-up for the more common causes of neuropathy in patients you suspect may have cancer. The reason: Paraneoplastic neuropathies are rare, and not all neuropathies in patients with cancer are paraneoplastic.¹³

CASE 1 › Ms. G describes diffuse paresthesias that are worse in her lower extremities, but she has a normal neurologic exam. Her physician suspects a neuropathic cause, and a normal exam makes small fiber neuropathy more likely. EDX is normal. The initial work-up includes an HbA1c, thyroid-stimulating hormone, vitamin B12 level, antinuclear antibody, erythrocyte sedimentation rate, IFE, and free light chain assay.

Testing reveals that Ms. G has a high free light chain ratio, which suggests a monoclonal gammopathy is the most likely etiology. Skin biopsy demonstrates decreased nerve fiber density consistent with a small fiber neuropathy. Her physician refers her to Hematology for bone marrow biopsy, and also prescribes gabapentin 300 mg/d at bedtime for symptomatic relief. Ms. G is currently being closely monitored for conversion to multiple myeloma.

CASE 2 › In Ms. T’s case, the exam helps localize the lesion. Areas supplied by the common fibular nerve, tibial nerve, and sural nerve are affected, while the area innervated by the femoral nerve and saphenous nerve and the proximal hip muscles are spared. This localizes a lesion to the sciatic nerve. EDX confirms a proximal sciatic lesion, but not the underlying etiology. Since the lesion had been precisely localized, her physician orders imaging.

Magnetic resonance imaging of Ms. T’s hip and upper leg shows a 10.7 cm x 7.8 cm x 13 cm heterogeneously enhancing mass in the expected location of the right sciatic nerve (FIGURE). Biopsy reveals a high grade, poorly differentiated synovial sarcoma. Her physician refers her to an oncologist for initiation of chemotherapy, radiation, and debulking surgery.

CORRESPONDENCE
Laura C. Mayans, MD, Department of Family and Community Medicine, University of Kansas School of Medicine-Wichita, 1010 N. Kansas, Wichita, KS 67214; [email protected].

CASE 1 › Sally G, age 46, has been experiencing paresthesias for the past 3 months. She says that when she is cycling, the air on her legs feels much cooler than normal, with a similar feeling in her hands. Whenever her hands or legs are in cool water, she says it feels as if she’s dipped them into an ice bucket. Summer heat makes her skin feel as if it's on fire, and she’s noticed increased sweating on her lower legs. She complains of itching (although she has no rash) and she’s had intermittent tingling and burning in her toes. On neurologic exam, she demonstrates normal strength, sensation, reflexes, coordination, and cranial nerve function.

Case 2 › Jessica T, age 25, comes in to see her family physician because she’s been experiencing numbness in her right leg. It had begun with numbness of the right great toe about a year ago. Subsequently, the numbness extended up her foot to the lateral aspect of the lower leg with an accompanying burning sensation. Three months prior to this visit, she developed weakness in her right foot and toes. She denies any symptoms in her left leg, upper extremities, or face.

A neurologic exam of the upper extremities is normal. Ms. T also has normal cranial nerve function, and normal strength, sensation, and reflexes in the left leg. A motor exam of the right leg reveals normal strength in the hip flexors, hip adductors, hip abductors, and quadriceps. On the Medical Research Council scale, she has 4/5 strength in the hamstrings, 0/5 in the ankle dorsiflexors, 1/5 in the posterior tibialis, and 3/5 in the gastrocnemius. She has a normal right patellar reflex, and an ankle jerk reflex and Babinski sign are absent. She has reduced sensation on the posterior and lateral portions of the right leg and the entire foot. Sensation is preserved on the medial side of the right lower leg and anterior thigh. She has right-sided steppage gait.

Look for positive neuropathic symptoms such as cramping and tingling, negative symptoms such as numbness and weakness, and autonomic symptoms such as constipation, diarrhea, and sweating.

If these 2 women were your patients, how would you proceed with their care?

Paresthesias such as numbness and tingling in the lower extremities are common complaints in family medicine. These symptoms can be challenging to evaluate because they have multiple potential etiologies with varied clinical presentations.¹

A well-honed understanding of lower extremity anatomy and the location and characteristics of common complaints is essential to making an accurate diagnosis and treatment plan. This article discusses the tests to use when evaluating a patient who presents with lower extremity numbness and pain. It also describes the typical presentation and findings of several types of peripheral neuropathy, and how to manage them.

Parasthesias are often the result of peripheral neuropathy

While paresthesias can arise from disorders of the central or peripheral nervous system, this article focuses on paresthesias that are the result of peripheral neuropathy. Peripheral neuropathy can be classified as mononeuropathy, multiple mononeuropathy, or polyneuropathy:

• Mononeuropathy is focal involvement of a single nerve resulting from a localized process such as compression or entrapment, as in carpal tunnel syndrome.¹
• Multiple mononeuropathy (mononeuritis multiplex) results from damage to multiple noncontiguous nerves that can occur simultaneously or sequentially, as in vasculitic causes of neuropathy.¹
• Polyneuropathy involves 2 or more contiguous nerves, usually symmetric and length-dependent, creating a “stocking-glove” pattern of paresthesias.¹ Polyneuropathy affects longer nerves first, and thus, patients will initially complain of symptoms in their feet and legs, and later their hands. Polyneuropathy is most commonly seen in diabetes.

Possible causes of peripheral neuropathy include numerous anatomic, systemic, metabolic, and toxic conditions (TABLE 1).^1,2

What's causing the neuropathy? The search for telltale clues

While obtaining the history, ask the patient about the presence of positive, negative, or autonomic neuropathic symptoms. Positive symptoms, which usually present first, are due to excess or inappropriate nerve activity and include cramping, twitching, burning, and tingling.³ Negative symptoms are due to reduced nerve activity and include numbness, weakness, decreased balance, and poor sensation. Autonomic symptoms include early satiety, constipation or diarrhea, impotence, sweating abnormalities, and orthostasis.³ The timing of onset, progression, and duration of such symptoms can give important diagnostic clues. For example, an acute onset of painful foot drop may indicate an inflammatory cause such as vasculitis, whereas slowly progressive numbness in both feet points toward a distal sensorimotor polyneuropathy, likely from a metabolic cause. Symmetry or asymmetry at presentation, as well as speed of progression of symptoms, can also significantly narrow the differential (TABLE 2).

Determining the exact location of symptoms is important and usually requires prompting. For example, when a patient refers to “the legs,” he could mean anywhere from the foot to the hip. The presence of radiating pain can also help localize the lesion, generally pointing to a radiculopathy (disease at the root of a nerve). Bowel or bladder involvement could suggest involvement of the spinal cord or autonomic nervous system.

A thorough social history can help identify potentially treatable causes of neuropathy. The probability of a toxic, infectious, or vitamin deficiency etiology can be ascertained by inquiring about a patient’s occupation, sexual history, dietary habits, and drug, alcohol, and tobacco history.³ Personal and family medical history can suggest possible genetic or endocrine causes of neuropathy. A personal or family history of childhood “clumsiness” (suggestive of a hereditary neuropathy, such as Charcot-Marie-Tooth disease), diabetes mellitus, or thyroid, renal, hepatic, or autoimmune diseases would be significant. A personal or family history of cancer is also an important diagnostic clue.³

These tests help narrow the diagnostic possibilities

An acute onset of painful foot drop may indicate an inflammatory cause of neuropathic symptoms, such as vasculitis.

Motor and sensory testing are essential, as is testing of coordination and reflexes. Motor examination involves manual muscle testing. In many patients, pain can limit effort, so encourage patients to try hard during testing so you can determine the true severity of weakness. Sensory testing should include pinprick, temperature differentiation, vibration, and proprioception. Also examine the cranial nerves and upper extremities because abnormal findings could suggest a central nervous system (CNS) lesion or proximal progression of disease, with the patient unaware of subtle symptom worsening or spreading. The pattern of deficits as well as predominance of motor vs sensory nerve involvement can further narrow the differential. For example, unilateral symptoms typically suggest either a structural lesion or inflammatory lesion as the cause, while unilateral weakness without numbness could be significant for the onset of amyotrophic lateral sclerosis.¹ A careful skin, hair, and mucous membrane exam is useful because many infectious, toxic, autoimmune, and genetic causes of peripheral neuropathy also cause changes in these areas. High arches, hammer toes, and inverted champagne bottle legs suggest a hereditary neuropathy.³

In addition to the history and examination, electrodiagnostic testing (EDX) is often helpful, and judicious laboratory testing can further narrow diagnostic possibilities. (See “How best to use EDX and lab testing to evaluate peripheral neuropathy”.^1-3)

So what type of neuropathy are you dealing with?

The details of your patient’s history and findings from the exam and testing will point you toward any one of a number of different types of neuropathies. The list below covers a range—from the common (distal sensorimotor polyneuropathy) to the more rare (paraneoplastic neuropathies).

Distal sensorimotor polyneuropathy (DSP)

DSP is the most common type of neuropathy.⁴ The typical presentation of DSP is chronic, distal, symmetric, and predominantly sensory.⁵ Any variation on this suggests an atypical neuropathy.⁵ Patients with DSP present with loss of function (loss of sensation to pinprick, temperature, vibration, proprioception) and/or tingling, burning, and pain starting symmetrically in the lower extremities. Over the course of years, paresthesias move up the legs to the knees before symptoms begin in the arms.

While the disorder can be quite painful, it is not usually functionally limiting unless the loss of sensation is severe enough to cause falls from sensory ataxia. Weakness is rare. When it occurs, it is usually a mild weakness of the distal leg with foot atrophy.

The most common cause of DSP is diabetes or impaired glucose tolerance. Other common causes are vitamin deficiencies (vitamin B1, B6, B12), folate deficiency, paraproteinemia, and hypo/hyperthyroidism. Also consider alcohol abuse, human immunodeficiency virus (HIV) infection, gastric bypass, chemotherapy, chronic kidney disease, and autoimmune conditions such as Sjögren’s syndrome, lupus, and rheumatoid arthritis.¹

Testing. EDX can help confirm a diagnosis of DSP. A 2009 American Academy of Neurology review of lab testing for DSP found the tests with the highest diagnostic yield were fasting blood glucose, vitamin B12 level with methylmalonic acid, and serum protein electrophoresis and immunofixation electrophoresis (IFE).⁴ If the initial screen with a fasting blood sugar or hemoglobin A1c (HbA1c) is negative, further testing with a glucose tolerance test is recommended.

Treatment of DSP depends on the underlying etiology. Vitamin deficiencies should be corrected and metabolic or autoimmune etiologies addressed as appropriate. There are multiple pharmacologic options for treating persistent pain or discomfort. Best evidence (Level A) exists for pregabalin.⁶ Moderate evidence of effectiveness (Level B) exists for gabapentin, sodium valproate, amitriptyline, venlafaxine, and duloxetine.⁶

Small fiber neuropathy

Small fiber neuropathy can present similarly to DSP, with distal painful paresthesias, but can spread to the upper extremities within a few weeks or months from onset, while DSP spreads to the hands years after onset. Small fiber neuropathy is also associated with early autonomic dysfunction. Examination usually reveals decreased sensation distally, but reflexes and strength are normal.

Common causes of small fiber neuropathy are diabetes, glucose intolerance, metabolic syndrome, hypo/hyperthyroidism, monoclonal gammopathy, alcohol abuse, vitamin B12 deficiency, and hypertriglyceridemia.⁷ Less common causes include Sjögren’s syndrome, HIV, Lyme disease, sarcoidosis, heavy metal toxicity, amyloidosis, and celiac disease.⁷

Testing and treatment. Skin biopsy is used to confirm the diagnosis of small fiber neuropathy.⁷ (EDX results are normal.⁷) Persistent pain can be treated with the same agents discussed above for treating DSP.

Acquired demyelinating neuropathy

Acquired demyelinating neuropathy is a rare condition, but one in which prompt recognition and treatment can prevent significant neurologic decline. There are both acute and chronic types of acquired demyelinating neuropathies.

Guillain-Barré syndrome (GBS) is an acute inflammatory demyelinating polyradiculoneuropathy. Nearly two-thirds of patients with GBS report a previous respiratory or gastrointestinal illness; cytomegalovirus and Campylobacter jejuni are the most frequently associated infections.⁸

Small fiber neuropathy can look like distal sensorimotor polyneuropathy, but can spread to the upper extremities quicker and can cause autonomic dysfunction.

The onset of GBS often involves pain in the back or limbs, followed by a rapid progression of sensory loss and weakness (over days to a few weeks) that typically starts in the feet and moves upward.⁸ Though the typical presentation of GBS is “ascending,” there are frequent exceptions to this pattern.⁸ Physical exam shows weakness, sensory loss, and absent reflexes. Severe cases can result in complete paralysis, even of extraocular movements. Autonomic dysfunction is common.

Testing. EDX and lumbar puncture are needed to accurately diagnose GBS.⁸ EDX initially may be unremarkable, but over time, areas of demyelination become apparent. Lumbar puncture shows albuminocytologic dissociation (no white cells, elevated protein).

Treatment. Patients with GBS are initially managed as inpatients because 33% of cases lead to respiratory failure.⁹ Treatments include intravenous immunoglobulin (IVIg) or plasmapheresis; both have similar outcomes, speeding neurologic recovery time but not affecting overall long-term prognosis.¹⁰ Response to treatment is often not immediate, and some patients continue to worsen after treatment.⁸ Still, long-term prognosis is good, even for severely affected patients, as long as they receive good supportive care. The relapse rate is between 2% and 6%.⁸

In chronic inflammatory demyelinating polyneuropathy (CIDP), patients develop stepwise nerve dysfunction over many weeks to months. One nerve is affected, then another, usually in a different limb. There is generally no antecedent illness, and pain is infrequent.⁸ Progressive limb weakness is by far the most common presentation, and manifests as a foot drop or wrist drop. Patients may report difficulty getting up from a chair, walking up stairs, or opening jars.⁸ Facial or extraocular nerve involvement is uncommon, as is respiratory involvement.⁸ Neurologic exam shows absent reflexes, weakness, and loss of sensation in the distribution of a particular nerve or nerves.

Testing and treatment. Diagnosis of CIDP is made by a combination of EDX that shows demyelination and lumbar puncture that demonstrates albuminocytologic dissociation. Treatments include long-term immunosuppression with oral prednisone, IVIg, plasmapheresis, and rarely, agents such as mycophenolate mofetil, azathioprine, cyclosporine, and rituximab.⁹

Entrapment neuropathy

This is the result of compression or entrapment of a nerve by another anatomic structure. It can be caused by internal or external factors, including fluid retention.¹¹ Damage from compression or entrapment progresses in stages and, over time, can result in demyelination and distal degeneration of the nerve.¹¹ More interior nerve fibers, such as pain nerve fibers, are often the last to be affected.¹¹ Therefore, patients often first experience loss of motor function or loss of sensation to light touch.

Common fibular nerve (formerly known as common peroneal nerve) entrapment at the fibular head is the most common entrapment neuropathy in the lower extremities. It’s usually the result of direct trauma, such as prolonged positioning in debilitated patients or surgical patients, habitual leg-crossing, tight boots, or tight casts.^11,12 Uncoordinated gait due to poor dorsiflexion of the foot at the ankle (foot drop) is common while plantar flexion is preserved. Pain and sensory loss depend on the degree of compression and the exact location of compression.

Testing and treatment. EDX is useful for identifying the location of compression or entrapment and can guide further imaging, if needed. Conservative treatments aimed at modifying or correcting the underlying etiology, such as removing a tight-fitting cast or brace or instructing a patient to stop leg crossing, can be effective. Occasionally, surgery is required.

Anterior tarsal tunnel syndrome is compression of the deep fibular nerve as it passes through the inferior extensor retinaculum of the distal lower leg. Characteristic symptoms include pain and burning over the dorsum of the foot.¹¹ Paresthesias in the first dorsal web space are also common.¹¹ This can be seen in athletes who perform repetitive ankle plantar flexion, such as ballet dancers, soccer players, and runners.¹² It can also be caused by recurrent ankle sprains, ganglion cysts, and tight-fitting shoes or boots.^11,12 Chronic cases can result in toe extensor weakness or atrophy of the extensor digitorum brevis muscle.

Testing and treatment. Again, EDX is very useful in identifying the exact area of compression and involved nerve segments. Management requires correcting the underlying etiology, which can usually be done conservatively. Surgical decompression may be needed.

Suspect a paraneoplastic process if a patient presents with subacute progressive onset of neuropathic symptoms in the upper extremities.

Paraneoplastic neuropathies

Paraneoplastic neuropathies are exceptionally rare but often develop before cancer is diagnosed. Therefore, early suspicion and recognition can greatly affect cancer prognosis.¹³ Certain characteristics should increase suspicion of a paraneoplastic process. For example, symptoms with a subacute progressive onset that involve the upper extremities early in the disease are characteristic of a paraneoplastic process.¹³

Coexisting CNS symptoms and/or constitutional symptoms of malignancy should also increase suspicion.¹³ Consider a paraneo­plastic process in patients who have a past history of cancer or significant cancer risk factors, such as smoking.

Testing. When you suspect a paraneoplastic process, the work-up should include antibody testing for the most common or likely cancers according to patient characteristics. Panels of the most common paraneoplastic antibodies are available from many commercial labs. Obtain imaging to identify a possible underlying malignancy.

That said, it’s also important to perform a basic work-up for the more common causes of neuropathy in patients you suspect may have cancer. The reason: Paraneoplastic neuropathies are rare, and not all neuropathies in patients with cancer are paraneoplastic.¹³

CASE 1 › Ms. G describes diffuse paresthesias that are worse in her lower extremities, but she has a normal neurologic exam. Her physician suspects a neuropathic cause, and a normal exam makes small fiber neuropathy more likely. EDX is normal. The initial work-up includes an HbA1c, thyroid-stimulating hormone, vitamin B12 level, antinuclear antibody, erythrocyte sedimentation rate, IFE, and free light chain assay.

Testing reveals that Ms. G has a high free light chain ratio, which suggests a monoclonal gammopathy is the most likely etiology. Skin biopsy demonstrates decreased nerve fiber density consistent with a small fiber neuropathy. Her physician refers her to Hematology for bone marrow biopsy, and also prescribes gabapentin 300 mg/d at bedtime for symptomatic relief. Ms. G is currently being closely monitored for conversion to multiple myeloma.

CASE 2 › In Ms. T’s case, the exam helps localize the lesion. Areas supplied by the common fibular nerve, tibial nerve, and sural nerve are affected, while the area innervated by the femoral nerve and saphenous nerve and the proximal hip muscles are spared. This localizes a lesion to the sciatic nerve. EDX confirms a proximal sciatic lesion, but not the underlying etiology. Since the lesion had been precisely localized, her physician orders imaging.

Magnetic resonance imaging of Ms. T’s hip and upper leg shows a 10.7 cm x 7.8 cm x 13 cm heterogeneously enhancing mass in the expected location of the right sciatic nerve (FIGURE). Biopsy reveals a high grade, poorly differentiated synovial sarcoma. Her physician refers her to an oncologist for initiation of chemotherapy, radiation, and debulking surgery.

CORRESPONDENCE
Laura C. Mayans, MD, Department of Family and Community Medicine, University of Kansas School of Medicine-Wichita, 1010 N. Kansas, Wichita, KS 67214; [email protected].

Each year, more than one in every 100 infants are born at less than 32 weeks postmenstrual age.¹ In industrialized countries, many of these infants are discharged from the neonatal intensive care unit (NICU) with home apnea monitors,¹ which alert caregivers to episodes of apnea and bradycardia, while also capturing and storing data surrounding significant events for later analysis.²

Evidence supporting the use of home apnea monitoring is sparse, and recommendations highlight the need to use this technology sparingly and to discontinue use once it is no longer necessary (TABLE).³ Counseling parents is critical. It’s important to explain that home apnea monitoring can be used to help reduce the likelihood that a child will die in his or her sleep, but it affords users no “guarantees.” In addition, home apnea monitoring can adversely affect parents. Parents who use home apnea monitoring for their infants have been shown to have higher stress scores, greater levels of fatigue, and poorer health than parents of infants without home apnea monitors.^4-8

As a family physician, you are likely to encounter home apnea monitoring in one of 3 scenarios: at the first visit after discharge by a premature infant who experienced apnea while hospitalized, at a follow-up visit after discharge from the hospital by an infant who experienced an apparent life-threatening event (ALTE), and at a follow-up visit by an infant whose sibling had died from sudden infant death syndrome (SIDS). This article presents case studies that illustrate each of these scenarios, and explains what to tell parents who ask about how long they should continue home apnea monitoring.

CASE 1 › Apnea of prematurity

Jacob is a newborn who is brought in to your clinic by his parents for an initial visit. The infant was born prematurely at 32 weeks and required a prolonged NICU stay. His mother says that Jacob spent 4 weeks there and was discharged home with home apnea monitoring. On exam, the infant has a monitor attached via a chest band. Jacob appears healthy and his exam is normal. The mother asks you how long her son should use the home monitor.

Pathologic apnea is a respiratory pause that lasts at least 20 seconds or is associated with cyanosis; abrupt, marked pallor or hypotonia; or bradycardia.² Apnea of prematurity is present in almost all infants born at <29 weeks postmenstrual age or who weigh <1000 g.⁹ It is found in 54% of infants born at 30 to 31 weeks, 15% born at 32 to 33 weeks, and 7% of infants born at 34 to 35 weeks.¹⁰

Apnea of prematurity is primarily due to an immature respiratory control system, which results in impaired breathing regulation, immature respiratory responses to hypercapnia and hypoxia, and an exaggerated inhibitory response to stimulation of airway receptors.^11-13 Although apnea of prematurity usually resolves by 36 to 40 weeks postmenstrual age, it often persists beyond 38 to 40 weeks in infants born before 28 weeks.¹⁰ In these infants, by 43 to 44 weeks postmenstrual age, the frequency of apneic episodes decreases to that of full-term infants.¹⁴

Apnea of prematurity is not associated with an increased risk of sudden infant death syndrome.

The differences in long-term outcomes of infants with apnea of prematurity vs infants without it are subtle, if present at all.^14,15 There does seem to be a correlation between the number of days with apnea and poor outcomes. Neurodevelopmental impairment and death are more likely in neonates who experience a greater number of days with apnea episodes.^16,17 However, apnea of prematurity is not associated with an increased risk of SIDS.¹⁸

According to the American Academy of Pediatrics (AAP), home apnea monitoring may be warranted for premature infants who are at high risk of recurrent episodes of apnea, bradycardia, and hypoxemia after hospital discharge.³ While there is general consensus that all infants born prior to 29 weeks meet this criterion, the use of home apnea monitors in older preterm infants varies significantly, and the decision to initiate monitoring in these patients is made by the discharging physician.³ Once initiated, the AAP recommends that the use of home apnea monitoring in this population be discontinued after approximately 43 weeks postmenstrual age or after the cessation of extreme episodes, whichever comes last.³

In Jacob’s case, the monitoring should be discontinued at approximately week 12 of life, or about age 3 months.

CASE 2 › Apparent life-threatening event

Sarah is brought to your office after being hospitalized for an ALTE. Her mother reports that she had witnessed her 13-day-old daughter not breathing for “about a minute.” Upon realizing what was happening, she “blew into the baby’s face,” whereupon Sarah awakened. The mother then called 911 and they went by ambulance to the emergency room. The newborn was admitted for observation overnight and received a thorough evaluation. She was discharged with a home apnea monitor.

You review the work-up and find nothing worrisome. Sarah is in a car seat attached to the apnea monitor with a chest strap. An examination of the child is normal. The mother asks you when they should stop using the home monitor.

An ALTE is “an event that is frightening to the observer and ... is characterized by some combination of apnea (central or occasionally obstructive), color change (usually cyanotic or pallid but occasionally erythematous or plethoric), marked change in muscle tone (usually marked limpness), choking, or gagging.”² ALTE is a descriptive term, and not a definitive diagnosis.

The true incidence of ALTE is unknown, but is reported to be 0.5% to 6%; most events occur in children younger than age 1.^19,20 The risk for ALTE is increased for premature infants, particularly those with respiratory syncytial virus or who had undergone general anesthesia; infants who feed rapidly, cough frequently, or choke during feeding; and male infants.^19,21

The most common causes of ALTE (in descending order) are gastroesophageal reflux, seizure disorder, and lower respiratory tract infection.²² The etiology is unknown for about half of patients with ALTE.²³

Tell parents that if their infant experiences an ALTE, they should seek medical attention without delay. The fear is that failing to respond to this concern will ultimately result in a sudden unexpected infant death, specifically as a result of SIDS.²⁴

SIDS is very rare, occurring in only 40 per 100,000 births. One analysis found that children who die from SIDS and those who experience ALTE have very similar histories and clinical factors.²⁵ Approximately 7% of infants who die from SIDS have had an ALTE.² Overall, the long-term prognosis for infants who have had an ALTE is very good, although it depends on seriousness of the underlying etiology.^8,26-28

Guidance on the effective use of home apnea monitors in infants who experience an ALTE is sparse. Despite this, the National Institutes of Health (NIH) Consensus Statement on Infantile Apnea and Home Monitoring² and the American Academy of Pediatrics policy statement on apnea, sudden infant death syndrome, and home monitoring³ recommend the use of home apnea monitoring for certain infants who’ve had an ALTE. The NIH Consensus Statement specifies home monitoring for infants with one or more severe episodes of ALTEs that require mouth-to-mouth resuscitation or vigorous stimulation.² There are no specific guidelines regarding the duration of monitoring.^2,3

In Sarah’s case, home monitoring should be discontinued as soon as the mother is comfortable with the decision.

CASE 3 › Sudden infant death syndrome

The parents of a 2-month-old boy, Stephen, come to your office to establish care. They recently relocated and their previous care provider had prescribed a home apnea monitor because a child they’d had 3 years ago had died of SIDS. Stephen is in a car seat attached to the apnea monitor with a chest strap. Your examination of him is normal. Stephen’s parents would like to stop using the home monitor, and ask you if it’s safe to do so.

The most common causes of an apparent life-threatening event in an infant are gastroesophageal reflux, seizure disorder, and lower respiratory tract infection.

SIDS is the death of an infant or young child that is unexplained by history and in which postmortem examination fails to find an adequate explanation of cause of death.² Since the introduction of the Back to Sleep campaign in the early 1990s, the incidence of SIDS has decreased by more than 50%.⁸ In 2013, approximately 1500 infant deaths were attributed to SIDS.²⁴ Three-quarters of deaths due to SIDS occur between 2 to 4 months of age, and 95% of deaths occur before 9 months of age.²⁹ Risk factors for SIDS include sleep environment (prone and side sleeping, bed sharing, soft bedding), prenatal and postnatal maternal tobacco use, exposure to tobacco smoke, maternal mental illness or substance abuse, male sex, poverty, prematurity, low birth weight (less than 2500 g), and no or poor prenatal care.³⁰

The etiology of SIDS is unclear.³¹ The leading hypothesis is the “triple-risk model,” which proposes that death from SIDS is due to 3 overlapping factors: a vulnerable infant, a critical developmental period in homeostatic control, and an exogenous stressor.³²

Although the NIH Consensus Statement suggests home apnea monitoring is indicated for infants who are siblings of 2 or more SIDS victims,² more recent policy statements from the AAP recommend against using home apnea monitors to reduce the incidence of SIDS due to a lack of evidence.^3,8

With this in mind, Stephen’s monitor should be discontinued and his parents should be educated on proven methods of preventing SIDS, including placing him on his back to sleep, breastfeeding him, letting him use a pacifier during sleep, and not sleeping in the same bed with him or overdressing him when putting him to sleep.^3,8

CORRESPONDENCE
Allen Perkins, MD, MPH, Department of Family Medicine, University of South Alabama, 1504 Springhill Avenue, Suite 3414, Mobile, AL 36604; [email protected].

Each year, more than one in every 100 infants are born at less than 32 weeks postmenstrual age.¹ In industrialized countries, many of these infants are discharged from the neonatal intensive care unit (NICU) with home apnea monitors,¹ which alert caregivers to episodes of apnea and bradycardia, while also capturing and storing data surrounding significant events for later analysis.²

Evidence supporting the use of home apnea monitoring is sparse, and recommendations highlight the need to use this technology sparingly and to discontinue use once it is no longer necessary (TABLE).³ Counseling parents is critical. It’s important to explain that home apnea monitoring can be used to help reduce the likelihood that a child will die in his or her sleep, but it affords users no “guarantees.” In addition, home apnea monitoring can adversely affect parents. Parents who use home apnea monitoring for their infants have been shown to have higher stress scores, greater levels of fatigue, and poorer health than parents of infants without home apnea monitors.^4-8

As a family physician, you are likely to encounter home apnea monitoring in one of 3 scenarios: at the first visit after discharge by a premature infant who experienced apnea while hospitalized, at a follow-up visit after discharge from the hospital by an infant who experienced an apparent life-threatening event (ALTE), and at a follow-up visit by an infant whose sibling had died from sudden infant death syndrome (SIDS). This article presents case studies that illustrate each of these scenarios, and explains what to tell parents who ask about how long they should continue home apnea monitoring.

CASE 1 › Apnea of prematurity

Jacob is a newborn who is brought in to your clinic by his parents for an initial visit. The infant was born prematurely at 32 weeks and required a prolonged NICU stay. His mother says that Jacob spent 4 weeks there and was discharged home with home apnea monitoring. On exam, the infant has a monitor attached via a chest band. Jacob appears healthy and his exam is normal. The mother asks you how long her son should use the home monitor.

Pathologic apnea is a respiratory pause that lasts at least 20 seconds or is associated with cyanosis; abrupt, marked pallor or hypotonia; or bradycardia.² Apnea of prematurity is present in almost all infants born at <29 weeks postmenstrual age or who weigh <1000 g.⁹ It is found in 54% of infants born at 30 to 31 weeks, 15% born at 32 to 33 weeks, and 7% of infants born at 34 to 35 weeks.¹⁰

Apnea of prematurity is primarily due to an immature respiratory control system, which results in impaired breathing regulation, immature respiratory responses to hypercapnia and hypoxia, and an exaggerated inhibitory response to stimulation of airway receptors.^11-13 Although apnea of prematurity usually resolves by 36 to 40 weeks postmenstrual age, it often persists beyond 38 to 40 weeks in infants born before 28 weeks.¹⁰ In these infants, by 43 to 44 weeks postmenstrual age, the frequency of apneic episodes decreases to that of full-term infants.¹⁴

Apnea of prematurity is not associated with an increased risk of sudden infant death syndrome.

The differences in long-term outcomes of infants with apnea of prematurity vs infants without it are subtle, if present at all.^14,15 There does seem to be a correlation between the number of days with apnea and poor outcomes. Neurodevelopmental impairment and death are more likely in neonates who experience a greater number of days with apnea episodes.^16,17 However, apnea of prematurity is not associated with an increased risk of SIDS.¹⁸

According to the American Academy of Pediatrics (AAP), home apnea monitoring may be warranted for premature infants who are at high risk of recurrent episodes of apnea, bradycardia, and hypoxemia after hospital discharge.³ While there is general consensus that all infants born prior to 29 weeks meet this criterion, the use of home apnea monitors in older preterm infants varies significantly, and the decision to initiate monitoring in these patients is made by the discharging physician.³ Once initiated, the AAP recommends that the use of home apnea monitoring in this population be discontinued after approximately 43 weeks postmenstrual age or after the cessation of extreme episodes, whichever comes last.³

In Jacob’s case, the monitoring should be discontinued at approximately week 12 of life, or about age 3 months.

CASE 2 › Apparent life-threatening event

Sarah is brought to your office after being hospitalized for an ALTE. Her mother reports that she had witnessed her 13-day-old daughter not breathing for “about a minute.” Upon realizing what was happening, she “blew into the baby’s face,” whereupon Sarah awakened. The mother then called 911 and they went by ambulance to the emergency room. The newborn was admitted for observation overnight and received a thorough evaluation. She was discharged with a home apnea monitor.

You review the work-up and find nothing worrisome. Sarah is in a car seat attached to the apnea monitor with a chest strap. An examination of the child is normal. The mother asks you when they should stop using the home monitor.

An ALTE is “an event that is frightening to the observer and ... is characterized by some combination of apnea (central or occasionally obstructive), color change (usually cyanotic or pallid but occasionally erythematous or plethoric), marked change in muscle tone (usually marked limpness), choking, or gagging.”² ALTE is a descriptive term, and not a definitive diagnosis.

The true incidence of ALTE is unknown, but is reported to be 0.5% to 6%; most events occur in children younger than age 1.^19,20 The risk for ALTE is increased for premature infants, particularly those with respiratory syncytial virus or who had undergone general anesthesia; infants who feed rapidly, cough frequently, or choke during feeding; and male infants.^19,21

The most common causes of ALTE (in descending order) are gastroesophageal reflux, seizure disorder, and lower respiratory tract infection.²² The etiology is unknown for about half of patients with ALTE.²³

Tell parents that if their infant experiences an ALTE, they should seek medical attention without delay. The fear is that failing to respond to this concern will ultimately result in a sudden unexpected infant death, specifically as a result of SIDS.²⁴

SIDS is very rare, occurring in only 40 per 100,000 births. One analysis found that children who die from SIDS and those who experience ALTE have very similar histories and clinical factors.²⁵ Approximately 7% of infants who die from SIDS have had an ALTE.² Overall, the long-term prognosis for infants who have had an ALTE is very good, although it depends on seriousness of the underlying etiology.^8,26-28

Guidance on the effective use of home apnea monitors in infants who experience an ALTE is sparse. Despite this, the National Institutes of Health (NIH) Consensus Statement on Infantile Apnea and Home Monitoring² and the American Academy of Pediatrics policy statement on apnea, sudden infant death syndrome, and home monitoring³ recommend the use of home apnea monitoring for certain infants who’ve had an ALTE. The NIH Consensus Statement specifies home monitoring for infants with one or more severe episodes of ALTEs that require mouth-to-mouth resuscitation or vigorous stimulation.² There are no specific guidelines regarding the duration of monitoring.^2,3

In Sarah’s case, home monitoring should be discontinued as soon as the mother is comfortable with the decision.

CASE 3 › Sudden infant death syndrome

The parents of a 2-month-old boy, Stephen, come to your office to establish care. They recently relocated and their previous care provider had prescribed a home apnea monitor because a child they’d had 3 years ago had died of SIDS. Stephen is in a car seat attached to the apnea monitor with a chest strap. Your examination of him is normal. Stephen’s parents would like to stop using the home monitor, and ask you if it’s safe to do so.

The most common causes of an apparent life-threatening event in an infant are gastroesophageal reflux, seizure disorder, and lower respiratory tract infection.

SIDS is the death of an infant or young child that is unexplained by history and in which postmortem examination fails to find an adequate explanation of cause of death.² Since the introduction of the Back to Sleep campaign in the early 1990s, the incidence of SIDS has decreased by more than 50%.⁸ In 2013, approximately 1500 infant deaths were attributed to SIDS.²⁴ Three-quarters of deaths due to SIDS occur between 2 to 4 months of age, and 95% of deaths occur before 9 months of age.²⁹ Risk factors for SIDS include sleep environment (prone and side sleeping, bed sharing, soft bedding), prenatal and postnatal maternal tobacco use, exposure to tobacco smoke, maternal mental illness or substance abuse, male sex, poverty, prematurity, low birth weight (less than 2500 g), and no or poor prenatal care.³⁰

The etiology of SIDS is unclear.³¹ The leading hypothesis is the “triple-risk model,” which proposes that death from SIDS is due to 3 overlapping factors: a vulnerable infant, a critical developmental period in homeostatic control, and an exogenous stressor.³²

Although the NIH Consensus Statement suggests home apnea monitoring is indicated for infants who are siblings of 2 or more SIDS victims,² more recent policy statements from the AAP recommend against using home apnea monitors to reduce the incidence of SIDS due to a lack of evidence.^3,8

With this in mind, Stephen’s monitor should be discontinued and his parents should be educated on proven methods of preventing SIDS, including placing him on his back to sleep, breastfeeding him, letting him use a pacifier during sleep, and not sleeping in the same bed with him or overdressing him when putting him to sleep.^3,8

CORRESPONDENCE
Allen Perkins, MD, MPH, Department of Family Medicine, University of South Alabama, 1504 Springhill Avenue, Suite 3414, Mobile, AL 36604; [email protected].

Each year, more than one in every 100 infants are born at less than 32 weeks postmenstrual age.¹ In industrialized countries, many of these infants are discharged from the neonatal intensive care unit (NICU) with home apnea monitors,¹ which alert caregivers to episodes of apnea and bradycardia, while also capturing and storing data surrounding significant events for later analysis.²

Evidence supporting the use of home apnea monitoring is sparse, and recommendations highlight the need to use this technology sparingly and to discontinue use once it is no longer necessary (TABLE).³ Counseling parents is critical. It’s important to explain that home apnea monitoring can be used to help reduce the likelihood that a child will die in his or her sleep, but it affords users no “guarantees.” In addition, home apnea monitoring can adversely affect parents. Parents who use home apnea monitoring for their infants have been shown to have higher stress scores, greater levels of fatigue, and poorer health than parents of infants without home apnea monitors.^4-8

As a family physician, you are likely to encounter home apnea monitoring in one of 3 scenarios: at the first visit after discharge by a premature infant who experienced apnea while hospitalized, at a follow-up visit after discharge from the hospital by an infant who experienced an apparent life-threatening event (ALTE), and at a follow-up visit by an infant whose sibling had died from sudden infant death syndrome (SIDS). This article presents case studies that illustrate each of these scenarios, and explains what to tell parents who ask about how long they should continue home apnea monitoring.

CASE 1 › Apnea of prematurity

Jacob is a newborn who is brought in to your clinic by his parents for an initial visit. The infant was born prematurely at 32 weeks and required a prolonged NICU stay. His mother says that Jacob spent 4 weeks there and was discharged home with home apnea monitoring. On exam, the infant has a monitor attached via a chest band. Jacob appears healthy and his exam is normal. The mother asks you how long her son should use the home monitor.

Pathologic apnea is a respiratory pause that lasts at least 20 seconds or is associated with cyanosis; abrupt, marked pallor or hypotonia; or bradycardia.² Apnea of prematurity is present in almost all infants born at <29 weeks postmenstrual age or who weigh <1000 g.⁹ It is found in 54% of infants born at 30 to 31 weeks, 15% born at 32 to 33 weeks, and 7% of infants born at 34 to 35 weeks.¹⁰

Apnea of prematurity is primarily due to an immature respiratory control system, which results in impaired breathing regulation, immature respiratory responses to hypercapnia and hypoxia, and an exaggerated inhibitory response to stimulation of airway receptors.^11-13 Although apnea of prematurity usually resolves by 36 to 40 weeks postmenstrual age, it often persists beyond 38 to 40 weeks in infants born before 28 weeks.¹⁰ In these infants, by 43 to 44 weeks postmenstrual age, the frequency of apneic episodes decreases to that of full-term infants.¹⁴

Apnea of prematurity is not associated with an increased risk of sudden infant death syndrome.

The differences in long-term outcomes of infants with apnea of prematurity vs infants without it are subtle, if present at all.^14,15 There does seem to be a correlation between the number of days with apnea and poor outcomes. Neurodevelopmental impairment and death are more likely in neonates who experience a greater number of days with apnea episodes.^16,17 However, apnea of prematurity is not associated with an increased risk of SIDS.¹⁸

According to the American Academy of Pediatrics (AAP), home apnea monitoring may be warranted for premature infants who are at high risk of recurrent episodes of apnea, bradycardia, and hypoxemia after hospital discharge.³ While there is general consensus that all infants born prior to 29 weeks meet this criterion, the use of home apnea monitors in older preterm infants varies significantly, and the decision to initiate monitoring in these patients is made by the discharging physician.³ Once initiated, the AAP recommends that the use of home apnea monitoring in this population be discontinued after approximately 43 weeks postmenstrual age or after the cessation of extreme episodes, whichever comes last.³

In Jacob’s case, the monitoring should be discontinued at approximately week 12 of life, or about age 3 months.

CASE 2 › Apparent life-threatening event

Sarah is brought to your office after being hospitalized for an ALTE. Her mother reports that she had witnessed her 13-day-old daughter not breathing for “about a minute.” Upon realizing what was happening, she “blew into the baby’s face,” whereupon Sarah awakened. The mother then called 911 and they went by ambulance to the emergency room. The newborn was admitted for observation overnight and received a thorough evaluation. She was discharged with a home apnea monitor.

You review the work-up and find nothing worrisome. Sarah is in a car seat attached to the apnea monitor with a chest strap. An examination of the child is normal. The mother asks you when they should stop using the home monitor.

An ALTE is “an event that is frightening to the observer and ... is characterized by some combination of apnea (central or occasionally obstructive), color change (usually cyanotic or pallid but occasionally erythematous or plethoric), marked change in muscle tone (usually marked limpness), choking, or gagging.”² ALTE is a descriptive term, and not a definitive diagnosis.

The true incidence of ALTE is unknown, but is reported to be 0.5% to 6%; most events occur in children younger than age 1.^19,20 The risk for ALTE is increased for premature infants, particularly those with respiratory syncytial virus or who had undergone general anesthesia; infants who feed rapidly, cough frequently, or choke during feeding; and male infants.^19,21

The most common causes of ALTE (in descending order) are gastroesophageal reflux, seizure disorder, and lower respiratory tract infection.²² The etiology is unknown for about half of patients with ALTE.²³

Tell parents that if their infant experiences an ALTE, they should seek medical attention without delay. The fear is that failing to respond to this concern will ultimately result in a sudden unexpected infant death, specifically as a result of SIDS.²⁴

SIDS is very rare, occurring in only 40 per 100,000 births. One analysis found that children who die from SIDS and those who experience ALTE have very similar histories and clinical factors.²⁵ Approximately 7% of infants who die from SIDS have had an ALTE.² Overall, the long-term prognosis for infants who have had an ALTE is very good, although it depends on seriousness of the underlying etiology.^8,26-28

Guidance on the effective use of home apnea monitors in infants who experience an ALTE is sparse. Despite this, the National Institutes of Health (NIH) Consensus Statement on Infantile Apnea and Home Monitoring² and the American Academy of Pediatrics policy statement on apnea, sudden infant death syndrome, and home monitoring³ recommend the use of home apnea monitoring for certain infants who’ve had an ALTE. The NIH Consensus Statement specifies home monitoring for infants with one or more severe episodes of ALTEs that require mouth-to-mouth resuscitation or vigorous stimulation.² There are no specific guidelines regarding the duration of monitoring.^2,3

In Sarah’s case, home monitoring should be discontinued as soon as the mother is comfortable with the decision.

CASE 3 › Sudden infant death syndrome

The parents of a 2-month-old boy, Stephen, come to your office to establish care. They recently relocated and their previous care provider had prescribed a home apnea monitor because a child they’d had 3 years ago had died of SIDS. Stephen is in a car seat attached to the apnea monitor with a chest strap. Your examination of him is normal. Stephen’s parents would like to stop using the home monitor, and ask you if it’s safe to do so.

The most common causes of an apparent life-threatening event in an infant are gastroesophageal reflux, seizure disorder, and lower respiratory tract infection.

SIDS is the death of an infant or young child that is unexplained by history and in which postmortem examination fails to find an adequate explanation of cause of death.² Since the introduction of the Back to Sleep campaign in the early 1990s, the incidence of SIDS has decreased by more than 50%.⁸ In 2013, approximately 1500 infant deaths were attributed to SIDS.²⁴ Three-quarters of deaths due to SIDS occur between 2 to 4 months of age, and 95% of deaths occur before 9 months of age.²⁹ Risk factors for SIDS include sleep environment (prone and side sleeping, bed sharing, soft bedding), prenatal and postnatal maternal tobacco use, exposure to tobacco smoke, maternal mental illness or substance abuse, male sex, poverty, prematurity, low birth weight (less than 2500 g), and no or poor prenatal care.³⁰

The etiology of SIDS is unclear.³¹ The leading hypothesis is the “triple-risk model,” which proposes that death from SIDS is due to 3 overlapping factors: a vulnerable infant, a critical developmental period in homeostatic control, and an exogenous stressor.³²

Although the NIH Consensus Statement suggests home apnea monitoring is indicated for infants who are siblings of 2 or more SIDS victims,² more recent policy statements from the AAP recommend against using home apnea monitors to reduce the incidence of SIDS due to a lack of evidence.^3,8

With this in mind, Stephen’s monitor should be discontinued and his parents should be educated on proven methods of preventing SIDS, including placing him on his back to sleep, breastfeeding him, letting him use a pacifier during sleep, and not sleeping in the same bed with him or overdressing him when putting him to sleep.^3,8

CORRESPONDENCE
Allen Perkins, MD, MPH, Department of Family Medicine, University of South Alabama, 1504 Springhill Avenue, Suite 3414, Mobile, AL 36604; [email protected].

With an estimated lifetime prevalence of 17% to 30%,¹ dizziness is a relatively common clinical symptom, but the underlying cause can be difficult to diagnose. That’s because patients’ descriptions of dizziness are often imprecise, and this symptom is associated with a wide range of conditions. A careful history and physical examination are key to diagnosis, as is an understanding of the mechanisms of dizziness.

This article covers the range of diagnoses that should be considered when a patient presents with dizziness, and provides insight regarding features of the patient’s history that can better elucidate the specific etiology.

What do patients mean when they say, “I feel dizzy”?

“Dizziness” is a vague term, and patients who report dizziness should be asked to further describe the sensation. Patients may use the word dizziness in an attempt to describe many sensations, including faintness, giddiness, light-headedness, or unsteadiness.² In 1972, Drachman and Hart proposed a classification system for dizziness that describes 4 categories—presyncope, vertigo, disequilibrium, and atypical (TABLE 1).³ These classifications are still commonly used today, and the discussion that follows describes potential causes of dizziness in each of these 4 categories. A stepwise approach for evaluating a patient who reports dizziness can be found in the ALGORITHM.^3-6

Syncopal-related dizziness can have a cardiovascular cause

Presyncope is a feeling of impending loss of consciousness that’s sometimes accompanied by generalized muscle weakness and/or partial vision loss. Taking a careful history regarding the events surrounding the episode should distinguish this type of dizziness, and doing so is essential because most of the underlying pathogenesis involves the cardiovascular system and requires specific interventions.

Dysrhythmias can cause syncope and may or may not be accompanied by a feeling of palpitations. Diagnosis is made by electrocardiogram (EKG) followed by the use of a Holter monitor.

Vasovagal syncope is caused by a sudden slowing of the pulse that’s the result of stimulation of the vagal nerve. It can occur from direct stimulation of the nerve from palpation (or strangulation), or from an intense autonomic discharge, as when people are frightened or confronted with something upsetting (eg, the sight of blood.)

Orthostatic hypotension results from a change in body position in which either autonomic mechanisms cannot maintain venous tone, causing a sudden drop in blood pressure, or in which the heart cannot compensate by speeding up, as when a patient is taking a beta-adrenergic antagonist or has first-degree heart block. It can also result from hypovolemia.

Measuring the patient’s blood pressure in the recumbent, seated, and standing positions can verify the diagnosis if an episode occurred soon before the examination. This kind of dizziness can be treated by instructing the patient to rise slowly, or by making appropriate medication adjustments. If conservative measures fail, medications such as midodrine or droxidopa can be tried.⁷

Hypoglycemia, hypoxia, or hyperventilation can also precipitate syncopal symptoms. Taking a careful history to assess for the presence of seizure-related features such as tonic/clonic movements or loss of bowel and bladder control can be helpful in distinguishing this form of dizziness.

Vertigo can have a central or peripheral cause

Vertigo is dizziness that is characterized by the sensation of spinning. The presence of vertigo implies disease of the inner ear or central nervous system. The “wiring diagram” of the vestibulo-ocular reflex is fairly straightforward, but sorting out the symptoms that arise from lesions within the system can be a diagnostic challenge. Vertigo has classically been divided into causes that are central (originating in the central nervous system) or peripheral (originating in the peripheral nervous system).

The HINTS (Head Impulse, Nystagmus, and Test of Skew) protocol is a group of 3 tests that can be used to differentiate central from peripheral vertigo (TABLE 2).^8,9 To perform the head impulse test, the examiner asks the patient to focus his gaze on a target and then rapidly turns the patient’s head to the side, watching the eyes for any corrective movements.¹⁰ When the eyes make a corrective saccade, the test is considered to be positive for a peripheral lesion.

Horizontal nystagmus is assessed by having the patient look in the direction of the fast phase of the nystagmus. If the nystagmus increases in intensity, then the test is considered positive for a peripheral lesion.

A careful description of the circumstances surrounding the dizziness episode can help identify underlying conditions such as orthostasis, hypoglycemia, or hyperventilation.

Vertigo can have many possible causes

Finally, the “test of skew” is performed by again having the patient fixate on the examiner’s nose. Each eye is tested by being covered, and then uncovered. If the uncovered eye has to move to refocus on the examiner’s nose, then the test is positive for a central lesion. A positive head impulse, positive horizontal nystagmus, and negative test of skew is 100% sensitive and 96% specific for a peripheral lesion.¹¹

Benign paroxysmal positional vertigo (BPPV) is vertigo that is triggered by movement of the head. It occurs when otoconia that are normally embedded in gel in the utricle become dislodged and migrate into the 3 fluid-filled semicircular canals, where they interfere with the normal fluid movement these canals use to sense head motion, causing the inner ear to send false signals to the brain.¹²

Diagnosis is confirmed by performing the Dix-Hallpike maneuver to elicit nystagmus. The patient is moved from a seated to a supine position with her head turned 45 degrees to the right and held for 30 seconds. For a demonstration of the Dix-Hallpike maneuver, see https://youtu.be/8RYB2QlO1N4. The Dix-Hallpike maneuver is also the first step of a treatment for BBPV known as the Epley maneuver. (See “The Epley maneuver: A procedure for treating BPPV”.^13,14)

Labyrinthitis—inflammation of the inner ear that can cause vertigo—is suggested by an acute, non-recurrent episode of dizziness that is often preceded by an upper respiratory infection. If the external canal is extremely painful and/or develops a vesicular rash, the patient might have herpes zoster of the geniculate ganglion (Ramsay Hunt syndrome type 2).

Dizziness related to presyncope often involves a cardiovascular pathology, such as a dysrhythmia or orthostatic hypotension.

Vertigo can have many possible causes

Vestibular migraine and Meniere’s disease. When a patient who has a history of migraines experiences symptoms of vertigo, vestibular migraine should be suspected, and treatment should focus on migraine therapy rather than vestibular therapy.¹⁵

Symptoms of Meniere’s disease and vestibular migraine can overlap.¹⁶ The current definition of Meniere’s disease requires ≥2 definitive episodes of vertigo with hearing loss plus tinnitus and/or aural symptoms.¹⁷ Thirty percent of vertigo episodes in patients with Meniere's disease can be attributed to BPPV.¹⁸

Acoustic neuroma. In addition to vertigo, acoustic neuroma is often associated with gradual hearing loss, tinnitus, and facial numbness (from compression of cranial nerve V preoperatively) or facial weakness (from compression of cranial nerve VII postoperatively). Unilateral hearing loss should prompt evaluation with magnetic resonance imaging.

“Acoustic neuroma” is a misnomer. The lesion arises from the vestibular (not the acoustic) portion of the 8th cranial nerve, and isn’t a neuroma; it is a schwannoma.¹⁹ Although it actually arises peripherally within the vestibular canal, it typically expands centrally and compresses other nerves centrally, which can make the clinical diagnosis more challenging if one were using the classical schema of differentiating between peripheral and central causes of vertigo.

Age-related vestibular loss occurs when the aging process causes deterioration of most of the components of the vestibulo-ocular reflex, resulting in dizziness and vertigo. Usually, the cerebral override mechanisms can compensate for the degeneration.

Other causes of vertigo include cerebellar infarction (3% of patients with vertigo),²⁰ sound-induced vertigo (Tullio phenomenon),²¹ obstructive sleep apnea,²² and systemic sclerosis.²³ Diabetes can cause a reduction in vestibular sensitivity that is evidenced by an increased reliance on visual stimuli to resolve vestibulo-visual conflict.²⁴

Disequilibrium

Disequilibrium is predominantly a loss of balance. Patients with disequilibrium have the feeling that they are about to fall, specifically without the sensation of spinning. They may appear to sway, and will reach out for something to support them. Disequilibrium can be a component of vertigo, or it may suggest a more specific diagnosis, such as ataxia, which is a lack of coordination when walking.

Atypical causes of dizziness

A positive head impulse test is highly suggestive of a peripheral lesion.

“Light-headedness” may have an element of euphoria or may be indistinguishable from the early part of a syncopal episode. Because other causes of light-headedness can be difficult to distinguish from presyncope, it is important to consider syncope in the differential diagnosis.

The differential of light-headedness can also include panic attack, early hyperventilation, and toxin exposure (such as diphenylarsinic acid,²⁵ pregabalin,²⁶ or paint thinner²⁷).

CORRESPONDENCE
Shannon Paul Starr, MD, Louisiana State University Health Sciences Center, 200 W. Esplanade #412, Kenner, LA 70065; [email protected].

With an estimated lifetime prevalence of 17% to 30%,¹ dizziness is a relatively common clinical symptom, but the underlying cause can be difficult to diagnose. That’s because patients’ descriptions of dizziness are often imprecise, and this symptom is associated with a wide range of conditions. A careful history and physical examination are key to diagnosis, as is an understanding of the mechanisms of dizziness.

This article covers the range of diagnoses that should be considered when a patient presents with dizziness, and provides insight regarding features of the patient’s history that can better elucidate the specific etiology.

What do patients mean when they say, “I feel dizzy”?

“Dizziness” is a vague term, and patients who report dizziness should be asked to further describe the sensation. Patients may use the word dizziness in an attempt to describe many sensations, including faintness, giddiness, light-headedness, or unsteadiness.² In 1972, Drachman and Hart proposed a classification system for dizziness that describes 4 categories—presyncope, vertigo, disequilibrium, and atypical (TABLE 1).³ These classifications are still commonly used today, and the discussion that follows describes potential causes of dizziness in each of these 4 categories. A stepwise approach for evaluating a patient who reports dizziness can be found in the ALGORITHM.^3-6

Syncopal-related dizziness can have a cardiovascular cause

Presyncope is a feeling of impending loss of consciousness that’s sometimes accompanied by generalized muscle weakness and/or partial vision loss. Taking a careful history regarding the events surrounding the episode should distinguish this type of dizziness, and doing so is essential because most of the underlying pathogenesis involves the cardiovascular system and requires specific interventions.

Dysrhythmias can cause syncope and may or may not be accompanied by a feeling of palpitations. Diagnosis is made by electrocardiogram (EKG) followed by the use of a Holter monitor.

Vasovagal syncope is caused by a sudden slowing of the pulse that’s the result of stimulation of the vagal nerve. It can occur from direct stimulation of the nerve from palpation (or strangulation), or from an intense autonomic discharge, as when people are frightened or confronted with something upsetting (eg, the sight of blood.)

Orthostatic hypotension results from a change in body position in which either autonomic mechanisms cannot maintain venous tone, causing a sudden drop in blood pressure, or in which the heart cannot compensate by speeding up, as when a patient is taking a beta-adrenergic antagonist or has first-degree heart block. It can also result from hypovolemia.

Measuring the patient’s blood pressure in the recumbent, seated, and standing positions can verify the diagnosis if an episode occurred soon before the examination. This kind of dizziness can be treated by instructing the patient to rise slowly, or by making appropriate medication adjustments. If conservative measures fail, medications such as midodrine or droxidopa can be tried.⁷

Hypoglycemia, hypoxia, or hyperventilation can also precipitate syncopal symptoms. Taking a careful history to assess for the presence of seizure-related features such as tonic/clonic movements or loss of bowel and bladder control can be helpful in distinguishing this form of dizziness.

Vertigo can have a central or peripheral cause

Vertigo is dizziness that is characterized by the sensation of spinning. The presence of vertigo implies disease of the inner ear or central nervous system. The “wiring diagram” of the vestibulo-ocular reflex is fairly straightforward, but sorting out the symptoms that arise from lesions within the system can be a diagnostic challenge. Vertigo has classically been divided into causes that are central (originating in the central nervous system) or peripheral (originating in the peripheral nervous system).

The HINTS (Head Impulse, Nystagmus, and Test of Skew) protocol is a group of 3 tests that can be used to differentiate central from peripheral vertigo (TABLE 2).^8,9 To perform the head impulse test, the examiner asks the patient to focus his gaze on a target and then rapidly turns the patient’s head to the side, watching the eyes for any corrective movements.¹⁰ When the eyes make a corrective saccade, the test is considered to be positive for a peripheral lesion.

Horizontal nystagmus is assessed by having the patient look in the direction of the fast phase of the nystagmus. If the nystagmus increases in intensity, then the test is considered positive for a peripheral lesion.

A careful description of the circumstances surrounding the dizziness episode can help identify underlying conditions such as orthostasis, hypoglycemia, or hyperventilation.

Vertigo can have many possible causes

Finally, the “test of skew” is performed by again having the patient fixate on the examiner’s nose. Each eye is tested by being covered, and then uncovered. If the uncovered eye has to move to refocus on the examiner’s nose, then the test is positive for a central lesion. A positive head impulse, positive horizontal nystagmus, and negative test of skew is 100% sensitive and 96% specific for a peripheral lesion.¹¹

Benign paroxysmal positional vertigo (BPPV) is vertigo that is triggered by movement of the head. It occurs when otoconia that are normally embedded in gel in the utricle become dislodged and migrate into the 3 fluid-filled semicircular canals, where they interfere with the normal fluid movement these canals use to sense head motion, causing the inner ear to send false signals to the brain.¹²

Diagnosis is confirmed by performing the Dix-Hallpike maneuver to elicit nystagmus. The patient is moved from a seated to a supine position with her head turned 45 degrees to the right and held for 30 seconds. For a demonstration of the Dix-Hallpike maneuver, see https://youtu.be/8RYB2QlO1N4. The Dix-Hallpike maneuver is also the first step of a treatment for BBPV known as the Epley maneuver. (See “The Epley maneuver: A procedure for treating BPPV”.^13,14)

Labyrinthitis—inflammation of the inner ear that can cause vertigo—is suggested by an acute, non-recurrent episode of dizziness that is often preceded by an upper respiratory infection. If the external canal is extremely painful and/or develops a vesicular rash, the patient might have herpes zoster of the geniculate ganglion (Ramsay Hunt syndrome type 2).

Dizziness related to presyncope often involves a cardiovascular pathology, such as a dysrhythmia or orthostatic hypotension.

Vertigo can have many possible causes

Vestibular migraine and Meniere’s disease. When a patient who has a history of migraines experiences symptoms of vertigo, vestibular migraine should be suspected, and treatment should focus on migraine therapy rather than vestibular therapy.¹⁵

Symptoms of Meniere’s disease and vestibular migraine can overlap.¹⁶ The current definition of Meniere’s disease requires ≥2 definitive episodes of vertigo with hearing loss plus tinnitus and/or aural symptoms.¹⁷ Thirty percent of vertigo episodes in patients with Meniere's disease can be attributed to BPPV.¹⁸

Acoustic neuroma. In addition to vertigo, acoustic neuroma is often associated with gradual hearing loss, tinnitus, and facial numbness (from compression of cranial nerve V preoperatively) or facial weakness (from compression of cranial nerve VII postoperatively). Unilateral hearing loss should prompt evaluation with magnetic resonance imaging.

“Acoustic neuroma” is a misnomer. The lesion arises from the vestibular (not the acoustic) portion of the 8th cranial nerve, and isn’t a neuroma; it is a schwannoma.¹⁹ Although it actually arises peripherally within the vestibular canal, it typically expands centrally and compresses other nerves centrally, which can make the clinical diagnosis more challenging if one were using the classical schema of differentiating between peripheral and central causes of vertigo.

Age-related vestibular loss occurs when the aging process causes deterioration of most of the components of the vestibulo-ocular reflex, resulting in dizziness and vertigo. Usually, the cerebral override mechanisms can compensate for the degeneration.

Other causes of vertigo include cerebellar infarction (3% of patients with vertigo),²⁰ sound-induced vertigo (Tullio phenomenon),²¹ obstructive sleep apnea,²² and systemic sclerosis.²³ Diabetes can cause a reduction in vestibular sensitivity that is evidenced by an increased reliance on visual stimuli to resolve vestibulo-visual conflict.²⁴

Disequilibrium

Disequilibrium is predominantly a loss of balance. Patients with disequilibrium have the feeling that they are about to fall, specifically without the sensation of spinning. They may appear to sway, and will reach out for something to support them. Disequilibrium can be a component of vertigo, or it may suggest a more specific diagnosis, such as ataxia, which is a lack of coordination when walking.

Atypical causes of dizziness

A positive head impulse test is highly suggestive of a peripheral lesion.

“Light-headedness” may have an element of euphoria or may be indistinguishable from the early part of a syncopal episode. Because other causes of light-headedness can be difficult to distinguish from presyncope, it is important to consider syncope in the differential diagnosis.

The differential of light-headedness can also include panic attack, early hyperventilation, and toxin exposure (such as diphenylarsinic acid,²⁵ pregabalin,²⁶ or paint thinner²⁷).

CORRESPONDENCE
Shannon Paul Starr, MD, Louisiana State University Health Sciences Center, 200 W. Esplanade #412, Kenner, LA 70065; [email protected].

With an estimated lifetime prevalence of 17% to 30%,¹ dizziness is a relatively common clinical symptom, but the underlying cause can be difficult to diagnose. That’s because patients’ descriptions of dizziness are often imprecise, and this symptom is associated with a wide range of conditions. A careful history and physical examination are key to diagnosis, as is an understanding of the mechanisms of dizziness.

This article covers the range of diagnoses that should be considered when a patient presents with dizziness, and provides insight regarding features of the patient’s history that can better elucidate the specific etiology.

What do patients mean when they say, “I feel dizzy”?

“Dizziness” is a vague term, and patients who report dizziness should be asked to further describe the sensation. Patients may use the word dizziness in an attempt to describe many sensations, including faintness, giddiness, light-headedness, or unsteadiness.² In 1972, Drachman and Hart proposed a classification system for dizziness that describes 4 categories—presyncope, vertigo, disequilibrium, and atypical (TABLE 1).³ These classifications are still commonly used today, and the discussion that follows describes potential causes of dizziness in each of these 4 categories. A stepwise approach for evaluating a patient who reports dizziness can be found in the ALGORITHM.^3-6

Syncopal-related dizziness can have a cardiovascular cause

Presyncope is a feeling of impending loss of consciousness that’s sometimes accompanied by generalized muscle weakness and/or partial vision loss. Taking a careful history regarding the events surrounding the episode should distinguish this type of dizziness, and doing so is essential because most of the underlying pathogenesis involves the cardiovascular system and requires specific interventions.

Dysrhythmias can cause syncope and may or may not be accompanied by a feeling of palpitations. Diagnosis is made by electrocardiogram (EKG) followed by the use of a Holter monitor.

Vasovagal syncope is caused by a sudden slowing of the pulse that’s the result of stimulation of the vagal nerve. It can occur from direct stimulation of the nerve from palpation (or strangulation), or from an intense autonomic discharge, as when people are frightened or confronted with something upsetting (eg, the sight of blood.)

Orthostatic hypotension results from a change in body position in which either autonomic mechanisms cannot maintain venous tone, causing a sudden drop in blood pressure, or in which the heart cannot compensate by speeding up, as when a patient is taking a beta-adrenergic antagonist or has first-degree heart block. It can also result from hypovolemia.

Measuring the patient’s blood pressure in the recumbent, seated, and standing positions can verify the diagnosis if an episode occurred soon before the examination. This kind of dizziness can be treated by instructing the patient to rise slowly, or by making appropriate medication adjustments. If conservative measures fail, medications such as midodrine or droxidopa can be tried.⁷

Hypoglycemia, hypoxia, or hyperventilation can also precipitate syncopal symptoms. Taking a careful history to assess for the presence of seizure-related features such as tonic/clonic movements or loss of bowel and bladder control can be helpful in distinguishing this form of dizziness.

Vertigo can have a central or peripheral cause

Vertigo is dizziness that is characterized by the sensation of spinning. The presence of vertigo implies disease of the inner ear or central nervous system. The “wiring diagram” of the vestibulo-ocular reflex is fairly straightforward, but sorting out the symptoms that arise from lesions within the system can be a diagnostic challenge. Vertigo has classically been divided into causes that are central (originating in the central nervous system) or peripheral (originating in the peripheral nervous system).

The HINTS (Head Impulse, Nystagmus, and Test of Skew) protocol is a group of 3 tests that can be used to differentiate central from peripheral vertigo (TABLE 2).^8,9 To perform the head impulse test, the examiner asks the patient to focus his gaze on a target and then rapidly turns the patient’s head to the side, watching the eyes for any corrective movements.¹⁰ When the eyes make a corrective saccade, the test is considered to be positive for a peripheral lesion.

Horizontal nystagmus is assessed by having the patient look in the direction of the fast phase of the nystagmus. If the nystagmus increases in intensity, then the test is considered positive for a peripheral lesion.

A careful description of the circumstances surrounding the dizziness episode can help identify underlying conditions such as orthostasis, hypoglycemia, or hyperventilation.

Vertigo can have many possible causes

Finally, the “test of skew” is performed by again having the patient fixate on the examiner’s nose. Each eye is tested by being covered, and then uncovered. If the uncovered eye has to move to refocus on the examiner’s nose, then the test is positive for a central lesion. A positive head impulse, positive horizontal nystagmus, and negative test of skew is 100% sensitive and 96% specific for a peripheral lesion.¹¹

Benign paroxysmal positional vertigo (BPPV) is vertigo that is triggered by movement of the head. It occurs when otoconia that are normally embedded in gel in the utricle become dislodged and migrate into the 3 fluid-filled semicircular canals, where they interfere with the normal fluid movement these canals use to sense head motion, causing the inner ear to send false signals to the brain.¹²

Diagnosis is confirmed by performing the Dix-Hallpike maneuver to elicit nystagmus. The patient is moved from a seated to a supine position with her head turned 45 degrees to the right and held for 30 seconds. For a demonstration of the Dix-Hallpike maneuver, see https://youtu.be/8RYB2QlO1N4. The Dix-Hallpike maneuver is also the first step of a treatment for BBPV known as the Epley maneuver. (See “The Epley maneuver: A procedure for treating BPPV”.^13,14)

Labyrinthitis—inflammation of the inner ear that can cause vertigo—is suggested by an acute, non-recurrent episode of dizziness that is often preceded by an upper respiratory infection. If the external canal is extremely painful and/or develops a vesicular rash, the patient might have herpes zoster of the geniculate ganglion (Ramsay Hunt syndrome type 2).

Dizziness related to presyncope often involves a cardiovascular pathology, such as a dysrhythmia or orthostatic hypotension.

Vertigo can have many possible causes

Vestibular migraine and Meniere’s disease. When a patient who has a history of migraines experiences symptoms of vertigo, vestibular migraine should be suspected, and treatment should focus on migraine therapy rather than vestibular therapy.¹⁵

Symptoms of Meniere’s disease and vestibular migraine can overlap.¹⁶ The current definition of Meniere’s disease requires ≥2 definitive episodes of vertigo with hearing loss plus tinnitus and/or aural symptoms.¹⁷ Thirty percent of vertigo episodes in patients with Meniere's disease can be attributed to BPPV.¹⁸

Acoustic neuroma. In addition to vertigo, acoustic neuroma is often associated with gradual hearing loss, tinnitus, and facial numbness (from compression of cranial nerve V preoperatively) or facial weakness (from compression of cranial nerve VII postoperatively). Unilateral hearing loss should prompt evaluation with magnetic resonance imaging.

“Acoustic neuroma” is a misnomer. The lesion arises from the vestibular (not the acoustic) portion of the 8th cranial nerve, and isn’t a neuroma; it is a schwannoma.¹⁹ Although it actually arises peripherally within the vestibular canal, it typically expands centrally and compresses other nerves centrally, which can make the clinical diagnosis more challenging if one were using the classical schema of differentiating between peripheral and central causes of vertigo.

Age-related vestibular loss occurs when the aging process causes deterioration of most of the components of the vestibulo-ocular reflex, resulting in dizziness and vertigo. Usually, the cerebral override mechanisms can compensate for the degeneration.

Other causes of vertigo include cerebellar infarction (3% of patients with vertigo),²⁰ sound-induced vertigo (Tullio phenomenon),²¹ obstructive sleep apnea,²² and systemic sclerosis.²³ Diabetes can cause a reduction in vestibular sensitivity that is evidenced by an increased reliance on visual stimuli to resolve vestibulo-visual conflict.²⁴

Disequilibrium

Disequilibrium is predominantly a loss of balance. Patients with disequilibrium have the feeling that they are about to fall, specifically without the sensation of spinning. They may appear to sway, and will reach out for something to support them. Disequilibrium can be a component of vertigo, or it may suggest a more specific diagnosis, such as ataxia, which is a lack of coordination when walking.

Atypical causes of dizziness

A positive head impulse test is highly suggestive of a peripheral lesion.

“Light-headedness” may have an element of euphoria or may be indistinguishable from the early part of a syncopal episode. Because other causes of light-headedness can be difficult to distinguish from presyncope, it is important to consider syncope in the differential diagnosis.

The differential of light-headedness can also include panic attack, early hyperventilation, and toxin exposure (such as diphenylarsinic acid,²⁵ pregabalin,²⁶ or paint thinner²⁷).

CORRESPONDENCE
Shannon Paul Starr, MD, Louisiana State University Health Sciences Center, 200 W. Esplanade #412, Kenner, LA 70065; [email protected].

When patients present with neurologic complaints in outpatient primary care practice, 2 key questions often arise: Should brain imaging be ordered, and if so, which study? Careful history-taking and physical exam findings can suggest differential diagnoses and help determine whether imaging studies could identify potential underlying causes. Further considerations in making a decision are the type of information each modality offers, the possible need for contrast media, benefits vs radiation exposure risks, potential contraindications, and cost and local availability. In this article, we present 3 common outpatient scenarios, and in each case we describe the evidence to support clinical decision-making about imaging.

The American College of Radiology (ACR) Appropriateness Criteria Web site (http://www.acr.org/Quality-Safety/Appropriateness-Criteria) provides radiation exposure information, numerical ratings of imaging studies for individual clinical scenarios, evidence tables, and reference tables for each of its recommendations.¹ ACR’s recommendations were developed by expert panels of diagnostic radiologists, interventional radiologists, and radiation oncologists, and designed to help physicians order the most appropriate imaging studies based on patients’ clinical conditions.² We used these criteria to develop an evaluation strategy for each of our clinical scenarios.

CASE 1 › Carrie D is a 45-year-old woman with a history of migraine without aura generally controlled with Excedrin (acetaminophen, aspirin, and caffeine). She arrives at your office with a 2-day history of severe headache over the top of her head and associated tingling sensation over the left side of her face, but with no vision changes, weakness, or slurred speech. She denies any prior history of numbness or tinging with past headaches. She is a business executive and reports that in the last few weeks, her company has been involved in a high-profile merger. On physical exam, her vital signs are within normal limits. She does not appear acutely ill, but on exam she reports diminished sensation to light touch over the left side of her face, left arm, and left leg compared with the right side.

›› What imaging options might you consider?

A prospective review of physicians in an ambulatory family practice setting found that neurologic imaging was typically ordered for patients with headache who were suspected of having a brain tumor or subarachnoid hemorrhage.³ For our patient, who has a history of migraines without aura and whose current severe headache is accompanied by an abnormal sensation on one side of the face, the following questions are relevant: Is this presentation part of her primary headache syndrome or could there be a different cause? If there is a different cause, is it likely to be detected with brain imaging such as computed tomography (CT) or magnetic resonance imaging (MRI)?

Patients with isolated headache and an absence of neurologic symptoms or abnormalities on neurologic exam are unlikely to have a clinically significant intracranial abnormality.^4-10 Imaging of the brain is typically not indicated for these patients.² However, given that this patient does have a positive focal neurologic finding, a CT or MRI is indicated, as findings are more likely to influence management decisions.

The decision to order CT or MRI should be based on how acutely ill the patient is. CT without contrast is an excellent tool to rule out suspected emergent intracranial abnormalities such as an intracranial hemorrhage, hydrocephalus, or a mass.¹¹ In patients presenting with symptoms suggesting acute illness such as carotid or vertebral artery dissection, the most appropriate test would be CT angiography of the head and neck.²

However, the list of less dire causes of headache is vast. Included in this list would be trauma, other vascular disorders such as arteriovenous malformation or temporal arteritis, infection, abnormal intracranial pressure (mass, pseudotumor cerebri, intracranial hypotension), and disorders of the head/face/spine (eg, temporomandibular joint disorder).¹²

In the non-acute setting where a patient has stable vital signs and is not in acute distress, an MRI with contrast would be the most appropriate test to identify such causes. Avoid contrast only if there is a firm contraindication, such as pregnancy, severely impaired renal function, or known allergy to gadolinium. If history and physical exam findings suggest possible stroke, arrange for MRI and MR angiography with contrast, even if the result of a head CT scan is negative. The ALGORITHM¹³ offers guidance for choosing imaging studies for headache based on history, physical exam, and laboratory findings.

›› And you order...

…an MRI of the brain with contrast.

Though Ms. D does have a focal neurologic finding in addition to her headache, she does not appear to be acutely ill. Ordering an MRI with contrast is the best first step.

Patients with isolated headache and no other symptoms on neurologic exam are unlikely to have a significant intracranial abnormality.

CASE 2 › Anne B is a 72-year-old woman with a history of hypertension, hyperlipidemia, and type 2 diabetes. Her daughter brings her in to see you because she is concerned about Ms. B’s memory. Ms. B’s daughter reports that she has become increasingly forgetful over the past 6 months, often forgetting recent events. At first the forgetfulness was occasional, but now it seems to happen daily and interfere with activities of daily living (ADLs). The week before this visit, Ms. B left a pot heating on the stove because she forgot she had started cooking. She realized what had happened only when her smoke alarm went off. Ms. B’s daughter also thinks her mother may be taking some of her medications incorrectly.

Physical exam and laboratory findings are unremarkable. On the mental status exam, Ms. B has difficulty with registration and recall.

›› What imaging options might you consider? 

Ms. B has exhibited progressive memory loss over 6 months and it is now affecting her ADLs. Her symptoms could be secondary to any one of many reversible medical causes, such as adverse medication effects, depression, or vitamin B12 deficiency. If clinical and laboratory evaluations exclude these reversible causes, consider dementia.

With numerous disorders having overlapping symptoms, the diagnosis of degenerative central nervous system (CNS) disease can be extremely tricky. Complicating the issue is the fact that a single patient can have 2 or more concurrent neurodegenerative diseases. Clinical testing is essential in the diagnosis and management of degenerative CNS diseases, but testing sensitivity and specificity are highly variable depending upon the disease.¹⁴

Neuroimaging is an important supplement to clinical testing in excluding intracranial abnormalities. There are significant negative consequences of missing reversible causes of memory problems and incorrectly assigning a clinical diagnosis of dementia. Neuroimaging can be subdivided into structural and functional imaging, and structural imaging is the first step in evaluation.¹⁵

The American Academy of Neurology recommends the use of structural neuroimaging with CT or MRI in the initial evaluation of patients with dementia to detect such treatable problems as a subdural hematoma, frontal lobe mass, or hydrocephalus.¹² Structural imaging may also identify anatomic changes characteristic of degenerative CNS diseases such as Alzheimer’s disease, dementia with Lewy bodies, frontotemporal dementia, vascular dementia, Creutzfeldt-Jakob disease, and Huntington’s disease; however, sensitivities and specificities of testing are low.¹⁴

›› And you order...

…an MRI of the brain without contrast.

In Ms. B’s case, structural neuroimaging is indicated as part of the initial work-up of supposed dementia. An MRI without contrast is recommended over CT because it is more sensitive in detecting white matter changes in vascular dementia.¹⁶ In cases where an MRI >is unavailable or contraindicated (eg, a patient with a pacemaker), a CT is a reasonable alternative.

CASE 3 › Bob C is a 78-year-old man with a history of chronic obstructive pulmonary disease and hypertension who arrives at your walk-in clinic accompanied by his home health aide a few hours after having tripped and fallen over a rug at home. At baseline, Mr. C is ambulatory and independent in ADLs.

He takes all of his medications, including a daily baby aspirin (81 mg). Mr. C says he did not lose consciousness at the time of the fall and insists he feels fine, but you notice a bruise developing over his right temporal skull.

›› What imaging options might you consider?  

With acute head trauma deemed severe enough clinically to warrant imaging, non-contrast CT is the most appropriate initial test to identify possible intracranial hemorrhage.¹¹ The Glasgow Coma Scale (GCS) is the tool most widely used for clinical evaluation¹⁷ (TABLE 1¹⁸). The score is based on an assessment of 3 features: eye response, speech, and movement. Head injury is classified as mild (13-15), moderate (9-12), or severe (≤8). It is universally agreed that patients with moderate or severe head injury should be further evaluated with a head CT.

With mild head injury, recommendations for follow-up are less straightforward. The New Orleans Criteria (NOC) and Canadian CT Head Rule (CCHR) are commonly used in triaging patients with minor head trauma in a cost effective way¹¹ (TABLES 2¹⁹ and 3²⁰). The cost-effectiveness of these assessment tools is still questionable, but both have very high sensitivity for identifying patients who will require neurosurgery intervention.^21,22 Although the NOC is slightly more sensitive at identifying patients with nonsurgical clinically significant abnormalities, it has a greatly reduced specificity compared with the CCHR.^23-25

›› And you order...

…a non-contrast head CT.

For patients with symptoms suggesting acute illness such as carotid or vertebral artery dissection, order CT angiography of the head and neck.

Mr. C presents with a GCS of 15, indicating mild head trauma. However, in elderly patients, especially ones taking anticoagulation medication, even mild trauma can result in clinically significant abnormalities such as a subdural hematoma.¹ Although Mr. C’s physical and neurologic exams are not worrisome, both the NOC and CCHR recommend further evaluation with a non-contrast head CT based on his age.

CORRESPONDENCE
Urmi A. Desai, MD, MS, Columbia University Medical Center, 610 West 158th Street, New York, NY 10032; [email protected].

When patients present with neurologic complaints in outpatient primary care practice, 2 key questions often arise: Should brain imaging be ordered, and if so, which study? Careful history-taking and physical exam findings can suggest differential diagnoses and help determine whether imaging studies could identify potential underlying causes. Further considerations in making a decision are the type of information each modality offers, the possible need for contrast media, benefits vs radiation exposure risks, potential contraindications, and cost and local availability. In this article, we present 3 common outpatient scenarios, and in each case we describe the evidence to support clinical decision-making about imaging.

The American College of Radiology (ACR) Appropriateness Criteria Web site (http://www.acr.org/Quality-Safety/Appropriateness-Criteria) provides radiation exposure information, numerical ratings of imaging studies for individual clinical scenarios, evidence tables, and reference tables for each of its recommendations.¹ ACR’s recommendations were developed by expert panels of diagnostic radiologists, interventional radiologists, and radiation oncologists, and designed to help physicians order the most appropriate imaging studies based on patients’ clinical conditions.² We used these criteria to develop an evaluation strategy for each of our clinical scenarios.

CASE 1 › Carrie D is a 45-year-old woman with a history of migraine without aura generally controlled with Excedrin (acetaminophen, aspirin, and caffeine). She arrives at your office with a 2-day history of severe headache over the top of her head and associated tingling sensation over the left side of her face, but with no vision changes, weakness, or slurred speech. She denies any prior history of numbness or tinging with past headaches. She is a business executive and reports that in the last few weeks, her company has been involved in a high-profile merger. On physical exam, her vital signs are within normal limits. She does not appear acutely ill, but on exam she reports diminished sensation to light touch over the left side of her face, left arm, and left leg compared with the right side.

›› What imaging options might you consider?

A prospective review of physicians in an ambulatory family practice setting found that neurologic imaging was typically ordered for patients with headache who were suspected of having a brain tumor or subarachnoid hemorrhage.³ For our patient, who has a history of migraines without aura and whose current severe headache is accompanied by an abnormal sensation on one side of the face, the following questions are relevant: Is this presentation part of her primary headache syndrome or could there be a different cause? If there is a different cause, is it likely to be detected with brain imaging such as computed tomography (CT) or magnetic resonance imaging (MRI)?

Patients with isolated headache and an absence of neurologic symptoms or abnormalities on neurologic exam are unlikely to have a clinically significant intracranial abnormality.^4-10 Imaging of the brain is typically not indicated for these patients.² However, given that this patient does have a positive focal neurologic finding, a CT or MRI is indicated, as findings are more likely to influence management decisions.

The decision to order CT or MRI should be based on how acutely ill the patient is. CT without contrast is an excellent tool to rule out suspected emergent intracranial abnormalities such as an intracranial hemorrhage, hydrocephalus, or a mass.¹¹ In patients presenting with symptoms suggesting acute illness such as carotid or vertebral artery dissection, the most appropriate test would be CT angiography of the head and neck.²

However, the list of less dire causes of headache is vast. Included in this list would be trauma, other vascular disorders such as arteriovenous malformation or temporal arteritis, infection, abnormal intracranial pressure (mass, pseudotumor cerebri, intracranial hypotension), and disorders of the head/face/spine (eg, temporomandibular joint disorder).¹²

In the non-acute setting where a patient has stable vital signs and is not in acute distress, an MRI with contrast would be the most appropriate test to identify such causes. Avoid contrast only if there is a firm contraindication, such as pregnancy, severely impaired renal function, or known allergy to gadolinium. If history and physical exam findings suggest possible stroke, arrange for MRI and MR angiography with contrast, even if the result of a head CT scan is negative. The ALGORITHM¹³ offers guidance for choosing imaging studies for headache based on history, physical exam, and laboratory findings.

›› And you order...

…an MRI of the brain with contrast.

Though Ms. D does have a focal neurologic finding in addition to her headache, she does not appear to be acutely ill. Ordering an MRI with contrast is the best first step.

Patients with isolated headache and no other symptoms on neurologic exam are unlikely to have a significant intracranial abnormality.

CASE 2 › Anne B is a 72-year-old woman with a history of hypertension, hyperlipidemia, and type 2 diabetes. Her daughter brings her in to see you because she is concerned about Ms. B’s memory. Ms. B’s daughter reports that she has become increasingly forgetful over the past 6 months, often forgetting recent events. At first the forgetfulness was occasional, but now it seems to happen daily and interfere with activities of daily living (ADLs). The week before this visit, Ms. B left a pot heating on the stove because she forgot she had started cooking. She realized what had happened only when her smoke alarm went off. Ms. B’s daughter also thinks her mother may be taking some of her medications incorrectly.

Physical exam and laboratory findings are unremarkable. On the mental status exam, Ms. B has difficulty with registration and recall.

›› What imaging options might you consider? 

Ms. B has exhibited progressive memory loss over 6 months and it is now affecting her ADLs. Her symptoms could be secondary to any one of many reversible medical causes, such as adverse medication effects, depression, or vitamin B12 deficiency. If clinical and laboratory evaluations exclude these reversible causes, consider dementia.

With numerous disorders having overlapping symptoms, the diagnosis of degenerative central nervous system (CNS) disease can be extremely tricky. Complicating the issue is the fact that a single patient can have 2 or more concurrent neurodegenerative diseases. Clinical testing is essential in the diagnosis and management of degenerative CNS diseases, but testing sensitivity and specificity are highly variable depending upon the disease.¹⁴

Neuroimaging is an important supplement to clinical testing in excluding intracranial abnormalities. There are significant negative consequences of missing reversible causes of memory problems and incorrectly assigning a clinical diagnosis of dementia. Neuroimaging can be subdivided into structural and functional imaging, and structural imaging is the first step in evaluation.¹⁵

The American Academy of Neurology recommends the use of structural neuroimaging with CT or MRI in the initial evaluation of patients with dementia to detect such treatable problems as a subdural hematoma, frontal lobe mass, or hydrocephalus.¹² Structural imaging may also identify anatomic changes characteristic of degenerative CNS diseases such as Alzheimer’s disease, dementia with Lewy bodies, frontotemporal dementia, vascular dementia, Creutzfeldt-Jakob disease, and Huntington’s disease; however, sensitivities and specificities of testing are low.¹⁴

›› And you order...

…an MRI of the brain without contrast.

In Ms. B’s case, structural neuroimaging is indicated as part of the initial work-up of supposed dementia. An MRI without contrast is recommended over CT because it is more sensitive in detecting white matter changes in vascular dementia.¹⁶ In cases where an MRI >is unavailable or contraindicated (eg, a patient with a pacemaker), a CT is a reasonable alternative.

CASE 3 › Bob C is a 78-year-old man with a history of chronic obstructive pulmonary disease and hypertension who arrives at your walk-in clinic accompanied by his home health aide a few hours after having tripped and fallen over a rug at home. At baseline, Mr. C is ambulatory and independent in ADLs.

He takes all of his medications, including a daily baby aspirin (81 mg). Mr. C says he did not lose consciousness at the time of the fall and insists he feels fine, but you notice a bruise developing over his right temporal skull.

›› What imaging options might you consider?  

With acute head trauma deemed severe enough clinically to warrant imaging, non-contrast CT is the most appropriate initial test to identify possible intracranial hemorrhage.¹¹ The Glasgow Coma Scale (GCS) is the tool most widely used for clinical evaluation¹⁷ (TABLE 1¹⁸). The score is based on an assessment of 3 features: eye response, speech, and movement. Head injury is classified as mild (13-15), moderate (9-12), or severe (≤8). It is universally agreed that patients with moderate or severe head injury should be further evaluated with a head CT.

With mild head injury, recommendations for follow-up are less straightforward. The New Orleans Criteria (NOC) and Canadian CT Head Rule (CCHR) are commonly used in triaging patients with minor head trauma in a cost effective way¹¹ (TABLES 2¹⁹ and 3²⁰). The cost-effectiveness of these assessment tools is still questionable, but both have very high sensitivity for identifying patients who will require neurosurgery intervention.^21,22 Although the NOC is slightly more sensitive at identifying patients with nonsurgical clinically significant abnormalities, it has a greatly reduced specificity compared with the CCHR.^23-25

›› And you order...

…a non-contrast head CT.

For patients with symptoms suggesting acute illness such as carotid or vertebral artery dissection, order CT angiography of the head and neck.

Mr. C presents with a GCS of 15, indicating mild head trauma. However, in elderly patients, especially ones taking anticoagulation medication, even mild trauma can result in clinically significant abnormalities such as a subdural hematoma.¹ Although Mr. C’s physical and neurologic exams are not worrisome, both the NOC and CCHR recommend further evaluation with a non-contrast head CT based on his age.

CORRESPONDENCE
Urmi A. Desai, MD, MS, Columbia University Medical Center, 610 West 158th Street, New York, NY 10032; [email protected].

When patients present with neurologic complaints in outpatient primary care practice, 2 key questions often arise: Should brain imaging be ordered, and if so, which study? Careful history-taking and physical exam findings can suggest differential diagnoses and help determine whether imaging studies could identify potential underlying causes. Further considerations in making a decision are the type of information each modality offers, the possible need for contrast media, benefits vs radiation exposure risks, potential contraindications, and cost and local availability. In this article, we present 3 common outpatient scenarios, and in each case we describe the evidence to support clinical decision-making about imaging.

The American College of Radiology (ACR) Appropriateness Criteria Web site (http://www.acr.org/Quality-Safety/Appropriateness-Criteria) provides radiation exposure information, numerical ratings of imaging studies for individual clinical scenarios, evidence tables, and reference tables for each of its recommendations.¹ ACR’s recommendations were developed by expert panels of diagnostic radiologists, interventional radiologists, and radiation oncologists, and designed to help physicians order the most appropriate imaging studies based on patients’ clinical conditions.² We used these criteria to develop an evaluation strategy for each of our clinical scenarios.

CASE 1 › Carrie D is a 45-year-old woman with a history of migraine without aura generally controlled with Excedrin (acetaminophen, aspirin, and caffeine). She arrives at your office with a 2-day history of severe headache over the top of her head and associated tingling sensation over the left side of her face, but with no vision changes, weakness, or slurred speech. She denies any prior history of numbness or tinging with past headaches. She is a business executive and reports that in the last few weeks, her company has been involved in a high-profile merger. On physical exam, her vital signs are within normal limits. She does not appear acutely ill, but on exam she reports diminished sensation to light touch over the left side of her face, left arm, and left leg compared with the right side.

›› What imaging options might you consider?

A prospective review of physicians in an ambulatory family practice setting found that neurologic imaging was typically ordered for patients with headache who were suspected of having a brain tumor or subarachnoid hemorrhage.³ For our patient, who has a history of migraines without aura and whose current severe headache is accompanied by an abnormal sensation on one side of the face, the following questions are relevant: Is this presentation part of her primary headache syndrome or could there be a different cause? If there is a different cause, is it likely to be detected with brain imaging such as computed tomography (CT) or magnetic resonance imaging (MRI)?

Patients with isolated headache and an absence of neurologic symptoms or abnormalities on neurologic exam are unlikely to have a clinically significant intracranial abnormality.^4-10 Imaging of the brain is typically not indicated for these patients.² However, given that this patient does have a positive focal neurologic finding, a CT or MRI is indicated, as findings are more likely to influence management decisions.

The decision to order CT or MRI should be based on how acutely ill the patient is. CT without contrast is an excellent tool to rule out suspected emergent intracranial abnormalities such as an intracranial hemorrhage, hydrocephalus, or a mass.¹¹ In patients presenting with symptoms suggesting acute illness such as carotid or vertebral artery dissection, the most appropriate test would be CT angiography of the head and neck.²

However, the list of less dire causes of headache is vast. Included in this list would be trauma, other vascular disorders such as arteriovenous malformation or temporal arteritis, infection, abnormal intracranial pressure (mass, pseudotumor cerebri, intracranial hypotension), and disorders of the head/face/spine (eg, temporomandibular joint disorder).¹²

In the non-acute setting where a patient has stable vital signs and is not in acute distress, an MRI with contrast would be the most appropriate test to identify such causes. Avoid contrast only if there is a firm contraindication, such as pregnancy, severely impaired renal function, or known allergy to gadolinium. If history and physical exam findings suggest possible stroke, arrange for MRI and MR angiography with contrast, even if the result of a head CT scan is negative. The ALGORITHM¹³ offers guidance for choosing imaging studies for headache based on history, physical exam, and laboratory findings.

›› And you order...

…an MRI of the brain with contrast.

Though Ms. D does have a focal neurologic finding in addition to her headache, she does not appear to be acutely ill. Ordering an MRI with contrast is the best first step.

Patients with isolated headache and no other symptoms on neurologic exam are unlikely to have a significant intracranial abnormality.

CASE 2 › Anne B is a 72-year-old woman with a history of hypertension, hyperlipidemia, and type 2 diabetes. Her daughter brings her in to see you because she is concerned about Ms. B’s memory. Ms. B’s daughter reports that she has become increasingly forgetful over the past 6 months, often forgetting recent events. At first the forgetfulness was occasional, but now it seems to happen daily and interfere with activities of daily living (ADLs). The week before this visit, Ms. B left a pot heating on the stove because she forgot she had started cooking. She realized what had happened only when her smoke alarm went off. Ms. B’s daughter also thinks her mother may be taking some of her medications incorrectly.

Physical exam and laboratory findings are unremarkable. On the mental status exam, Ms. B has difficulty with registration and recall.

›› What imaging options might you consider? 

Ms. B has exhibited progressive memory loss over 6 months and it is now affecting her ADLs. Her symptoms could be secondary to any one of many reversible medical causes, such as adverse medication effects, depression, or vitamin B12 deficiency. If clinical and laboratory evaluations exclude these reversible causes, consider dementia.

With numerous disorders having overlapping symptoms, the diagnosis of degenerative central nervous system (CNS) disease can be extremely tricky. Complicating the issue is the fact that a single patient can have 2 or more concurrent neurodegenerative diseases. Clinical testing is essential in the diagnosis and management of degenerative CNS diseases, but testing sensitivity and specificity are highly variable depending upon the disease.¹⁴

Neuroimaging is an important supplement to clinical testing in excluding intracranial abnormalities. There are significant negative consequences of missing reversible causes of memory problems and incorrectly assigning a clinical diagnosis of dementia. Neuroimaging can be subdivided into structural and functional imaging, and structural imaging is the first step in evaluation.¹⁵

The American Academy of Neurology recommends the use of structural neuroimaging with CT or MRI in the initial evaluation of patients with dementia to detect such treatable problems as a subdural hematoma, frontal lobe mass, or hydrocephalus.¹² Structural imaging may also identify anatomic changes characteristic of degenerative CNS diseases such as Alzheimer’s disease, dementia with Lewy bodies, frontotemporal dementia, vascular dementia, Creutzfeldt-Jakob disease, and Huntington’s disease; however, sensitivities and specificities of testing are low.¹⁴

›› And you order...

…an MRI of the brain without contrast.

In Ms. B’s case, structural neuroimaging is indicated as part of the initial work-up of supposed dementia. An MRI without contrast is recommended over CT because it is more sensitive in detecting white matter changes in vascular dementia.¹⁶ In cases where an MRI >is unavailable or contraindicated (eg, a patient with a pacemaker), a CT is a reasonable alternative.

CASE 3 › Bob C is a 78-year-old man with a history of chronic obstructive pulmonary disease and hypertension who arrives at your walk-in clinic accompanied by his home health aide a few hours after having tripped and fallen over a rug at home. At baseline, Mr. C is ambulatory and independent in ADLs.

He takes all of his medications, including a daily baby aspirin (81 mg). Mr. C says he did not lose consciousness at the time of the fall and insists he feels fine, but you notice a bruise developing over his right temporal skull.

›› What imaging options might you consider?  

With acute head trauma deemed severe enough clinically to warrant imaging, non-contrast CT is the most appropriate initial test to identify possible intracranial hemorrhage.¹¹ The Glasgow Coma Scale (GCS) is the tool most widely used for clinical evaluation¹⁷ (TABLE 1¹⁸). The score is based on an assessment of 3 features: eye response, speech, and movement. Head injury is classified as mild (13-15), moderate (9-12), or severe (≤8). It is universally agreed that patients with moderate or severe head injury should be further evaluated with a head CT.

With mild head injury, recommendations for follow-up are less straightforward. The New Orleans Criteria (NOC) and Canadian CT Head Rule (CCHR) are commonly used in triaging patients with minor head trauma in a cost effective way¹¹ (TABLES 2¹⁹ and 3²⁰). The cost-effectiveness of these assessment tools is still questionable, but both have very high sensitivity for identifying patients who will require neurosurgery intervention.^21,22 Although the NOC is slightly more sensitive at identifying patients with nonsurgical clinically significant abnormalities, it has a greatly reduced specificity compared with the CCHR.^23-25

›› And you order...

…a non-contrast head CT.

For patients with symptoms suggesting acute illness such as carotid or vertebral artery dissection, order CT angiography of the head and neck.

Mr. C presents with a GCS of 15, indicating mild head trauma. However, in elderly patients, especially ones taking anticoagulation medication, even mild trauma can result in clinically significant abnormalities such as a subdural hematoma.¹ Although Mr. C’s physical and neurologic exams are not worrisome, both the NOC and CCHR recommend further evaluation with a non-contrast head CT based on his age.

CORRESPONDENCE
Urmi A. Desai, MD, MS, Columbia University Medical Center, 610 West 158th Street, New York, NY 10032; [email protected].

It is no secret that about half of all pregnancies in the United States are unintended, and that teens have the highest rate of unplanned pregnancy. What’s not so well known is that women in their 40s have the second highest rate.¹

Optimal use of contraception throughout perimenopause is crucial, but finding the right method of birth control for this patient population can be a bit of a balancing act. Long-acting reversible contraceptives (LARCs), such as an intrauterine device or progestin-only implant, are preferred first-line contraceptive options when preventing pregnancy is the primary goal, given their increased efficacy and limited number of contraindications.^2,3 However, women experiencing perimenopausal symptoms often need a combination hormonal contraceptive (CHC)—typically an estrogen-containing pill, a patch, or a vaginal ring—for relief of vasomotor symptoms and cycle control.

Women in their 40s should have access to a full array of options to help improve adherence. However, physicians may be reluctant to prescribe estrogen-containing products for patients who often have a more complex medical history than their younger counterparts, including increased risks for breast cancer, cardiovascular disease, and venous thromboembolism (VTE).

With this in mind, the Centers for Disease Control and Prevention (CDC) has identified medical conditions that may affect the use of the various types of contraceptives by perimenopausal women and issued evidence-based recommendations on the appropriateness of each method using a one-to-4 rating system (TABLE 1).² To help you address the contraceptive needs of such patients, we review the key risk factors, CDC guidelines, and optimal choices in the 4 case studies that follow.

CASE 1 › Sara G: VTE risk 

Sara G, a healthy 45-year-old, recently started dating again following her divorce. She wants to avoid pregnancy. She has no personal or family history of clotting disorders and does not smoke. However, she is obese (body mass index [BMI]=32 kg/m²), and her job as a visiting nurse requires her to spend most of the day in her car. Ms. G also has acne and wants an estrogen-containing contraceptive to help treat it.

If Ms. G were your patient, what would you offer her?

The risk for VTE increases substantially for women older than 40 years. In a recent cohort study, those ages 45 to 49 faced approximately twice the risk of women ages 25 to 29. However, the absolute risk for the older women was still low (4.7-5.3 per 10,000 woman-years).⁴ What’s more, the risk of VTE from the use of a CHC is substantially less than the risk associated with pregnancy and the postpartum period (TABLE 2).⁵

Obesity increases the risk. Women like Ms. G who are obese (BMI >30) have an increased risk for VTE associated with CHCs, but the CDC rates them as a Category 2 risk, even for obese women in their 40s—a determination that the advantages outweigh the risks.²

Progestin choice and estrogen dose matter. Combination oral contraceptives (COCs) that contain certain third-generation progestins (gestodene and desogestrel) may be more thrombophilic than those containing first- or second-generation progestins (TABLE 3).⁶ The relative risk (RR) for VTE with third-generation vs second-generation progestins is 1.3 (95% confidence interval [CI], 1.0-1.8).⁷ Formulations containing higher doses of estrogen are also more likely to be associated with VTE.⁷

Drospirenone is a newer progestin. Found in several COCs, drospirenone has antimineralocorticoid properties that help to minimize bloating and fluid retention but may also lead to a hypercoagulable state.⁵ Numerous studies have investigated the association between drospirenone and VTE risk, with conflicting results.⁸ Most recently, a large international prospective observational study involving more than 85,000 women showed no increased risk for VTE among women taking COCs with drospirenone compared with pills that do not contain this progestin.⁹

Non-oral CHCs, including the vaginal ring and the patch, offer the convenience of weekly or monthly use while providing similar benefits to COCs. Some fear that the continuous exposure to hormones associated with these methods may increase the risk for VTE, but evidence is mixed.

A large (N=1.6 million) Danish registry study published in 2012 demonstrated a 2-fold increased risk of VTE among vaginal ring users vs women taking COCs.⁴ But a multinational prospective cohort study of more than 33,000 women found no increased VTE risk in ring users,10 and a recent US database study involving more than 800,000 women reported nonsignificant VTE risk estimates for both the ring (RR=1.09; 95% CI, 0.55-2.16) and the patch (RR=1.35; 95% CI, 0.90-2.02) compared with COCs.¹¹

THE BOTTOM LINE For Ms. G, the benefits of contraception likely outweigh any small increase in her absolute risk for VTE. To minimize her risk, however, select a pill that contains a low dose (20-35 mcg) of ethinyl estradiol (EE) combined with a progestin that has not been associated with an increased VTE risk. Because of their mechanism of action, most COCs will improve acne, regardless of the progestin in the formulation.^12-14

CASE 2 › Stephanie T: CV risk

Stephanie T, 47, is in need of contraception and treatment for severe hot flashes. She has no significant past medical history, but she is obese (BMI =36), her blood pressure (BP) is 130/80 mm Hg, and her most recent labs reveal a fasting glucose of 115 and a hemoglobin A1c of 6.1%. Ms. T is concerned about arterial thromboembolic disease because of her family history: Her father had a myocardial infarction (MI) at age 56 and a maternal aunt had a stroke when she was 65.

What evidence should you consider?

Baseline arterial thromboembolic events are considerably more rare in premenopausal women than VTEs (13.2 MIs vs 24.2 thrombotic strokes per 100,000 woman-years).¹⁵ Thus, a small increased RR from a CHC is unlikely to have a significant clinical impact.

Some third-generation progestins appear to be more thrombophilic than firs tor second-generation progestins.

A systemic review and meta-analysis of studies between 1995 and 2012 showed that the odds ratio (OR) of ischemic stroke in users of COCs vs nonusers was 1.9 (95% CI, 1.24–2.91).¹⁶ This study included very few estrogen formulations with <35 mcg EE, however; even so, no increased risk of MI was found (OR=1.34; 95% CI, 0.87–2.08).¹⁶ A 15-year retrospective cohort study of 1.6 million Danish women showed that lowering the dose of EE to 20 mcg (from 30-40 mcg) significantly reduced the risk of arterial events.¹⁵ It is unclear whether the vaginal ring is associated with an increased RR of stroke compared with COCs because studies have had mixed results.^10,15 There is no compelling evidence to suggest a difference in the risk of arterial events based on the type of progestin used in the COC.¹⁵

Hypertension is a key consideration. It is important to remember that perimenopausal women may have comorbid conditions that increase their risk of arterial thromboembolic events. CHCs should be used with caution in women with hypertension, even if BP is adequately controlled—a Category 3 recommendation from the CDC. In such patients, LARC or a progestin-only pill is preferred unless there is a compelling reason to use a CHC, such as acne, vasomotor symptoms, or hirsutism.²

CHCs are contraindicated for women with a BP ≥160/100 mm Hg and/or any manifestation of vascular disease (Category 4).² Although progestin-only methods are often preferred for women with established vascular disease, depot medroxyprogesterone acetate (DMPA) is an exception (Category 3).² DMPA is not a first-line choice for such patients because of its potential to cause weight gain and worsening lipids, glucose, and insulin metabolism. Women with hypertriglyceridemia should have follow-up testing of lipid levels after initiation of hormonal contraception, especially if it contains estrogen.

Diabetes is not an absolute contraindication. Many women with diabetes can safely use CHCs (Category 2). The exceptions: those who have vascular disease, nephropathy, retinopathy, or neuropathy (Category 4) or have had diabetes for >20 years and therefore have the potential for undiagnosed vascular disease.² Generally, the use of insulin should not affect decisions regarding CHCs, and patients can be reassured that the hormones will not worsen their diabetes control.

When caring for women who have multiple risk factors for cardiovascular disease, it is important to exercise clinical judgment regarding the appropriateness of CHCs (Categories 3 and 4). Progestin-only methods have a more favorable risk profile for women at the highest risk and may provide ample relief of perimenopausal symptoms.²

THE BOTTOM LINE Ms. T may benefit from a CHC due to her severe hot flashes. She should be encouraged to adopt healthy lifestyle changes, including diet and exercise, to decrease her risk of arterial thromboembolism and VTE, but she has no contraindications to the use of a CHC at this time.

CASE 3 › Leslie C: Bone health

Leslie C, age 45, is happy with the contraceptive he has used for the past 3 years—DMPA injections every 3 months. She has no perimenopausal symptoms. However, her mother had an osteoporotic hip fracture at age 70 and Ms. C is concerned about the long-term use of DMPA.

Should Ms. C be worried?

Because of DMPA’s association with bone loss, the US Food and Drug Administration issued a black box warning in 2004 recommending that this method be used for more than 2 years only by women for whom other birth control methods are deemed inappropriate.¹⁷

Bone loss associated with longer-term use of DMPA is a greater concern for perimenopausal women because they have fewer years to recover the bone mineral density after discontinuing the contraceptive.

The bone loss may be reversed. Evidence suggests that the bone loss is reversible, however, and the American College of Obstetricians and Gynecologists has stated that a potential fracture risk need not limit a woman’s use of DMPA to 2 years.¹⁸ A retrospective cohort review of 312,295 women in the United Kingdom did not find evidence of an increased risk of fracture with long-term use of DMPA.¹⁹ It is important to note, however, that because of declining estrogen levels, perimenopausal women have fewer years than their younger counterparts to recover bone density upon discontinuation of DMPA.^20,21

THE BOTTOM LINE Because Ms. C has no perimenopausal symptoms, she may do well with LARC, which—like DMPA —would free her of the need to remember to take, apply, or insert a contraceptive regularly. It may help to point out that LARCs provide superior contraceptive efficacy compared with DMPA injections (99% vs 94%).³ Nonetheless, she and other women in their 40s who need ongoing contraception should not be discouraged from using DMPA if that is their preference.

CASE 4 › Alissa B: Breast cancer risk

Alissa B, 49, has polycystic ovaries and wonders if it is safe for her to continue her COC. She has been happy with the treatment for years because it gives her relief from hot flashes and regulates her cycles. Her 46-year-old sister was recently diagnosed with invasive breast cancer, however, and Ms. B is afraid that the hormones she takes put her at increased risk.

Should you recommend another method?

Breast cancer is an important concern for many women as they age. Although Ms. B’s family history increases her risk for developing breast cancer, a systematic review indicates that COCs do not add to this risk.²²

Weak association between family history and OC use. The review included 10 observational studies and one meta-analysis that investigated the association between COC use and breast cancer in women with a family history of the disease. Only 2 fair-quality studies showed an association, one of which included women who had begun taking the pill before 1975, when formulations typically contained higher doses of estrogen than present-day preparations.²²

The lower doses of estrogen in today’s combination oral contraceptives do not appear to significantly increase the risk of breast cancer.

Data from a recently published meta-analysis also indicate that there is no increased risk for breast cancer from COCs among women with BRCA 1 or BRCA 2 mutations. The summary RR for breast cancer in such patients was 1.13 (95% CI, 0.88-1.45), but OC users had a lower risk for ovarian cancer (summary RR=0.50; 95% CI, 0.33-0.75).²³ Additionally, investigators found no association between specific currently used COC formulations and breast cancer.²⁴

THE BOTTOM LINE Based on an independent review of the evidence, the CDC has given a family history of breast cancer a Category 1 rating. Thus, Ms. B can be reassured that she may safely continue taking her COC, which is unlikely to increase her breast cancer risk.

CORRESPONDENCE
Pelin Batur, MD, NCMP, CCD, Cleveland Clinic Independence Family Health Center, 5001 Rockside Road, IN30, Cleveland, OH 44131; [email protected].

It is no secret that about half of all pregnancies in the United States are unintended, and that teens have the highest rate of unplanned pregnancy. What’s not so well known is that women in their 40s have the second highest rate.¹

Optimal use of contraception throughout perimenopause is crucial, but finding the right method of birth control for this patient population can be a bit of a balancing act. Long-acting reversible contraceptives (LARCs), such as an intrauterine device or progestin-only implant, are preferred first-line contraceptive options when preventing pregnancy is the primary goal, given their increased efficacy and limited number of contraindications.^2,3 However, women experiencing perimenopausal symptoms often need a combination hormonal contraceptive (CHC)—typically an estrogen-containing pill, a patch, or a vaginal ring—for relief of vasomotor symptoms and cycle control.

Women in their 40s should have access to a full array of options to help improve adherence. However, physicians may be reluctant to prescribe estrogen-containing products for patients who often have a more complex medical history than their younger counterparts, including increased risks for breast cancer, cardiovascular disease, and venous thromboembolism (VTE).

With this in mind, the Centers for Disease Control and Prevention (CDC) has identified medical conditions that may affect the use of the various types of contraceptives by perimenopausal women and issued evidence-based recommendations on the appropriateness of each method using a one-to-4 rating system (TABLE 1).² To help you address the contraceptive needs of such patients, we review the key risk factors, CDC guidelines, and optimal choices in the 4 case studies that follow.

CASE 1 › Sara G: VTE risk 

Sara G, a healthy 45-year-old, recently started dating again following her divorce. She wants to avoid pregnancy. She has no personal or family history of clotting disorders and does not smoke. However, she is obese (body mass index [BMI]=32 kg/m²), and her job as a visiting nurse requires her to spend most of the day in her car. Ms. G also has acne and wants an estrogen-containing contraceptive to help treat it.

If Ms. G were your patient, what would you offer her?

The risk for VTE increases substantially for women older than 40 years. In a recent cohort study, those ages 45 to 49 faced approximately twice the risk of women ages 25 to 29. However, the absolute risk for the older women was still low (4.7-5.3 per 10,000 woman-years).⁴ What’s more, the risk of VTE from the use of a CHC is substantially less than the risk associated with pregnancy and the postpartum period (TABLE 2).⁵

Obesity increases the risk. Women like Ms. G who are obese (BMI >30) have an increased risk for VTE associated with CHCs, but the CDC rates them as a Category 2 risk, even for obese women in their 40s—a determination that the advantages outweigh the risks.²

Progestin choice and estrogen dose matter. Combination oral contraceptives (COCs) that contain certain third-generation progestins (gestodene and desogestrel) may be more thrombophilic than those containing first- or second-generation progestins (TABLE 3).⁶ The relative risk (RR) for VTE with third-generation vs second-generation progestins is 1.3 (95% confidence interval [CI], 1.0-1.8).⁷ Formulations containing higher doses of estrogen are also more likely to be associated with VTE.⁷

Drospirenone is a newer progestin. Found in several COCs, drospirenone has antimineralocorticoid properties that help to minimize bloating and fluid retention but may also lead to a hypercoagulable state.⁵ Numerous studies have investigated the association between drospirenone and VTE risk, with conflicting results.⁸ Most recently, a large international prospective observational study involving more than 85,000 women showed no increased risk for VTE among women taking COCs with drospirenone compared with pills that do not contain this progestin.⁹

Non-oral CHCs, including the vaginal ring and the patch, offer the convenience of weekly or monthly use while providing similar benefits to COCs. Some fear that the continuous exposure to hormones associated with these methods may increase the risk for VTE, but evidence is mixed.

A large (N=1.6 million) Danish registry study published in 2012 demonstrated a 2-fold increased risk of VTE among vaginal ring users vs women taking COCs.⁴ But a multinational prospective cohort study of more than 33,000 women found no increased VTE risk in ring users,10 and a recent US database study involving more than 800,000 women reported nonsignificant VTE risk estimates for both the ring (RR=1.09; 95% CI, 0.55-2.16) and the patch (RR=1.35; 95% CI, 0.90-2.02) compared with COCs.¹¹

THE BOTTOM LINE For Ms. G, the benefits of contraception likely outweigh any small increase in her absolute risk for VTE. To minimize her risk, however, select a pill that contains a low dose (20-35 mcg) of ethinyl estradiol (EE) combined with a progestin that has not been associated with an increased VTE risk. Because of their mechanism of action, most COCs will improve acne, regardless of the progestin in the formulation.^12-14

CASE 2 › Stephanie T: CV risk

Stephanie T, 47, is in need of contraception and treatment for severe hot flashes. She has no significant past medical history, but she is obese (BMI =36), her blood pressure (BP) is 130/80 mm Hg, and her most recent labs reveal a fasting glucose of 115 and a hemoglobin A1c of 6.1%. Ms. T is concerned about arterial thromboembolic disease because of her family history: Her father had a myocardial infarction (MI) at age 56 and a maternal aunt had a stroke when she was 65.

What evidence should you consider?

Baseline arterial thromboembolic events are considerably more rare in premenopausal women than VTEs (13.2 MIs vs 24.2 thrombotic strokes per 100,000 woman-years).¹⁵ Thus, a small increased RR from a CHC is unlikely to have a significant clinical impact.

Some third-generation progestins appear to be more thrombophilic than firs tor second-generation progestins.

A systemic review and meta-analysis of studies between 1995 and 2012 showed that the odds ratio (OR) of ischemic stroke in users of COCs vs nonusers was 1.9 (95% CI, 1.24–2.91).¹⁶ This study included very few estrogen formulations with <35 mcg EE, however; even so, no increased risk of MI was found (OR=1.34; 95% CI, 0.87–2.08).¹⁶ A 15-year retrospective cohort study of 1.6 million Danish women showed that lowering the dose of EE to 20 mcg (from 30-40 mcg) significantly reduced the risk of arterial events.¹⁵ It is unclear whether the vaginal ring is associated with an increased RR of stroke compared with COCs because studies have had mixed results.^10,15 There is no compelling evidence to suggest a difference in the risk of arterial events based on the type of progestin used in the COC.¹⁵

Hypertension is a key consideration. It is important to remember that perimenopausal women may have comorbid conditions that increase their risk of arterial thromboembolic events. CHCs should be used with caution in women with hypertension, even if BP is adequately controlled—a Category 3 recommendation from the CDC. In such patients, LARC or a progestin-only pill is preferred unless there is a compelling reason to use a CHC, such as acne, vasomotor symptoms, or hirsutism.²

CHCs are contraindicated for women with a BP ≥160/100 mm Hg and/or any manifestation of vascular disease (Category 4).² Although progestin-only methods are often preferred for women with established vascular disease, depot medroxyprogesterone acetate (DMPA) is an exception (Category 3).² DMPA is not a first-line choice for such patients because of its potential to cause weight gain and worsening lipids, glucose, and insulin metabolism. Women with hypertriglyceridemia should have follow-up testing of lipid levels after initiation of hormonal contraception, especially if it contains estrogen.

Diabetes is not an absolute contraindication. Many women with diabetes can safely use CHCs (Category 2). The exceptions: those who have vascular disease, nephropathy, retinopathy, or neuropathy (Category 4) or have had diabetes for >20 years and therefore have the potential for undiagnosed vascular disease.² Generally, the use of insulin should not affect decisions regarding CHCs, and patients can be reassured that the hormones will not worsen their diabetes control.

When caring for women who have multiple risk factors for cardiovascular disease, it is important to exercise clinical judgment regarding the appropriateness of CHCs (Categories 3 and 4). Progestin-only methods have a more favorable risk profile for women at the highest risk and may provide ample relief of perimenopausal symptoms.²

THE BOTTOM LINE Ms. T may benefit from a CHC due to her severe hot flashes. She should be encouraged to adopt healthy lifestyle changes, including diet and exercise, to decrease her risk of arterial thromboembolism and VTE, but she has no contraindications to the use of a CHC at this time.

CASE 3 › Leslie C: Bone health

Leslie C, age 45, is happy with the contraceptive he has used for the past 3 years—DMPA injections every 3 months. She has no perimenopausal symptoms. However, her mother had an osteoporotic hip fracture at age 70 and Ms. C is concerned about the long-term use of DMPA.

Should Ms. C be worried?

Because of DMPA’s association with bone loss, the US Food and Drug Administration issued a black box warning in 2004 recommending that this method be used for more than 2 years only by women for whom other birth control methods are deemed inappropriate.¹⁷

Bone loss associated with longer-term use of DMPA is a greater concern for perimenopausal women because they have fewer years to recover the bone mineral density after discontinuing the contraceptive.

The bone loss may be reversed. Evidence suggests that the bone loss is reversible, however, and the American College of Obstetricians and Gynecologists has stated that a potential fracture risk need not limit a woman’s use of DMPA to 2 years.¹⁸ A retrospective cohort review of 312,295 women in the United Kingdom did not find evidence of an increased risk of fracture with long-term use of DMPA.¹⁹ It is important to note, however, that because of declining estrogen levels, perimenopausal women have fewer years than their younger counterparts to recover bone density upon discontinuation of DMPA.^20,21

THE BOTTOM LINE Because Ms. C has no perimenopausal symptoms, she may do well with LARC, which—like DMPA —would free her of the need to remember to take, apply, or insert a contraceptive regularly. It may help to point out that LARCs provide superior contraceptive efficacy compared with DMPA injections (99% vs 94%).³ Nonetheless, she and other women in their 40s who need ongoing contraception should not be discouraged from using DMPA if that is their preference.

CASE 4 › Alissa B: Breast cancer risk

Alissa B, 49, has polycystic ovaries and wonders if it is safe for her to continue her COC. She has been happy with the treatment for years because it gives her relief from hot flashes and regulates her cycles. Her 46-year-old sister was recently diagnosed with invasive breast cancer, however, and Ms. B is afraid that the hormones she takes put her at increased risk.

Should you recommend another method?

Breast cancer is an important concern for many women as they age. Although Ms. B’s family history increases her risk for developing breast cancer, a systematic review indicates that COCs do not add to this risk.²²

Weak association between family history and OC use. The review included 10 observational studies and one meta-analysis that investigated the association between COC use and breast cancer in women with a family history of the disease. Only 2 fair-quality studies showed an association, one of which included women who had begun taking the pill before 1975, when formulations typically contained higher doses of estrogen than present-day preparations.²²

The lower doses of estrogen in today’s combination oral contraceptives do not appear to significantly increase the risk of breast cancer.

Data from a recently published meta-analysis also indicate that there is no increased risk for breast cancer from COCs among women with BRCA 1 or BRCA 2 mutations. The summary RR for breast cancer in such patients was 1.13 (95% CI, 0.88-1.45), but OC users had a lower risk for ovarian cancer (summary RR=0.50; 95% CI, 0.33-0.75).²³ Additionally, investigators found no association between specific currently used COC formulations and breast cancer.²⁴

THE BOTTOM LINE Based on an independent review of the evidence, the CDC has given a family history of breast cancer a Category 1 rating. Thus, Ms. B can be reassured that she may safely continue taking her COC, which is unlikely to increase her breast cancer risk.

CORRESPONDENCE
Pelin Batur, MD, NCMP, CCD, Cleveland Clinic Independence Family Health Center, 5001 Rockside Road, IN30, Cleveland, OH 44131; [email protected].

It is no secret that about half of all pregnancies in the United States are unintended, and that teens have the highest rate of unplanned pregnancy. What’s not so well known is that women in their 40s have the second highest rate.¹

Optimal use of contraception throughout perimenopause is crucial, but finding the right method of birth control for this patient population can be a bit of a balancing act. Long-acting reversible contraceptives (LARCs), such as an intrauterine device or progestin-only implant, are preferred first-line contraceptive options when preventing pregnancy is the primary goal, given their increased efficacy and limited number of contraindications.^2,3 However, women experiencing perimenopausal symptoms often need a combination hormonal contraceptive (CHC)—typically an estrogen-containing pill, a patch, or a vaginal ring—for relief of vasomotor symptoms and cycle control.

Women in their 40s should have access to a full array of options to help improve adherence. However, physicians may be reluctant to prescribe estrogen-containing products for patients who often have a more complex medical history than their younger counterparts, including increased risks for breast cancer, cardiovascular disease, and venous thromboembolism (VTE).

With this in mind, the Centers for Disease Control and Prevention (CDC) has identified medical conditions that may affect the use of the various types of contraceptives by perimenopausal women and issued evidence-based recommendations on the appropriateness of each method using a one-to-4 rating system (TABLE 1).² To help you address the contraceptive needs of such patients, we review the key risk factors, CDC guidelines, and optimal choices in the 4 case studies that follow.

CASE 1 › Sara G: VTE risk 

Sara G, a healthy 45-year-old, recently started dating again following her divorce. She wants to avoid pregnancy. She has no personal or family history of clotting disorders and does not smoke. However, she is obese (body mass index [BMI]=32 kg/m²), and her job as a visiting nurse requires her to spend most of the day in her car. Ms. G also has acne and wants an estrogen-containing contraceptive to help treat it.

If Ms. G were your patient, what would you offer her?

The risk for VTE increases substantially for women older than 40 years. In a recent cohort study, those ages 45 to 49 faced approximately twice the risk of women ages 25 to 29. However, the absolute risk for the older women was still low (4.7-5.3 per 10,000 woman-years).⁴ What’s more, the risk of VTE from the use of a CHC is substantially less than the risk associated with pregnancy and the postpartum period (TABLE 2).⁵

Obesity increases the risk. Women like Ms. G who are obese (BMI >30) have an increased risk for VTE associated with CHCs, but the CDC rates them as a Category 2 risk, even for obese women in their 40s—a determination that the advantages outweigh the risks.²

Progestin choice and estrogen dose matter. Combination oral contraceptives (COCs) that contain certain third-generation progestins (gestodene and desogestrel) may be more thrombophilic than those containing first- or second-generation progestins (TABLE 3).⁶ The relative risk (RR) for VTE with third-generation vs second-generation progestins is 1.3 (95% confidence interval [CI], 1.0-1.8).⁷ Formulations containing higher doses of estrogen are also more likely to be associated with VTE.⁷

Drospirenone is a newer progestin. Found in several COCs, drospirenone has antimineralocorticoid properties that help to minimize bloating and fluid retention but may also lead to a hypercoagulable state.⁵ Numerous studies have investigated the association between drospirenone and VTE risk, with conflicting results.⁸ Most recently, a large international prospective observational study involving more than 85,000 women showed no increased risk for VTE among women taking COCs with drospirenone compared with pills that do not contain this progestin.⁹

Non-oral CHCs, including the vaginal ring and the patch, offer the convenience of weekly or monthly use while providing similar benefits to COCs. Some fear that the continuous exposure to hormones associated with these methods may increase the risk for VTE, but evidence is mixed.

A large (N=1.6 million) Danish registry study published in 2012 demonstrated a 2-fold increased risk of VTE among vaginal ring users vs women taking COCs.⁴ But a multinational prospective cohort study of more than 33,000 women found no increased VTE risk in ring users,10 and a recent US database study involving more than 800,000 women reported nonsignificant VTE risk estimates for both the ring (RR=1.09; 95% CI, 0.55-2.16) and the patch (RR=1.35; 95% CI, 0.90-2.02) compared with COCs.¹¹

THE BOTTOM LINE For Ms. G, the benefits of contraception likely outweigh any small increase in her absolute risk for VTE. To minimize her risk, however, select a pill that contains a low dose (20-35 mcg) of ethinyl estradiol (EE) combined with a progestin that has not been associated with an increased VTE risk. Because of their mechanism of action, most COCs will improve acne, regardless of the progestin in the formulation.^12-14

CASE 2 › Stephanie T: CV risk

Stephanie T, 47, is in need of contraception and treatment for severe hot flashes. She has no significant past medical history, but she is obese (BMI =36), her blood pressure (BP) is 130/80 mm Hg, and her most recent labs reveal a fasting glucose of 115 and a hemoglobin A1c of 6.1%. Ms. T is concerned about arterial thromboembolic disease because of her family history: Her father had a myocardial infarction (MI) at age 56 and a maternal aunt had a stroke when she was 65.

What evidence should you consider?

Baseline arterial thromboembolic events are considerably more rare in premenopausal women than VTEs (13.2 MIs vs 24.2 thrombotic strokes per 100,000 woman-years).¹⁵ Thus, a small increased RR from a CHC is unlikely to have a significant clinical impact.

Some third-generation progestins appear to be more thrombophilic than firs tor second-generation progestins.

A systemic review and meta-analysis of studies between 1995 and 2012 showed that the odds ratio (OR) of ischemic stroke in users of COCs vs nonusers was 1.9 (95% CI, 1.24–2.91).¹⁶ This study included very few estrogen formulations with <35 mcg EE, however; even so, no increased risk of MI was found (OR=1.34; 95% CI, 0.87–2.08).¹⁶ A 15-year retrospective cohort study of 1.6 million Danish women showed that lowering the dose of EE to 20 mcg (from 30-40 mcg) significantly reduced the risk of arterial events.¹⁵ It is unclear whether the vaginal ring is associated with an increased RR of stroke compared with COCs because studies have had mixed results.^10,15 There is no compelling evidence to suggest a difference in the risk of arterial events based on the type of progestin used in the COC.¹⁵

Hypertension is a key consideration. It is important to remember that perimenopausal women may have comorbid conditions that increase their risk of arterial thromboembolic events. CHCs should be used with caution in women with hypertension, even if BP is adequately controlled—a Category 3 recommendation from the CDC. In such patients, LARC or a progestin-only pill is preferred unless there is a compelling reason to use a CHC, such as acne, vasomotor symptoms, or hirsutism.²

CHCs are contraindicated for women with a BP ≥160/100 mm Hg and/or any manifestation of vascular disease (Category 4).² Although progestin-only methods are often preferred for women with established vascular disease, depot medroxyprogesterone acetate (DMPA) is an exception (Category 3).² DMPA is not a first-line choice for such patients because of its potential to cause weight gain and worsening lipids, glucose, and insulin metabolism. Women with hypertriglyceridemia should have follow-up testing of lipid levels after initiation of hormonal contraception, especially if it contains estrogen.

Diabetes is not an absolute contraindication. Many women with diabetes can safely use CHCs (Category 2). The exceptions: those who have vascular disease, nephropathy, retinopathy, or neuropathy (Category 4) or have had diabetes for >20 years and therefore have the potential for undiagnosed vascular disease.² Generally, the use of insulin should not affect decisions regarding CHCs, and patients can be reassured that the hormones will not worsen their diabetes control.

When caring for women who have multiple risk factors for cardiovascular disease, it is important to exercise clinical judgment regarding the appropriateness of CHCs (Categories 3 and 4). Progestin-only methods have a more favorable risk profile for women at the highest risk and may provide ample relief of perimenopausal symptoms.²

THE BOTTOM LINE Ms. T may benefit from a CHC due to her severe hot flashes. She should be encouraged to adopt healthy lifestyle changes, including diet and exercise, to decrease her risk of arterial thromboembolism and VTE, but she has no contraindications to the use of a CHC at this time.

CASE 3 › Leslie C: Bone health

Leslie C, age 45, is happy with the contraceptive he has used for the past 3 years—DMPA injections every 3 months. She has no perimenopausal symptoms. However, her mother had an osteoporotic hip fracture at age 70 and Ms. C is concerned about the long-term use of DMPA.

Should Ms. C be worried?

Because of DMPA’s association with bone loss, the US Food and Drug Administration issued a black box warning in 2004 recommending that this method be used for more than 2 years only by women for whom other birth control methods are deemed inappropriate.¹⁷

Bone loss associated with longer-term use of DMPA is a greater concern for perimenopausal women because they have fewer years to recover the bone mineral density after discontinuing the contraceptive.

The bone loss may be reversed. Evidence suggests that the bone loss is reversible, however, and the American College of Obstetricians and Gynecologists has stated that a potential fracture risk need not limit a woman’s use of DMPA to 2 years.¹⁸ A retrospective cohort review of 312,295 women in the United Kingdom did not find evidence of an increased risk of fracture with long-term use of DMPA.¹⁹ It is important to note, however, that because of declining estrogen levels, perimenopausal women have fewer years than their younger counterparts to recover bone density upon discontinuation of DMPA.^20,21

THE BOTTOM LINE Because Ms. C has no perimenopausal symptoms, she may do well with LARC, which—like DMPA —would free her of the need to remember to take, apply, or insert a contraceptive regularly. It may help to point out that LARCs provide superior contraceptive efficacy compared with DMPA injections (99% vs 94%).³ Nonetheless, she and other women in their 40s who need ongoing contraception should not be discouraged from using DMPA if that is their preference.

CASE 4 › Alissa B: Breast cancer risk

Alissa B, 49, has polycystic ovaries and wonders if it is safe for her to continue her COC. She has been happy with the treatment for years because it gives her relief from hot flashes and regulates her cycles. Her 46-year-old sister was recently diagnosed with invasive breast cancer, however, and Ms. B is afraid that the hormones she takes put her at increased risk.

Should you recommend another method?

Breast cancer is an important concern for many women as they age. Although Ms. B’s family history increases her risk for developing breast cancer, a systematic review indicates that COCs do not add to this risk.²²

Weak association between family history and OC use. The review included 10 observational studies and one meta-analysis that investigated the association between COC use and breast cancer in women with a family history of the disease. Only 2 fair-quality studies showed an association, one of which included women who had begun taking the pill before 1975, when formulations typically contained higher doses of estrogen than present-day preparations.²²

The lower doses of estrogen in today’s combination oral contraceptives do not appear to significantly increase the risk of breast cancer.

Data from a recently published meta-analysis also indicate that there is no increased risk for breast cancer from COCs among women with BRCA 1 or BRCA 2 mutations. The summary RR for breast cancer in such patients was 1.13 (95% CI, 0.88-1.45), but OC users had a lower risk for ovarian cancer (summary RR=0.50; 95% CI, 0.33-0.75).²³ Additionally, investigators found no association between specific currently used COC formulations and breast cancer.²⁴

THE BOTTOM LINE Based on an independent review of the evidence, the CDC has given a family history of breast cancer a Category 1 rating. Thus, Ms. B can be reassured that she may safely continue taking her COC, which is unlikely to increase her breast cancer risk.

CORRESPONDENCE
Pelin Batur, MD, NCMP, CCD, Cleveland Clinic Independence Family Health Center, 5001 Rockside Road, IN30, Cleveland, OH 44131; [email protected].

Chronic obstructive pulmonary disease (COPD) carries a high disease burden. In 2012, it was the 4th leading cause of death worldwide.^1,2 In 2015, the World Health Organization updated its Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, classifying patients with COPD based on disease burden as determined by symptoms, airflow obstruction, and exacerbation history.³ These revisions, coupled with expanded therapeutic options within established classes of medications and new combination drugs to treat COPD (TABLE 1),^3-6 have led to questions about interclass differences and the best treatment regimen for particular patients.

Comparisons of various agents within a therapeutic class and their impact on lung function and rate of exacerbations address many of these concerns. In the text and tables that follow, we present the latest evidence highlighting differences in dosing, safety, and efficacy. We also include the updated GOLD classifications, evidence of efficacy for pulmonary rehabilitation, and practical implications of these findings for the optimal management of patients with COPD.

But first, a word about terminology.

Understanding COPD

COPD is a chronic lung disease characterized by progressive airflow limitation, usually measured by spirometry (TABLE 2),³ and chronic airway inflammation. Emphysema and chronic bronchitis are often used synonymously with COPD. In fact, there are important differences.

Individuals with chronic bronchitis do not necessarily have the airflow limitations found in those with COPD. And patients with COPD develop pathologic lung changes beyond the alveolar damage characteristic of emphysema, including airway fibrosis and inflammation, luminal plugging, and loss of elastic recoil.³

The medications included in this review aim to reduce both the morbidity and mortality associated with COPD. These drugs can also help relieve the symptoms of patients with chronic bronchitis and emphysema, but have limited effect on patient mortality.

Short- and long-acting beta₂-agonists

Bronchodilator therapy with beta₂-agonists improves forced expiratory volume in one second (FEV₁) through relaxation of airway smooth muscle. Beta₂-agonists have proven to be safe and effective when used as needed or scheduled for patients with COPD.⁷

Inhaled short-acting beta₂-agonists (SABAs) improve FEV₁ and symptoms within 10 minutes, with effects lasting up to 4 to 6 hours; long-acting beta₂-agonists (LABAs) have a variable onset, with effects lasting 12 to 24 hours.⁸ Inhaled levalbuterol, the last SABA to receive US Food and Drug Administration approval, has not proven to be superior to conventional bronchodilators in ambulatory patients with stable COPD.³ In clinical trials, however, the slightly longer half-life of the nebulized formulation of levalbuterol was found to reduce both the frequency of administration and the overall cost of therapy in patients hospitalized with acute exacerbations of COPD.^9,10

Recently approved LABAs

Clinical trials have studied the safety and efficacy of newer agents vs older LABAs in patients with moderate to severe COPD. Compared with theophylline, for example, formoterol 12 mcg inhaled every 12 hours for a 12-month period provided a clinically significant increase of >120 ml in FEV₁ (P=.026).¹¹ Higher doses of formoterol did not provide any additional improvement.

In a trial comparing indacaterol and tiotropium, an inhaled anticholinergic, both treatment groups had a clinically significant increase in FEV₁, but patients receiving indacaterol achieved an additional increase of 40 to 50 mL at 12 weeks.¹²

Exacerbation rates for all LABAs range from 22% to 44%.^5,12,13 In a study of patients receiving formoterol 12 mcg compared with 15-mcg and 25-mcg doses of arformoterol, those taking formoterol had a lower exacerbation rate than those on either strength of arformoterol (22% vs 32% and 31%, respectively).¹⁰ In various studies, doses greater than the FDA-approved regimens for indacaterol, arformoterol, and olodaterol did not result in a significant improvement in either FEV₁ or exacerbation rates compared with placebo.^5,12,14

Exacerbation rates for all long-acting beta₂-agonists range from 22% to 44%.

Studies that assessed the use of rescue medication as well as exacerbation rates in patients taking LABAs reported reductions in the use of the rescue drugs ranging from 0.46 to 1.32 actuations per day, but the findings had limited clinical relevance.^5,13 With the exception of indacaterol and olodaterol—both of which may be preferable because of their once-daily dosing regimen—no significant differences in safety and efficacy among LABAs have been found.^5,12,13

Long-acting inhaled anticholinergics

Inhaled anticholinergic agents (IACs) can be used in place of, or in conjunction with, LABAs to provide bronchodilation for up to 24 hours.³ The introduction of long-acting IACs dosed once or twice daily has the potential to improve medication adherence over traditional short-acting ipratropium, which requires multiple daily doses for symptom control. Over 4 years, tiotropium has been shown to increase time to first exacerbation by approximately 4 months. It did not, however, significantly reduce the number of exacerbations compared with placebo.¹⁵

Long-term use of tiotropium appears to have the potential to preserve lung function. In one trial, it slowed the rate of decline in FEV₁ by 5 mL per year, but this finding lacked clinical significance.¹³ In clinical trials of patients with moderate to severe COPD, however, once-daily tiotropium and umeclidinium provided clinically significant improvements in FEV₁ (>120 mL; P<.01), regardless of the dose administered.^6,16 In another trial, patients taking aclidinium 200 mcg or 400 mcg every 12 hours did not achieve a clinically significant improvement in FEV₁ compared with placebo.¹⁷

In patients with moderate to severe COPD, the combination of umeclidinium/vilanterol, a LABA, administered once daily resulted in a clinically significant improvement in FEV₁ (167 mL; P<.001) vs placebo—but was not significantly better than treatment with either agent alone.¹⁸

Long-acting inhaled anticholinergic agents—when used in combination with LABAS—have a positive effect on FEV₁, but their effect on exacerbation rates has not been established.

Few studies have evaluated time to exacerbation in patients receiving aclidinium or umeclidinium. In comparison to salmeterol, tiotropium reduced the time to first exacerbation by 42 days at one year (hazard ratio=0.83; 95% confidence interval [CI], 0.77-0.9; P<.001).¹⁹ The evidence suggests that when used in combination with LABAs, long-acting IACs have a positive impact on FEV₁, but their effect on exacerbation rates has not been established.

Combination therapy with steroids and LABAs

The combination of inhaled corticosteroids (ICS) and LABAs has been found to improve FEV₁ and symptoms in patients with moderate to severe COPD more than monotherapy with either drug class.^20,21 In fact, ICS alone have not been proven to slow the progression of the disease or to lower mortality rates in patients with COPD.²²

Fluticasone/salmeterol demonstrated a 25% reduction in exacerbation rates compared with placebo (P<.0001), a greater reduction than that of either drug alone.²⁰ A retrospective observational study comparing fixed dose fluticasone/salmeterol with budesonide/formoterol reported a similar reduction in exacerbation rates, but the number of patients requiring the addition of an IAC was 16% lower in the latter group.²³

The combination of fluticasone/vilanterol has the potential to improve adherence, given that it is dosed once daily, unlike other COPD combination drugs. Its clinical efficacy is comparable to that of fluticasone/salmeterol after 12 weeks of therapy, with similar improvements in FEV₁,²⁴ but fluticasone/vilanterol is associated with an increased risk of pneumonia.³

Chronic use of oral corticosteroids

Oral corticosteroids (OCS) are clinically indicated in individuals whose symptoms continue despite optimal therapy with inhaled agents that have demonstrated efficacy. Such patients are often referred to as “steroid dependent.”

While OCS are prescribed for both their anti-inflammatory activity and their ability to slow the progression of COPD,^25,26 no well-designed studies have investigated their benefits for this patient population. One study concluded that patients who were slowly withdrawn from their OCS regimen had no more frequent exacerbations than those who maintained chronic usage. The withdrawal group did, however, lose weight.²⁷

GOLD guidelines do not recommend OCS for chronic management of COPD due to the risk of toxicity.³ The well-established adverse effects of chronic OCS include hyperglycemia, hypertension, osteoporosis, and myopathy.^28,29 A study of muscle function in 21 COPD patients receiving corticosteroids revealed decreases in quadriceps muscle strength and pulmonary function.³⁰ Daily use of OCS will likely result in additional therapies to control drug-induced conditions, as well—another antihypertensive secondary to fluid retention caused by chronic use of OCS in patients with high blood pressure, for example, or additional medication to control elevated blood glucose levels in patients with diabetes.

Phosphodiesterase-4 inhibitors

In one study, patients slowly withdrawn from oral corticosteroids had no more frequent exacerbations than those who maintained chronic usage.

The recommendation for roflumilast in patients with GOLD Class 2 to 4 symptoms remains unchanged since the introduction of this agent as a treatment option for COPD.³ Phosphodiesterase-4 (PDE-4) inhibitors such as roflumilast reduce inflammation in the lungs and have no activity as a bronchodilator.^31,32

Roflumilast has been shown to improve FEV₁ in patients concurrently receiving a long-acting bronchodilator and to reduce exacerbations in steroid-dependent patients, a recent systematic review of 29 PDE-4 trials found.³³ Patients taking roflumilast, however, suffered from more adverse events (nausea, appetite reduction, diarrhea, weight loss, sleep disturbances, and headache) than those on placebo.³³

Antibiotics

GOLD guidelines do not recommend the use of antibiotics for patients with COPD, except to treat acute exacerbations.¹ However, recent studies suggest that routine or pulsed dosing of prophylactic antibiotics can reduce the number of exacerbations.^34-36 A 2013 review of 7 studies determined that continuous antibiotics, particularly macrolides, reduced the number of COPD exacerbations in patients with a mean age of 66 years (odds ratio [OR]=0.55; 95% CI, 0.39-0.77).³⁷

Patients with limited mobility can benefit from non-exercise components of pulmonary rehabilitation.

A more recent trial randomized 92 patients with a history of ≥3 exacerbations in the previous year to receive either prophylactic azithromycin or placebo daily for 12 months. The treatment group experienced a significant decrease in the number of exacerbations (OR=0.58; 95% CI, 0.42-0.79; P=.001).³⁸ This benefit must be weighed against the potential development of antibiotic resistance and adverse effects, so careful patient selection is important.

Pulmonary rehabilitation has proven benefits

GOLD, the American College of Chest Physicians, the American Thoracic Society, and the European Respiratory Society all recommend pulmonary rehabilitation for patients with COPD.^39-41 In addition to reducing morbidity and mortality rates—including a reduction in number of hospitalizations and length of stay and improved post-discharge recovery—pulmonary rehabilitation has been shown to have other physical and psychological benefits.⁴² Specific benefits include improved exercise capacity, greater arm strength and endurance, reduced perception of intensity of breathlessness, and improved overall health-related quality of life.

Key features of rehab programs

Important components of pulmonary rehabilitation include counseling on tobacco cessation, nutrition, education—including correct inhalation technique—and exercise training. There are few contraindications to participation, and patients can derive benefit from both its non-exercise components and upper extremity training regardless of their mobility level.

A 2006 Cochrane review concluded that an effective pulmonary rehabilitation program should be at least 4 weeks in duration,⁴³ and longer programs have been shown to produce greater benefits.⁴⁴ However, there is no agreement on an optimal time frame. Studies are inconclusive on other specific aspects of pulmonary rehab programs, as well, such as the number of sessions per week, number of hours per session, duration and intensity of exercise regimens, and staff-to-patient ratios.

An effective pulmonary rehabilitation program should be at least 4 weeks long.

Home-based exercise training may produce many of the same benefits as a formal pulmonary rehabilitation program. A systematic review found improved quality of life and exercise capacity associated with patient care that lacked formal pulmonary rehabilitation, with no differences between results from home-based training and hospital-based outpatient pulmonary rehabilitation programs.⁴⁵

Given the lack of availability of formal rehab programs in many communities, homebased training for patients with COPD is important to consider.

Implications for practice

What is the takeaway from this evidence-based review? Overall, it is clear that, with the possible exception of the effect of once-daily dosing on adherence, there is little difference among the therapeutic agents within a particular class of medications—and that more is not necessarily better. Indeed, evidence suggests that higher doses of LABAs may reduce their effectiveness, rendering them no better than placebo. In addition, there is no significant difference in the rate of exacerbations in patients taking ICS/LABA combinations and those receiving IACs alone.

Determining the optimal treatment for a particular patient requires an assessment of comorbidities, including potential adverse drug effects.

Pulmonary rehabilitation should be recommended for all newly diagnosed patients, while appropriate drug therapies should be individualized based on the GOLD symptoms/risk evaluation categories (TABLE 3).³ While daily OCS and daily antibiotics have the potential to reduce exacerbation rates, for example, the risks of adverse effects and toxicities outweigh the benefits for patients whose condition is stable.

Determining the optimal treatment for a particular patient also requires an assessment of comorbidities, including potential adverse drug effects (TABLE 4).^{3,27-29,33,46-52} Selection of medication should be driven by patient and physician preference to optimize adherence and clinical outcomes, although cost and accessibility often play a significant role, as well.

CORRESPONDENCE
Nabila Ahmed-Sarwar, PharmD, BCPS, CDE, St. John Fisher College, Wegmans School of Pharmacy, 3690 East Avenue, Rochester, NY 14618; [email protected]

ACKNOWLEDGEMENTS
The authors thank the following people for their assistance in the preparation of this manuscript: Matthew Stryker, PharmD, Timothy Adler, PharmD, and Angela K. Nagel, PharmD, BCPS.

Chronic obstructive pulmonary disease (COPD) carries a high disease burden. In 2012, it was the 4th leading cause of death worldwide.^1,2 In 2015, the World Health Organization updated its Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, classifying patients with COPD based on disease burden as determined by symptoms, airflow obstruction, and exacerbation history.³ These revisions, coupled with expanded therapeutic options within established classes of medications and new combination drugs to treat COPD (TABLE 1),^3-6 have led to questions about interclass differences and the best treatment regimen for particular patients.

Comparisons of various agents within a therapeutic class and their impact on lung function and rate of exacerbations address many of these concerns. In the text and tables that follow, we present the latest evidence highlighting differences in dosing, safety, and efficacy. We also include the updated GOLD classifications, evidence of efficacy for pulmonary rehabilitation, and practical implications of these findings for the optimal management of patients with COPD.

But first, a word about terminology.

Understanding COPD

COPD is a chronic lung disease characterized by progressive airflow limitation, usually measured by spirometry (TABLE 2),³ and chronic airway inflammation. Emphysema and chronic bronchitis are often used synonymously with COPD. In fact, there are important differences.

Individuals with chronic bronchitis do not necessarily have the airflow limitations found in those with COPD. And patients with COPD develop pathologic lung changes beyond the alveolar damage characteristic of emphysema, including airway fibrosis and inflammation, luminal plugging, and loss of elastic recoil.³

The medications included in this review aim to reduce both the morbidity and mortality associated with COPD. These drugs can also help relieve the symptoms of patients with chronic bronchitis and emphysema, but have limited effect on patient mortality.

Short- and long-acting beta₂-agonists

Bronchodilator therapy with beta₂-agonists improves forced expiratory volume in one second (FEV₁) through relaxation of airway smooth muscle. Beta₂-agonists have proven to be safe and effective when used as needed or scheduled for patients with COPD.⁷

Inhaled short-acting beta₂-agonists (SABAs) improve FEV₁ and symptoms within 10 minutes, with effects lasting up to 4 to 6 hours; long-acting beta₂-agonists (LABAs) have a variable onset, with effects lasting 12 to 24 hours.⁸ Inhaled levalbuterol, the last SABA to receive US Food and Drug Administration approval, has not proven to be superior to conventional bronchodilators in ambulatory patients with stable COPD.³ In clinical trials, however, the slightly longer half-life of the nebulized formulation of levalbuterol was found to reduce both the frequency of administration and the overall cost of therapy in patients hospitalized with acute exacerbations of COPD.^9,10

Recently approved LABAs

Clinical trials have studied the safety and efficacy of newer agents vs older LABAs in patients with moderate to severe COPD. Compared with theophylline, for example, formoterol 12 mcg inhaled every 12 hours for a 12-month period provided a clinically significant increase of >120 ml in FEV₁ (P=.026).¹¹ Higher doses of formoterol did not provide any additional improvement.

In a trial comparing indacaterol and tiotropium, an inhaled anticholinergic, both treatment groups had a clinically significant increase in FEV₁, but patients receiving indacaterol achieved an additional increase of 40 to 50 mL at 12 weeks.¹²

Exacerbation rates for all LABAs range from 22% to 44%.^5,12,13 In a study of patients receiving formoterol 12 mcg compared with 15-mcg and 25-mcg doses of arformoterol, those taking formoterol had a lower exacerbation rate than those on either strength of arformoterol (22% vs 32% and 31%, respectively).¹⁰ In various studies, doses greater than the FDA-approved regimens for indacaterol, arformoterol, and olodaterol did not result in a significant improvement in either FEV₁ or exacerbation rates compared with placebo.^5,12,14

Exacerbation rates for all long-acting beta₂-agonists range from 22% to 44%.

Studies that assessed the use of rescue medication as well as exacerbation rates in patients taking LABAs reported reductions in the use of the rescue drugs ranging from 0.46 to 1.32 actuations per day, but the findings had limited clinical relevance.^5,13 With the exception of indacaterol and olodaterol—both of which may be preferable because of their once-daily dosing regimen—no significant differences in safety and efficacy among LABAs have been found.^5,12,13

Long-acting inhaled anticholinergics

Inhaled anticholinergic agents (IACs) can be used in place of, or in conjunction with, LABAs to provide bronchodilation for up to 24 hours.³ The introduction of long-acting IACs dosed once or twice daily has the potential to improve medication adherence over traditional short-acting ipratropium, which requires multiple daily doses for symptom control. Over 4 years, tiotropium has been shown to increase time to first exacerbation by approximately 4 months. It did not, however, significantly reduce the number of exacerbations compared with placebo.¹⁵

Long-term use of tiotropium appears to have the potential to preserve lung function. In one trial, it slowed the rate of decline in FEV₁ by 5 mL per year, but this finding lacked clinical significance.¹³ In clinical trials of patients with moderate to severe COPD, however, once-daily tiotropium and umeclidinium provided clinically significant improvements in FEV₁ (>120 mL; P<.01), regardless of the dose administered.^6,16 In another trial, patients taking aclidinium 200 mcg or 400 mcg every 12 hours did not achieve a clinically significant improvement in FEV₁ compared with placebo.¹⁷

In patients with moderate to severe COPD, the combination of umeclidinium/vilanterol, a LABA, administered once daily resulted in a clinically significant improvement in FEV₁ (167 mL; P<.001) vs placebo—but was not significantly better than treatment with either agent alone.¹⁸

Long-acting inhaled anticholinergic agents—when used in combination with LABAS—have a positive effect on FEV₁, but their effect on exacerbation rates has not been established.

Few studies have evaluated time to exacerbation in patients receiving aclidinium or umeclidinium. In comparison to salmeterol, tiotropium reduced the time to first exacerbation by 42 days at one year (hazard ratio=0.83; 95% confidence interval [CI], 0.77-0.9; P<.001).¹⁹ The evidence suggests that when used in combination with LABAs, long-acting IACs have a positive impact on FEV₁, but their effect on exacerbation rates has not been established.

Combination therapy with steroids and LABAs

The combination of inhaled corticosteroids (ICS) and LABAs has been found to improve FEV₁ and symptoms in patients with moderate to severe COPD more than monotherapy with either drug class.^20,21 In fact, ICS alone have not been proven to slow the progression of the disease or to lower mortality rates in patients with COPD.²²

Fluticasone/salmeterol demonstrated a 25% reduction in exacerbation rates compared with placebo (P<.0001), a greater reduction than that of either drug alone.²⁰ A retrospective observational study comparing fixed dose fluticasone/salmeterol with budesonide/formoterol reported a similar reduction in exacerbation rates, but the number of patients requiring the addition of an IAC was 16% lower in the latter group.²³

The combination of fluticasone/vilanterol has the potential to improve adherence, given that it is dosed once daily, unlike other COPD combination drugs. Its clinical efficacy is comparable to that of fluticasone/salmeterol after 12 weeks of therapy, with similar improvements in FEV₁,²⁴ but fluticasone/vilanterol is associated with an increased risk of pneumonia.³

Chronic use of oral corticosteroids

Oral corticosteroids (OCS) are clinically indicated in individuals whose symptoms continue despite optimal therapy with inhaled agents that have demonstrated efficacy. Such patients are often referred to as “steroid dependent.”

While OCS are prescribed for both their anti-inflammatory activity and their ability to slow the progression of COPD,^25,26 no well-designed studies have investigated their benefits for this patient population. One study concluded that patients who were slowly withdrawn from their OCS regimen had no more frequent exacerbations than those who maintained chronic usage. The withdrawal group did, however, lose weight.²⁷

GOLD guidelines do not recommend OCS for chronic management of COPD due to the risk of toxicity.³ The well-established adverse effects of chronic OCS include hyperglycemia, hypertension, osteoporosis, and myopathy.^28,29 A study of muscle function in 21 COPD patients receiving corticosteroids revealed decreases in quadriceps muscle strength and pulmonary function.³⁰ Daily use of OCS will likely result in additional therapies to control drug-induced conditions, as well—another antihypertensive secondary to fluid retention caused by chronic use of OCS in patients with high blood pressure, for example, or additional medication to control elevated blood glucose levels in patients with diabetes.

Phosphodiesterase-4 inhibitors

In one study, patients slowly withdrawn from oral corticosteroids had no more frequent exacerbations than those who maintained chronic usage.

The recommendation for roflumilast in patients with GOLD Class 2 to 4 symptoms remains unchanged since the introduction of this agent as a treatment option for COPD.³ Phosphodiesterase-4 (PDE-4) inhibitors such as roflumilast reduce inflammation in the lungs and have no activity as a bronchodilator.^31,32

Roflumilast has been shown to improve FEV₁ in patients concurrently receiving a long-acting bronchodilator and to reduce exacerbations in steroid-dependent patients, a recent systematic review of 29 PDE-4 trials found.³³ Patients taking roflumilast, however, suffered from more adverse events (nausea, appetite reduction, diarrhea, weight loss, sleep disturbances, and headache) than those on placebo.³³

Antibiotics

GOLD guidelines do not recommend the use of antibiotics for patients with COPD, except to treat acute exacerbations.¹ However, recent studies suggest that routine or pulsed dosing of prophylactic antibiotics can reduce the number of exacerbations.^34-36 A 2013 review of 7 studies determined that continuous antibiotics, particularly macrolides, reduced the number of COPD exacerbations in patients with a mean age of 66 years (odds ratio [OR]=0.55; 95% CI, 0.39-0.77).³⁷

Patients with limited mobility can benefit from non-exercise components of pulmonary rehabilitation.

A more recent trial randomized 92 patients with a history of ≥3 exacerbations in the previous year to receive either prophylactic azithromycin or placebo daily for 12 months. The treatment group experienced a significant decrease in the number of exacerbations (OR=0.58; 95% CI, 0.42-0.79; P=.001).³⁸ This benefit must be weighed against the potential development of antibiotic resistance and adverse effects, so careful patient selection is important.

Pulmonary rehabilitation has proven benefits

GOLD, the American College of Chest Physicians, the American Thoracic Society, and the European Respiratory Society all recommend pulmonary rehabilitation for patients with COPD.^39-41 In addition to reducing morbidity and mortality rates—including a reduction in number of hospitalizations and length of stay and improved post-discharge recovery—pulmonary rehabilitation has been shown to have other physical and psychological benefits.⁴² Specific benefits include improved exercise capacity, greater arm strength and endurance, reduced perception of intensity of breathlessness, and improved overall health-related quality of life.

Key features of rehab programs

Important components of pulmonary rehabilitation include counseling on tobacco cessation, nutrition, education—including correct inhalation technique—and exercise training. There are few contraindications to participation, and patients can derive benefit from both its non-exercise components and upper extremity training regardless of their mobility level.

A 2006 Cochrane review concluded that an effective pulmonary rehabilitation program should be at least 4 weeks in duration,⁴³ and longer programs have been shown to produce greater benefits.⁴⁴ However, there is no agreement on an optimal time frame. Studies are inconclusive on other specific aspects of pulmonary rehab programs, as well, such as the number of sessions per week, number of hours per session, duration and intensity of exercise regimens, and staff-to-patient ratios.

An effective pulmonary rehabilitation program should be at least 4 weeks long.

Home-based exercise training may produce many of the same benefits as a formal pulmonary rehabilitation program. A systematic review found improved quality of life and exercise capacity associated with patient care that lacked formal pulmonary rehabilitation, with no differences between results from home-based training and hospital-based outpatient pulmonary rehabilitation programs.⁴⁵

Given the lack of availability of formal rehab programs in many communities, homebased training for patients with COPD is important to consider.

Implications for practice

What is the takeaway from this evidence-based review? Overall, it is clear that, with the possible exception of the effect of once-daily dosing on adherence, there is little difference among the therapeutic agents within a particular class of medications—and that more is not necessarily better. Indeed, evidence suggests that higher doses of LABAs may reduce their effectiveness, rendering them no better than placebo. In addition, there is no significant difference in the rate of exacerbations in patients taking ICS/LABA combinations and those receiving IACs alone.

Determining the optimal treatment for a particular patient requires an assessment of comorbidities, including potential adverse drug effects.

Pulmonary rehabilitation should be recommended for all newly diagnosed patients, while appropriate drug therapies should be individualized based on the GOLD symptoms/risk evaluation categories (TABLE 3).³ While daily OCS and daily antibiotics have the potential to reduce exacerbation rates, for example, the risks of adverse effects and toxicities outweigh the benefits for patients whose condition is stable.

Determining the optimal treatment for a particular patient also requires an assessment of comorbidities, including potential adverse drug effects (TABLE 4).^{3,27-29,33,46-52} Selection of medication should be driven by patient and physician preference to optimize adherence and clinical outcomes, although cost and accessibility often play a significant role, as well.

CORRESPONDENCE
Nabila Ahmed-Sarwar, PharmD, BCPS, CDE, St. John Fisher College, Wegmans School of Pharmacy, 3690 East Avenue, Rochester, NY 14618; [email protected]

ACKNOWLEDGEMENTS
The authors thank the following people for their assistance in the preparation of this manuscript: Matthew Stryker, PharmD, Timothy Adler, PharmD, and Angela K. Nagel, PharmD, BCPS.

Chronic obstructive pulmonary disease (COPD) carries a high disease burden. In 2012, it was the 4th leading cause of death worldwide.^1,2 In 2015, the World Health Organization updated its Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, classifying patients with COPD based on disease burden as determined by symptoms, airflow obstruction, and exacerbation history.³ These revisions, coupled with expanded therapeutic options within established classes of medications and new combination drugs to treat COPD (TABLE 1),^3-6 have led to questions about interclass differences and the best treatment regimen for particular patients.

Comparisons of various agents within a therapeutic class and their impact on lung function and rate of exacerbations address many of these concerns. In the text and tables that follow, we present the latest evidence highlighting differences in dosing, safety, and efficacy. We also include the updated GOLD classifications, evidence of efficacy for pulmonary rehabilitation, and practical implications of these findings for the optimal management of patients with COPD.

But first, a word about terminology.

Understanding COPD

COPD is a chronic lung disease characterized by progressive airflow limitation, usually measured by spirometry (TABLE 2),³ and chronic airway inflammation. Emphysema and chronic bronchitis are often used synonymously with COPD. In fact, there are important differences.

Individuals with chronic bronchitis do not necessarily have the airflow limitations found in those with COPD. And patients with COPD develop pathologic lung changes beyond the alveolar damage characteristic of emphysema, including airway fibrosis and inflammation, luminal plugging, and loss of elastic recoil.³

The medications included in this review aim to reduce both the morbidity and mortality associated with COPD. These drugs can also help relieve the symptoms of patients with chronic bronchitis and emphysema, but have limited effect on patient mortality.

Short- and long-acting beta₂-agonists

Bronchodilator therapy with beta₂-agonists improves forced expiratory volume in one second (FEV₁) through relaxation of airway smooth muscle. Beta₂-agonists have proven to be safe and effective when used as needed or scheduled for patients with COPD.⁷

Inhaled short-acting beta₂-agonists (SABAs) improve FEV₁ and symptoms within 10 minutes, with effects lasting up to 4 to 6 hours; long-acting beta₂-agonists (LABAs) have a variable onset, with effects lasting 12 to 24 hours.⁸ Inhaled levalbuterol, the last SABA to receive US Food and Drug Administration approval, has not proven to be superior to conventional bronchodilators in ambulatory patients with stable COPD.³ In clinical trials, however, the slightly longer half-life of the nebulized formulation of levalbuterol was found to reduce both the frequency of administration and the overall cost of therapy in patients hospitalized with acute exacerbations of COPD.^9,10

Recently approved LABAs

Clinical trials have studied the safety and efficacy of newer agents vs older LABAs in patients with moderate to severe COPD. Compared with theophylline, for example, formoterol 12 mcg inhaled every 12 hours for a 12-month period provided a clinically significant increase of >120 ml in FEV₁ (P=.026).¹¹ Higher doses of formoterol did not provide any additional improvement.

In a trial comparing indacaterol and tiotropium, an inhaled anticholinergic, both treatment groups had a clinically significant increase in FEV₁, but patients receiving indacaterol achieved an additional increase of 40 to 50 mL at 12 weeks.¹²

Exacerbation rates for all LABAs range from 22% to 44%.^5,12,13 In a study of patients receiving formoterol 12 mcg compared with 15-mcg and 25-mcg doses of arformoterol, those taking formoterol had a lower exacerbation rate than those on either strength of arformoterol (22% vs 32% and 31%, respectively).¹⁰ In various studies, doses greater than the FDA-approved regimens for indacaterol, arformoterol, and olodaterol did not result in a significant improvement in either FEV₁ or exacerbation rates compared with placebo.^5,12,14

Exacerbation rates for all long-acting beta₂-agonists range from 22% to 44%.

Studies that assessed the use of rescue medication as well as exacerbation rates in patients taking LABAs reported reductions in the use of the rescue drugs ranging from 0.46 to 1.32 actuations per day, but the findings had limited clinical relevance.^5,13 With the exception of indacaterol and olodaterol—both of which may be preferable because of their once-daily dosing regimen—no significant differences in safety and efficacy among LABAs have been found.^5,12,13

Long-acting inhaled anticholinergics

Inhaled anticholinergic agents (IACs) can be used in place of, or in conjunction with, LABAs to provide bronchodilation for up to 24 hours.³ The introduction of long-acting IACs dosed once or twice daily has the potential to improve medication adherence over traditional short-acting ipratropium, which requires multiple daily doses for symptom control. Over 4 years, tiotropium has been shown to increase time to first exacerbation by approximately 4 months. It did not, however, significantly reduce the number of exacerbations compared with placebo.¹⁵

Long-term use of tiotropium appears to have the potential to preserve lung function. In one trial, it slowed the rate of decline in FEV₁ by 5 mL per year, but this finding lacked clinical significance.¹³ In clinical trials of patients with moderate to severe COPD, however, once-daily tiotropium and umeclidinium provided clinically significant improvements in FEV₁ (>120 mL; P<.01), regardless of the dose administered.^6,16 In another trial, patients taking aclidinium 200 mcg or 400 mcg every 12 hours did not achieve a clinically significant improvement in FEV₁ compared with placebo.¹⁷

In patients with moderate to severe COPD, the combination of umeclidinium/vilanterol, a LABA, administered once daily resulted in a clinically significant improvement in FEV₁ (167 mL; P<.001) vs placebo—but was not significantly better than treatment with either agent alone.¹⁸

Long-acting inhaled anticholinergic agents—when used in combination with LABAS—have a positive effect on FEV₁, but their effect on exacerbation rates has not been established.

Few studies have evaluated time to exacerbation in patients receiving aclidinium or umeclidinium. In comparison to salmeterol, tiotropium reduced the time to first exacerbation by 42 days at one year (hazard ratio=0.83; 95% confidence interval [CI], 0.77-0.9; P<.001).¹⁹ The evidence suggests that when used in combination with LABAs, long-acting IACs have a positive impact on FEV₁, but their effect on exacerbation rates has not been established.

Combination therapy with steroids and LABAs

The combination of inhaled corticosteroids (ICS) and LABAs has been found to improve FEV₁ and symptoms in patients with moderate to severe COPD more than monotherapy with either drug class.^20,21 In fact, ICS alone have not been proven to slow the progression of the disease or to lower mortality rates in patients with COPD.²²

Fluticasone/salmeterol demonstrated a 25% reduction in exacerbation rates compared with placebo (P<.0001), a greater reduction than that of either drug alone.²⁰ A retrospective observational study comparing fixed dose fluticasone/salmeterol with budesonide/formoterol reported a similar reduction in exacerbation rates, but the number of patients requiring the addition of an IAC was 16% lower in the latter group.²³

The combination of fluticasone/vilanterol has the potential to improve adherence, given that it is dosed once daily, unlike other COPD combination drugs. Its clinical efficacy is comparable to that of fluticasone/salmeterol after 12 weeks of therapy, with similar improvements in FEV₁,²⁴ but fluticasone/vilanterol is associated with an increased risk of pneumonia.³

Chronic use of oral corticosteroids

Oral corticosteroids (OCS) are clinically indicated in individuals whose symptoms continue despite optimal therapy with inhaled agents that have demonstrated efficacy. Such patients are often referred to as “steroid dependent.”

While OCS are prescribed for both their anti-inflammatory activity and their ability to slow the progression of COPD,^25,26 no well-designed studies have investigated their benefits for this patient population. One study concluded that patients who were slowly withdrawn from their OCS regimen had no more frequent exacerbations than those who maintained chronic usage. The withdrawal group did, however, lose weight.²⁷

GOLD guidelines do not recommend OCS for chronic management of COPD due to the risk of toxicity.³ The well-established adverse effects of chronic OCS include hyperglycemia, hypertension, osteoporosis, and myopathy.^28,29 A study of muscle function in 21 COPD patients receiving corticosteroids revealed decreases in quadriceps muscle strength and pulmonary function.³⁰ Daily use of OCS will likely result in additional therapies to control drug-induced conditions, as well—another antihypertensive secondary to fluid retention caused by chronic use of OCS in patients with high blood pressure, for example, or additional medication to control elevated blood glucose levels in patients with diabetes.

Phosphodiesterase-4 inhibitors

In one study, patients slowly withdrawn from oral corticosteroids had no more frequent exacerbations than those who maintained chronic usage.

The recommendation for roflumilast in patients with GOLD Class 2 to 4 symptoms remains unchanged since the introduction of this agent as a treatment option for COPD.³ Phosphodiesterase-4 (PDE-4) inhibitors such as roflumilast reduce inflammation in the lungs and have no activity as a bronchodilator.^31,32

Roflumilast has been shown to improve FEV₁ in patients concurrently receiving a long-acting bronchodilator and to reduce exacerbations in steroid-dependent patients, a recent systematic review of 29 PDE-4 trials found.³³ Patients taking roflumilast, however, suffered from more adverse events (nausea, appetite reduction, diarrhea, weight loss, sleep disturbances, and headache) than those on placebo.³³

Antibiotics

GOLD guidelines do not recommend the use of antibiotics for patients with COPD, except to treat acute exacerbations.¹ However, recent studies suggest that routine or pulsed dosing of prophylactic antibiotics can reduce the number of exacerbations.^34-36 A 2013 review of 7 studies determined that continuous antibiotics, particularly macrolides, reduced the number of COPD exacerbations in patients with a mean age of 66 years (odds ratio [OR]=0.55; 95% CI, 0.39-0.77).³⁷

Patients with limited mobility can benefit from non-exercise components of pulmonary rehabilitation.

A more recent trial randomized 92 patients with a history of ≥3 exacerbations in the previous year to receive either prophylactic azithromycin or placebo daily for 12 months. The treatment group experienced a significant decrease in the number of exacerbations (OR=0.58; 95% CI, 0.42-0.79; P=.001).³⁸ This benefit must be weighed against the potential development of antibiotic resistance and adverse effects, so careful patient selection is important.

Pulmonary rehabilitation has proven benefits

GOLD, the American College of Chest Physicians, the American Thoracic Society, and the European Respiratory Society all recommend pulmonary rehabilitation for patients with COPD.^39-41 In addition to reducing morbidity and mortality rates—including a reduction in number of hospitalizations and length of stay and improved post-discharge recovery—pulmonary rehabilitation has been shown to have other physical and psychological benefits.⁴² Specific benefits include improved exercise capacity, greater arm strength and endurance, reduced perception of intensity of breathlessness, and improved overall health-related quality of life.

Key features of rehab programs

Important components of pulmonary rehabilitation include counseling on tobacco cessation, nutrition, education—including correct inhalation technique—and exercise training. There are few contraindications to participation, and patients can derive benefit from both its non-exercise components and upper extremity training regardless of their mobility level.

A 2006 Cochrane review concluded that an effective pulmonary rehabilitation program should be at least 4 weeks in duration,⁴³ and longer programs have been shown to produce greater benefits.⁴⁴ However, there is no agreement on an optimal time frame. Studies are inconclusive on other specific aspects of pulmonary rehab programs, as well, such as the number of sessions per week, number of hours per session, duration and intensity of exercise regimens, and staff-to-patient ratios.

An effective pulmonary rehabilitation program should be at least 4 weeks long.

Home-based exercise training may produce many of the same benefits as a formal pulmonary rehabilitation program. A systematic review found improved quality of life and exercise capacity associated with patient care that lacked formal pulmonary rehabilitation, with no differences between results from home-based training and hospital-based outpatient pulmonary rehabilitation programs.⁴⁵

Given the lack of availability of formal rehab programs in many communities, homebased training for patients with COPD is important to consider.

Implications for practice

What is the takeaway from this evidence-based review? Overall, it is clear that, with the possible exception of the effect of once-daily dosing on adherence, there is little difference among the therapeutic agents within a particular class of medications—and that more is not necessarily better. Indeed, evidence suggests that higher doses of LABAs may reduce their effectiveness, rendering them no better than placebo. In addition, there is no significant difference in the rate of exacerbations in patients taking ICS/LABA combinations and those receiving IACs alone.

Determining the optimal treatment for a particular patient requires an assessment of comorbidities, including potential adverse drug effects.

Pulmonary rehabilitation should be recommended for all newly diagnosed patients, while appropriate drug therapies should be individualized based on the GOLD symptoms/risk evaluation categories (TABLE 3).³ While daily OCS and daily antibiotics have the potential to reduce exacerbation rates, for example, the risks of adverse effects and toxicities outweigh the benefits for patients whose condition is stable.

Determining the optimal treatment for a particular patient also requires an assessment of comorbidities, including potential adverse drug effects (TABLE 4).^{3,27-29,33,46-52} Selection of medication should be driven by patient and physician preference to optimize adherence and clinical outcomes, although cost and accessibility often play a significant role, as well.

CORRESPONDENCE
Nabila Ahmed-Sarwar, PharmD, BCPS, CDE, St. John Fisher College, Wegmans School of Pharmacy, 3690 East Avenue, Rochester, NY 14618; [email protected]

ACKNOWLEDGEMENTS
The authors thank the following people for their assistance in the preparation of this manuscript: Matthew Stryker, PharmD, Timothy Adler, PharmD, and Angela K. Nagel, PharmD, BCPS.

Vaccines have been proven effective in preventing disease and are one of the most cost-effective and successful public health initiatives of the 20th century. Nevertheless, adult vaccination rates in the United States for vaccine-preventable diseases are low for most routinely recommended vaccines.¹ In 2013 alone, there were an estimated 3700 deaths in the United States (95% of which were adults) from pneumococcal infections—a vaccine-preventable disorder.²

Consider the threat posed by the flu. Annually, most people who die of influenza and its complications are adults, with estimates ranging from a low of 3000 to a high of 49,000 based on Centers for Disease Control and Prevention (CDC) data from the 1976-1977 flu season to the 2006-2007 season.³ Vaccination during the 2013-2014 season resulted in an estimated 7.2 million fewer cases of influenza, 90,000 fewer hospitalizations, and 3.1 million fewer medically attended cases than would have been expected without vaccination.⁴ If vaccination levels had reached the Healthy People 2020 target of 70%, an additional 5.9 million illnesses, 2.3 million medically attended illnesses, and 42,000 hospitalizations might have been averted.⁴

How are we doing with other vaccines? Based on the 2013 National Health Interview Survey, the CDC assessed vaccination coverage among adults ages ≥19 years for selected vaccines: pneumococcal vaccine, tetanus toxoid-containing vaccines (tetanus and diphtheria vaccine [Td] or tetanus and diphtheria with acellular pertussis vaccine [Tdap]), and vaccines for hepatitis A, hepatitis B, herpes zoster, and human papillomavirus (HPV). (With the exception of influenza vaccination, which is recommended annually for all adults, other vaccinations are directed at specific populations based on age, health conditions, behavioral risk factors, occupation, or travel conditions.)

Overall, coverage rates for hepatitis A and B, pneumococcal, Td, and human papillomavirus (HPV) for all adults did not improve from 2012 to 2013; rates increased only modestly for Tdap among adults ≥19 years, for herpes zoster among adults ≥60 years, and for HPV among men ages 19 to 26. Furthermore, racial and ethnic gaps in coverage are seen in all vaccines, and these gaps widened since 2012 for Tdap, herpes zoster, and HPV vaccination.¹

Commonly cited barriers to improved vaccine uptake in adults include lack of regular assessment of vaccine status; lack of physician and other health care provider knowledge on current vaccine recommendations; cost; insufficient stocking of some vaccines; financial disincentives for vaccination in the primary care setting; limited use of electronic records, tools, and immunization registries; missed opportunities; and patient hesitancy and vaccine refusal.⁵

Removing barriers to immunization. Several recommendations on ways to improve adult vaccination rates are made by many federal organizations as well as by The Community Preventive Services Task Force (Task Force), an independent, nonfederal, unpaid panel of public health and prevention experts. The Task Force—which makes recommendations based on systematic reviews of the evidence of effectiveness, the applicability of the evidence, economic evaluations, and barriers to implementation of interventions⁶—advocates a 3-pronged approach to improve adult vaccination rates: 1) enhance access to vaccination services; 2) increase community demand for vaccinations; and 3) incorporate physician- or system-based interventions into practice.⁷

Using your state’s immunization information system can help ensure accurate tracking of patients’ immunization status.

The CDC and other groups such as the National Vaccine Advisory Committee (NVAC) recommend that every routine adult office visit include a vaccination needs assessment, recommendation, and offer of vaccination.⁸ Additionally, the Task Force recommends 3 means of enhancing adult access to vaccination services: make home visits, reduce patient costs, and offer vaccination programs in the community.⁷

This article describes a number of simple steps physicians can take to increase the likelihood that adults will get their vaccines and reviews the literature on using new media such as smartphones and other Internet-based tools to improve immunization coverage.⁹

Increasing community demands for vaccinations

Physicians and other healthcare providers can increase community demand for vaccinations by improving their own knowledge on the subject, recommending vaccination to patients, and increasing their community and political involvement to strengthen or change laws to better support immunization uptake.

To increase awareness and education, keep abreast of the Advisory Committee on Immunization Practices (ACIP) recommendations and guidelines, which are updated annually and reported on in this journal’s Practice Alert column. Consider taking advantage of free immunization apps that are available from the CDC (“CDC Vaccine Schedules” http://www.cdc.gov/vaccines/schedules/hcp/schedule-app.html), the Society of Teachers of Family Medicine (STFM; “Shots Immunizations” http://www.immunizationed.org/Shots-Mobile-App), and the American College of Physicians (“ACP Immunization Advisor” http://immunization.acponline.org/app/).

Take steps to put guidelines into practice. Despite wide promulgation, clinical practice guidelines alone have had limited effect on changing physician behavior and improving patient outcomes. Interactive techniques are more effective than guidelines and didactic presentations alone at changing physician care and patient outcomes. Such techniques include audit/feedback (the reporting of an individual clinician’s vaccination rates compared with desired or target rates, for example), academic detailing/outreach, and reminders by way of electronic or other alerts.^10,11

Promote immunization to patients. Physicians are highly influential in determining a patient’s decision to vaccinate, and it is well documented that a strong recommendation about the importance of immunizations makes a difference to patients.^12,13

What you say and how you say it matters. A halfhearted recommendation for vaccination may result in the patient remaining unvaccinated.¹⁴ For example, “If you want, you can get your pneumonia shot today” is much less persuasive than, “I recommend you get your pneumonia vaccine today to prevent a potentially serious disease that affects thousands of adults each year.” Most adults believe that vaccines are important and are likely to get them if recommended by their health care professionals.¹⁵

At the time of a visit, chart reminders—electronic or paper—can keep the need for immunization visible amid competing priorities.

The CDC recommends that physicians encourage patients to make an informed decision about vaccination by sharing critical information highlighting the importance of vaccinations and reminding patients what vaccines protect against while addressing their concerns (www.cdc.gov/vaccines/adultstandards). Free educational materials for patients can be found at www.cdc.gov/vaccines/AdultPatientEd.

Draw on community resources. Laws and policies that require vaccinations as a prerequisite for attending childcare, school, or college increase coverage. Community and faith-based organizations are likely to play an important role in reducing racial and ethnic disparities in adult immunizations because they can deliver education that is culturally sensitive and tailored to specific subpopulations.^16,17 Physicians and other health care providers can get involved with community and faith-based groups and local and federal legislative efforts to improve immunization rates.

Consider implementing these system-based interventions

The following 6 system-based interventions can help improve adult immunization rates:

1. Develop a practice team. The practice team, based on the Patient-Centered Medical Home (PCMH), includes physicians, midlevel providers, nurses, medical assistants, pharmacists, social workers, and other staff. The PCMH team model can facilitate a shift of responsibilities among individuals to better orient the practice toward patients’ health and preventive services.^18,19 While physicians have traditionally held all of the responsibility for patient care, including screening for disease and prevention, shifting the responsibility of vaccine screening to nurses or medical assistants can free up time for longer physician/patient interactions.¹⁸

The creation of a practice champion within the PCMH team—a physician, midlevel provider, or nurse—to oversee quality improvement for vaccine rates and work to generate support and cooperation from coworkers has also been shown to improve vaccination rates.²⁰ The vaccine champion should keep abreast of new vaccine recommendations and relay that information to the practice through regular staff meetings, announcements, and office postings. The champion can also supervise pre-visit planning for immunizations.¹⁹

2. Use electronic immunization information systems (IIS). All states except New Hampshire have an IIS.²¹ Accurate tracking of adult immunizations in a registry provides a complete record and is essential to improving adult immunization rates,²² as does the use of chart notes, computerized alerts, checklists, and other tools that remind health care providers when patients are due for vaccinations.¹⁸ NVAC recommends that all physicians use their state IIS and create a process in their practice to include its use.

3. Incorporate physician feedback. Many health care systems and payers are using benchmarking and incentives to provide physician feedback on vaccination performance.²³ Using achievable benchmarks enhances the effectiveness of physician performance feedback.²⁴ The Task Force conducted a systematic review of the evidence on the effectiveness of health care provider assessment and feedback for increasing coverage rates and found that this strategy remains an effective means to increase vaccination rates.²⁵

4. Use reminders/alerts. Even though you may intend to routinely recommend immunizations, remembering to do so at the time of each visit can be difficult when there are so many other issues to address. Reminders at the time of the visit can help. Some electronic records have reminder prompts, or “best practice alerts” (BPAs), programmed into their systems.²⁶ These BPAs will prompt for needed immunizations whether the patient is being seen for a well, acute, or routine follow-up visit. These reminder/recall activities can be greatly simplified by participation in a population-based IIS.

Practices that don’t have an electronic health record can still improve vaccination rates by conveying the reminder with a brightly colored paper form attached to the front of a patient’s chart during the check-in process. One recent study showed that this approach increased rates of influenza vaccination in an urban practice by 12 percentage points.²⁷

Furthermore, simply reminding patients to vaccinate increases the vaccination rate.²⁸ Patient reminder/recall systems using telephone calls or mailings (phone calls are more effective than mailings) improve both childhood and adult vaccinations in all medical settings. More intensive systems using multiple reminders appear to be more effective than single reminders, and while costly, the benefits of increasing preventive visits/services and vaccine uptake help offset this cost.²⁸

5. Implement standing orders. Standing orders—which allow nurses and other appropriately trained health care personnel to assess immunization status and administer vaccinations according to protocol—help improve immunization rates.²⁹ ACIP advises that standing order programs be used in long-term care facilities under the supervision of a medical director to ensure the administration of recommended vaccinations for adults, and in inpatient and outpatient facilities. Because of the societal burden of influenza and pneumococcal disease, implementation of standing orders programs to improve adult vaccination coverage for these diseases is considered a national public health priority.³⁰

6. Develop an encouraging communication style. Studies show that how one communicates with patients is just as important as what one communicates. Certain communication styles and techniques may be more or less effective when discussing vaccination needs with some patients, especially those with vaccine hesitancy or low confidence in vaccine safety or effectiveness. For example, styles that are “directing” are usually unhelpful in addressing concerns about vaccination. These styles typically use information and persuasion to achieve change and may be perceived as confrontational. This approach can lead to cues being missed, jargon being used, and vaccine safety being overstated.

Styles shown to be helpful are those that elicit patient concerns, ask permission to discuss, acknowledge/listen/empathize, determine readiness to change, inform about benefits and risks, and give appropriate resources. These helpful forms of communication are more of a “May I help you?” style vs a “This is what you should do” style of communication.³¹

Telling a patient that vaccines are safe and, “You are silly not to get yours” is not as effective as saying, “What are your concerns about vaccines? Let’s talk about them.”

Assure patients that recommendations are based on the best interest of their health and on the best available science. Listen to a patient’s concerns and acknowledge them in a nonconfrontational manner, allowing patients to express their concerns and thereby increase their willingness to listen.³² Saying that there is “absolutely no need to worry—vaccines are safe and you are silly not to get yours” is not as effective as saying, “What are your concerns regarding vaccines? Let’s talk about them.”

For the vaccine-hesitant group, building trust is essential through a respectful, nonjudgmental approach that aims to elicit and address specific concerns. For those who refuse vaccines, keep the consultation brief, keep the door open for further discussion, and provide appropriate resources if the patient wants them.³³

Increase use of new media

Mass communication through smartphones and other Internet-based tools such as Facebook and Twitter brings a new dimension to health care, allowing patients and health professionals to communicate about health issues and possibly improve health outcomes.³⁴ The number of people using social media increased by almost 570% worldwide between 2000 and 2012 and surpassed 2.75 billion in 2013.³⁵

Sixty-one percent of adults in the United States look online for health information.³⁶ In a survey conducted in September 2014, the Pew Research Center found that Facebook is the most popular social media site in the United States. Seventy-one percent of online-knowledgeable adults use Facebook, and multiplatform use is on the rise: 52% of adult Internet users now use 2 or more social media sites, a significant increase from 2013, when it stood at 42%. (Other platforms such as Twitter, Instagram, Pinterest, and LinkedIn saw significant increases over the past year in the proportion of online adults who use them).³⁷

One RCT showed that patient access to a personalized Web-based portal increased influenza vaccination rates.

Health information provided by social media can answer medical questions and concerns and enhance health promotion and education.³⁵ A recent review of 98 research studies provided evidence that social media can create a space to share, comment, and discuss health information.³⁴ Compared with traditional communication methods, the widespread availability of social media makes health information more accessible, broadening access to various population groups, regardless of age, education, race, ethnicity, and locale.

New media platforms are proving effective. The first systematic assessment of available evidence on the use of new media to increase vaccine uptake and immunization coverage (a review of 7 randomized controlled trials [RCTs], 5 non-RCTs, 3 cross-sectional studies, one case-control study and 3 operational research studies published between 2000-2013) found that text messaging, accessing immunization campaign Web sites, using patient-held Web-based portals, computerized reminders, and standing orders increased immunization coverage rates.³⁵ However, evidence was insufficient in this regard on the value of social networks, email communication, and smartphone applications.

One RCT showed that having access to a personalized Web-based portal where patients could manage health records as well as interact with both health care providers and other members of the community through social forums and messaging tools increased influenza vaccination rates.³⁵

CORRESPONDENCE
Pamela G. Rockwell, DO, Department of Family Medicine, University of Michigan, 24 Frank Lloyd Wright Drive, P.O. Box 431, Ann Arbor, MI 48106-0795; [email protected].

Vaccines have been proven effective in preventing disease and are one of the most cost-effective and successful public health initiatives of the 20th century. Nevertheless, adult vaccination rates in the United States for vaccine-preventable diseases are low for most routinely recommended vaccines.¹ In 2013 alone, there were an estimated 3700 deaths in the United States (95% of which were adults) from pneumococcal infections—a vaccine-preventable disorder.²

Consider the threat posed by the flu. Annually, most people who die of influenza and its complications are adults, with estimates ranging from a low of 3000 to a high of 49,000 based on Centers for Disease Control and Prevention (CDC) data from the 1976-1977 flu season to the 2006-2007 season.³ Vaccination during the 2013-2014 season resulted in an estimated 7.2 million fewer cases of influenza, 90,000 fewer hospitalizations, and 3.1 million fewer medically attended cases than would have been expected without vaccination.⁴ If vaccination levels had reached the Healthy People 2020 target of 70%, an additional 5.9 million illnesses, 2.3 million medically attended illnesses, and 42,000 hospitalizations might have been averted.⁴

How are we doing with other vaccines? Based on the 2013 National Health Interview Survey, the CDC assessed vaccination coverage among adults ages ≥19 years for selected vaccines: pneumococcal vaccine, tetanus toxoid-containing vaccines (tetanus and diphtheria vaccine [Td] or tetanus and diphtheria with acellular pertussis vaccine [Tdap]), and vaccines for hepatitis A, hepatitis B, herpes zoster, and human papillomavirus (HPV). (With the exception of influenza vaccination, which is recommended annually for all adults, other vaccinations are directed at specific populations based on age, health conditions, behavioral risk factors, occupation, or travel conditions.)

Overall, coverage rates for hepatitis A and B, pneumococcal, Td, and human papillomavirus (HPV) for all adults did not improve from 2012 to 2013; rates increased only modestly for Tdap among adults ≥19 years, for herpes zoster among adults ≥60 years, and for HPV among men ages 19 to 26. Furthermore, racial and ethnic gaps in coverage are seen in all vaccines, and these gaps widened since 2012 for Tdap, herpes zoster, and HPV vaccination.¹

Commonly cited barriers to improved vaccine uptake in adults include lack of regular assessment of vaccine status; lack of physician and other health care provider knowledge on current vaccine recommendations; cost; insufficient stocking of some vaccines; financial disincentives for vaccination in the primary care setting; limited use of electronic records, tools, and immunization registries; missed opportunities; and patient hesitancy and vaccine refusal.⁵

Removing barriers to immunization. Several recommendations on ways to improve adult vaccination rates are made by many federal organizations as well as by The Community Preventive Services Task Force (Task Force), an independent, nonfederal, unpaid panel of public health and prevention experts. The Task Force—which makes recommendations based on systematic reviews of the evidence of effectiveness, the applicability of the evidence, economic evaluations, and barriers to implementation of interventions⁶—advocates a 3-pronged approach to improve adult vaccination rates: 1) enhance access to vaccination services; 2) increase community demand for vaccinations; and 3) incorporate physician- or system-based interventions into practice.⁷

Using your state’s immunization information system can help ensure accurate tracking of patients’ immunization status.

The CDC and other groups such as the National Vaccine Advisory Committee (NVAC) recommend that every routine adult office visit include a vaccination needs assessment, recommendation, and offer of vaccination.⁸ Additionally, the Task Force recommends 3 means of enhancing adult access to vaccination services: make home visits, reduce patient costs, and offer vaccination programs in the community.⁷

This article describes a number of simple steps physicians can take to increase the likelihood that adults will get their vaccines and reviews the literature on using new media such as smartphones and other Internet-based tools to improve immunization coverage.⁹

Increasing community demands for vaccinations

Physicians and other healthcare providers can increase community demand for vaccinations by improving their own knowledge on the subject, recommending vaccination to patients, and increasing their community and political involvement to strengthen or change laws to better support immunization uptake.

To increase awareness and education, keep abreast of the Advisory Committee on Immunization Practices (ACIP) recommendations and guidelines, which are updated annually and reported on in this journal’s Practice Alert column. Consider taking advantage of free immunization apps that are available from the CDC (“CDC Vaccine Schedules” http://www.cdc.gov/vaccines/schedules/hcp/schedule-app.html), the Society of Teachers of Family Medicine (STFM; “Shots Immunizations” http://www.immunizationed.org/Shots-Mobile-App), and the American College of Physicians (“ACP Immunization Advisor” http://immunization.acponline.org/app/).

Take steps to put guidelines into practice. Despite wide promulgation, clinical practice guidelines alone have had limited effect on changing physician behavior and improving patient outcomes. Interactive techniques are more effective than guidelines and didactic presentations alone at changing physician care and patient outcomes. Such techniques include audit/feedback (the reporting of an individual clinician’s vaccination rates compared with desired or target rates, for example), academic detailing/outreach, and reminders by way of electronic or other alerts.^10,11

Promote immunization to patients. Physicians are highly influential in determining a patient’s decision to vaccinate, and it is well documented that a strong recommendation about the importance of immunizations makes a difference to patients.^12,13

What you say and how you say it matters. A halfhearted recommendation for vaccination may result in the patient remaining unvaccinated.¹⁴ For example, “If you want, you can get your pneumonia shot today” is much less persuasive than, “I recommend you get your pneumonia vaccine today to prevent a potentially serious disease that affects thousands of adults each year.” Most adults believe that vaccines are important and are likely to get them if recommended by their health care professionals.¹⁵

At the time of a visit, chart reminders—electronic or paper—can keep the need for immunization visible amid competing priorities.

The CDC recommends that physicians encourage patients to make an informed decision about vaccination by sharing critical information highlighting the importance of vaccinations and reminding patients what vaccines protect against while addressing their concerns (www.cdc.gov/vaccines/adultstandards). Free educational materials for patients can be found at www.cdc.gov/vaccines/AdultPatientEd.

Draw on community resources. Laws and policies that require vaccinations as a prerequisite for attending childcare, school, or college increase coverage. Community and faith-based organizations are likely to play an important role in reducing racial and ethnic disparities in adult immunizations because they can deliver education that is culturally sensitive and tailored to specific subpopulations.^16,17 Physicians and other health care providers can get involved with community and faith-based groups and local and federal legislative efforts to improve immunization rates.

Consider implementing these system-based interventions

The following 6 system-based interventions can help improve adult immunization rates:

1. Develop a practice team. The practice team, based on the Patient-Centered Medical Home (PCMH), includes physicians, midlevel providers, nurses, medical assistants, pharmacists, social workers, and other staff. The PCMH team model can facilitate a shift of responsibilities among individuals to better orient the practice toward patients’ health and preventive services.^18,19 While physicians have traditionally held all of the responsibility for patient care, including screening for disease and prevention, shifting the responsibility of vaccine screening to nurses or medical assistants can free up time for longer physician/patient interactions.¹⁸

The creation of a practice champion within the PCMH team—a physician, midlevel provider, or nurse—to oversee quality improvement for vaccine rates and work to generate support and cooperation from coworkers has also been shown to improve vaccination rates.²⁰ The vaccine champion should keep abreast of new vaccine recommendations and relay that information to the practice through regular staff meetings, announcements, and office postings. The champion can also supervise pre-visit planning for immunizations.¹⁹

2. Use electronic immunization information systems (IIS). All states except New Hampshire have an IIS.²¹ Accurate tracking of adult immunizations in a registry provides a complete record and is essential to improving adult immunization rates,²² as does the use of chart notes, computerized alerts, checklists, and other tools that remind health care providers when patients are due for vaccinations.¹⁸ NVAC recommends that all physicians use their state IIS and create a process in their practice to include its use.

3. Incorporate physician feedback. Many health care systems and payers are using benchmarking and incentives to provide physician feedback on vaccination performance.²³ Using achievable benchmarks enhances the effectiveness of physician performance feedback.²⁴ The Task Force conducted a systematic review of the evidence on the effectiveness of health care provider assessment and feedback for increasing coverage rates and found that this strategy remains an effective means to increase vaccination rates.²⁵

4. Use reminders/alerts. Even though you may intend to routinely recommend immunizations, remembering to do so at the time of each visit can be difficult when there are so many other issues to address. Reminders at the time of the visit can help. Some electronic records have reminder prompts, or “best practice alerts” (BPAs), programmed into their systems.²⁶ These BPAs will prompt for needed immunizations whether the patient is being seen for a well, acute, or routine follow-up visit. These reminder/recall activities can be greatly simplified by participation in a population-based IIS.

Practices that don’t have an electronic health record can still improve vaccination rates by conveying the reminder with a brightly colored paper form attached to the front of a patient’s chart during the check-in process. One recent study showed that this approach increased rates of influenza vaccination in an urban practice by 12 percentage points.²⁷

Furthermore, simply reminding patients to vaccinate increases the vaccination rate.²⁸ Patient reminder/recall systems using telephone calls or mailings (phone calls are more effective than mailings) improve both childhood and adult vaccinations in all medical settings. More intensive systems using multiple reminders appear to be more effective than single reminders, and while costly, the benefits of increasing preventive visits/services and vaccine uptake help offset this cost.²⁸

5. Implement standing orders. Standing orders—which allow nurses and other appropriately trained health care personnel to assess immunization status and administer vaccinations according to protocol—help improve immunization rates.²⁹ ACIP advises that standing order programs be used in long-term care facilities under the supervision of a medical director to ensure the administration of recommended vaccinations for adults, and in inpatient and outpatient facilities. Because of the societal burden of influenza and pneumococcal disease, implementation of standing orders programs to improve adult vaccination coverage for these diseases is considered a national public health priority.³⁰

6. Develop an encouraging communication style. Studies show that how one communicates with patients is just as important as what one communicates. Certain communication styles and techniques may be more or less effective when discussing vaccination needs with some patients, especially those with vaccine hesitancy or low confidence in vaccine safety or effectiveness. For example, styles that are “directing” are usually unhelpful in addressing concerns about vaccination. These styles typically use information and persuasion to achieve change and may be perceived as confrontational. This approach can lead to cues being missed, jargon being used, and vaccine safety being overstated.

Styles shown to be helpful are those that elicit patient concerns, ask permission to discuss, acknowledge/listen/empathize, determine readiness to change, inform about benefits and risks, and give appropriate resources. These helpful forms of communication are more of a “May I help you?” style vs a “This is what you should do” style of communication.³¹

Telling a patient that vaccines are safe and, “You are silly not to get yours” is not as effective as saying, “What are your concerns about vaccines? Let’s talk about them.”

Assure patients that recommendations are based on the best interest of their health and on the best available science. Listen to a patient’s concerns and acknowledge them in a nonconfrontational manner, allowing patients to express their concerns and thereby increase their willingness to listen.³² Saying that there is “absolutely no need to worry—vaccines are safe and you are silly not to get yours” is not as effective as saying, “What are your concerns regarding vaccines? Let’s talk about them.”

For the vaccine-hesitant group, building trust is essential through a respectful, nonjudgmental approach that aims to elicit and address specific concerns. For those who refuse vaccines, keep the consultation brief, keep the door open for further discussion, and provide appropriate resources if the patient wants them.³³

Increase use of new media

Mass communication through smartphones and other Internet-based tools such as Facebook and Twitter brings a new dimension to health care, allowing patients and health professionals to communicate about health issues and possibly improve health outcomes.³⁴ The number of people using social media increased by almost 570% worldwide between 2000 and 2012 and surpassed 2.75 billion in 2013.³⁵

Sixty-one percent of adults in the United States look online for health information.³⁶ In a survey conducted in September 2014, the Pew Research Center found that Facebook is the most popular social media site in the United States. Seventy-one percent of online-knowledgeable adults use Facebook, and multiplatform use is on the rise: 52% of adult Internet users now use 2 or more social media sites, a significant increase from 2013, when it stood at 42%. (Other platforms such as Twitter, Instagram, Pinterest, and LinkedIn saw significant increases over the past year in the proportion of online adults who use them).³⁷

One RCT showed that patient access to a personalized Web-based portal increased influenza vaccination rates.

Health information provided by social media can answer medical questions and concerns and enhance health promotion and education.³⁵ A recent review of 98 research studies provided evidence that social media can create a space to share, comment, and discuss health information.³⁴ Compared with traditional communication methods, the widespread availability of social media makes health information more accessible, broadening access to various population groups, regardless of age, education, race, ethnicity, and locale.

New media platforms are proving effective. The first systematic assessment of available evidence on the use of new media to increase vaccine uptake and immunization coverage (a review of 7 randomized controlled trials [RCTs], 5 non-RCTs, 3 cross-sectional studies, one case-control study and 3 operational research studies published between 2000-2013) found that text messaging, accessing immunization campaign Web sites, using patient-held Web-based portals, computerized reminders, and standing orders increased immunization coverage rates.³⁵ However, evidence was insufficient in this regard on the value of social networks, email communication, and smartphone applications.

One RCT showed that having access to a personalized Web-based portal where patients could manage health records as well as interact with both health care providers and other members of the community through social forums and messaging tools increased influenza vaccination rates.³⁵

CORRESPONDENCE
Pamela G. Rockwell, DO, Department of Family Medicine, University of Michigan, 24 Frank Lloyd Wright Drive, P.O. Box 431, Ann Arbor, MI 48106-0795; [email protected].

Vaccines have been proven effective in preventing disease and are one of the most cost-effective and successful public health initiatives of the 20th century. Nevertheless, adult vaccination rates in the United States for vaccine-preventable diseases are low for most routinely recommended vaccines.¹ In 2013 alone, there were an estimated 3700 deaths in the United States (95% of which were adults) from pneumococcal infections—a vaccine-preventable disorder.²

Consider the threat posed by the flu. Annually, most people who die of influenza and its complications are adults, with estimates ranging from a low of 3000 to a high of 49,000 based on Centers for Disease Control and Prevention (CDC) data from the 1976-1977 flu season to the 2006-2007 season.³ Vaccination during the 2013-2014 season resulted in an estimated 7.2 million fewer cases of influenza, 90,000 fewer hospitalizations, and 3.1 million fewer medically attended cases than would have been expected without vaccination.⁴ If vaccination levels had reached the Healthy People 2020 target of 70%, an additional 5.9 million illnesses, 2.3 million medically attended illnesses, and 42,000 hospitalizations might have been averted.⁴

How are we doing with other vaccines? Based on the 2013 National Health Interview Survey, the CDC assessed vaccination coverage among adults ages ≥19 years for selected vaccines: pneumococcal vaccine, tetanus toxoid-containing vaccines (tetanus and diphtheria vaccine [Td] or tetanus and diphtheria with acellular pertussis vaccine [Tdap]), and vaccines for hepatitis A, hepatitis B, herpes zoster, and human papillomavirus (HPV). (With the exception of influenza vaccination, which is recommended annually for all adults, other vaccinations are directed at specific populations based on age, health conditions, behavioral risk factors, occupation, or travel conditions.)

Overall, coverage rates for hepatitis A and B, pneumococcal, Td, and human papillomavirus (HPV) for all adults did not improve from 2012 to 2013; rates increased only modestly for Tdap among adults ≥19 years, for herpes zoster among adults ≥60 years, and for HPV among men ages 19 to 26. Furthermore, racial and ethnic gaps in coverage are seen in all vaccines, and these gaps widened since 2012 for Tdap, herpes zoster, and HPV vaccination.¹

Commonly cited barriers to improved vaccine uptake in adults include lack of regular assessment of vaccine status; lack of physician and other health care provider knowledge on current vaccine recommendations; cost; insufficient stocking of some vaccines; financial disincentives for vaccination in the primary care setting; limited use of electronic records, tools, and immunization registries; missed opportunities; and patient hesitancy and vaccine refusal.⁵

Removing barriers to immunization. Several recommendations on ways to improve adult vaccination rates are made by many federal organizations as well as by The Community Preventive Services Task Force (Task Force), an independent, nonfederal, unpaid panel of public health and prevention experts. The Task Force—which makes recommendations based on systematic reviews of the evidence of effectiveness, the applicability of the evidence, economic evaluations, and barriers to implementation of interventions⁶—advocates a 3-pronged approach to improve adult vaccination rates: 1) enhance access to vaccination services; 2) increase community demand for vaccinations; and 3) incorporate physician- or system-based interventions into practice.⁷

Using your state’s immunization information system can help ensure accurate tracking of patients’ immunization status.

The CDC and other groups such as the National Vaccine Advisory Committee (NVAC) recommend that every routine adult office visit include a vaccination needs assessment, recommendation, and offer of vaccination.⁸ Additionally, the Task Force recommends 3 means of enhancing adult access to vaccination services: make home visits, reduce patient costs, and offer vaccination programs in the community.⁷

This article describes a number of simple steps physicians can take to increase the likelihood that adults will get their vaccines and reviews the literature on using new media such as smartphones and other Internet-based tools to improve immunization coverage.⁹

Increasing community demands for vaccinations

Physicians and other healthcare providers can increase community demand for vaccinations by improving their own knowledge on the subject, recommending vaccination to patients, and increasing their community and political involvement to strengthen or change laws to better support immunization uptake.

To increase awareness and education, keep abreast of the Advisory Committee on Immunization Practices (ACIP) recommendations and guidelines, which are updated annually and reported on in this journal’s Practice Alert column. Consider taking advantage of free immunization apps that are available from the CDC (“CDC Vaccine Schedules” http://www.cdc.gov/vaccines/schedules/hcp/schedule-app.html), the Society of Teachers of Family Medicine (STFM; “Shots Immunizations” http://www.immunizationed.org/Shots-Mobile-App), and the American College of Physicians (“ACP Immunization Advisor” http://immunization.acponline.org/app/).

Take steps to put guidelines into practice. Despite wide promulgation, clinical practice guidelines alone have had limited effect on changing physician behavior and improving patient outcomes. Interactive techniques are more effective than guidelines and didactic presentations alone at changing physician care and patient outcomes. Such techniques include audit/feedback (the reporting of an individual clinician’s vaccination rates compared with desired or target rates, for example), academic detailing/outreach, and reminders by way of electronic or other alerts.^10,11

Promote immunization to patients. Physicians are highly influential in determining a patient’s decision to vaccinate, and it is well documented that a strong recommendation about the importance of immunizations makes a difference to patients.^12,13

What you say and how you say it matters. A halfhearted recommendation for vaccination may result in the patient remaining unvaccinated.¹⁴ For example, “If you want, you can get your pneumonia shot today” is much less persuasive than, “I recommend you get your pneumonia vaccine today to prevent a potentially serious disease that affects thousands of adults each year.” Most adults believe that vaccines are important and are likely to get them if recommended by their health care professionals.¹⁵

At the time of a visit, chart reminders—electronic or paper—can keep the need for immunization visible amid competing priorities.

The CDC recommends that physicians encourage patients to make an informed decision about vaccination by sharing critical information highlighting the importance of vaccinations and reminding patients what vaccines protect against while addressing their concerns (www.cdc.gov/vaccines/adultstandards). Free educational materials for patients can be found at www.cdc.gov/vaccines/AdultPatientEd.

Draw on community resources. Laws and policies that require vaccinations as a prerequisite for attending childcare, school, or college increase coverage. Community and faith-based organizations are likely to play an important role in reducing racial and ethnic disparities in adult immunizations because they can deliver education that is culturally sensitive and tailored to specific subpopulations.^16,17 Physicians and other health care providers can get involved with community and faith-based groups and local and federal legislative efforts to improve immunization rates.

Consider implementing these system-based interventions

The following 6 system-based interventions can help improve adult immunization rates:

1. Develop a practice team. The practice team, based on the Patient-Centered Medical Home (PCMH), includes physicians, midlevel providers, nurses, medical assistants, pharmacists, social workers, and other staff. The PCMH team model can facilitate a shift of responsibilities among individuals to better orient the practice toward patients’ health and preventive services.^18,19 While physicians have traditionally held all of the responsibility for patient care, including screening for disease and prevention, shifting the responsibility of vaccine screening to nurses or medical assistants can free up time for longer physician/patient interactions.¹⁸

The creation of a practice champion within the PCMH team—a physician, midlevel provider, or nurse—to oversee quality improvement for vaccine rates and work to generate support and cooperation from coworkers has also been shown to improve vaccination rates.²⁰ The vaccine champion should keep abreast of new vaccine recommendations and relay that information to the practice through regular staff meetings, announcements, and office postings. The champion can also supervise pre-visit planning for immunizations.¹⁹

2. Use electronic immunization information systems (IIS). All states except New Hampshire have an IIS.²¹ Accurate tracking of adult immunizations in a registry provides a complete record and is essential to improving adult immunization rates,²² as does the use of chart notes, computerized alerts, checklists, and other tools that remind health care providers when patients are due for vaccinations.¹⁸ NVAC recommends that all physicians use their state IIS and create a process in their practice to include its use.

3. Incorporate physician feedback. Many health care systems and payers are using benchmarking and incentives to provide physician feedback on vaccination performance.²³ Using achievable benchmarks enhances the effectiveness of physician performance feedback.²⁴ The Task Force conducted a systematic review of the evidence on the effectiveness of health care provider assessment and feedback for increasing coverage rates and found that this strategy remains an effective means to increase vaccination rates.²⁵

4. Use reminders/alerts. Even though you may intend to routinely recommend immunizations, remembering to do so at the time of each visit can be difficult when there are so many other issues to address. Reminders at the time of the visit can help. Some electronic records have reminder prompts, or “best practice alerts” (BPAs), programmed into their systems.²⁶ These BPAs will prompt for needed immunizations whether the patient is being seen for a well, acute, or routine follow-up visit. These reminder/recall activities can be greatly simplified by participation in a population-based IIS.

Practices that don’t have an electronic health record can still improve vaccination rates by conveying the reminder with a brightly colored paper form attached to the front of a patient’s chart during the check-in process. One recent study showed that this approach increased rates of influenza vaccination in an urban practice by 12 percentage points.²⁷

Furthermore, simply reminding patients to vaccinate increases the vaccination rate.²⁸ Patient reminder/recall systems using telephone calls or mailings (phone calls are more effective than mailings) improve both childhood and adult vaccinations in all medical settings. More intensive systems using multiple reminders appear to be more effective than single reminders, and while costly, the benefits of increasing preventive visits/services and vaccine uptake help offset this cost.²⁸

5. Implement standing orders. Standing orders—which allow nurses and other appropriately trained health care personnel to assess immunization status and administer vaccinations according to protocol—help improve immunization rates.²⁹ ACIP advises that standing order programs be used in long-term care facilities under the supervision of a medical director to ensure the administration of recommended vaccinations for adults, and in inpatient and outpatient facilities. Because of the societal burden of influenza and pneumococcal disease, implementation of standing orders programs to improve adult vaccination coverage for these diseases is considered a national public health priority.³⁰

6. Develop an encouraging communication style. Studies show that how one communicates with patients is just as important as what one communicates. Certain communication styles and techniques may be more or less effective when discussing vaccination needs with some patients, especially those with vaccine hesitancy or low confidence in vaccine safety or effectiveness. For example, styles that are “directing” are usually unhelpful in addressing concerns about vaccination. These styles typically use information and persuasion to achieve change and may be perceived as confrontational. This approach can lead to cues being missed, jargon being used, and vaccine safety being overstated.

Styles shown to be helpful are those that elicit patient concerns, ask permission to discuss, acknowledge/listen/empathize, determine readiness to change, inform about benefits and risks, and give appropriate resources. These helpful forms of communication are more of a “May I help you?” style vs a “This is what you should do” style of communication.³¹

Telling a patient that vaccines are safe and, “You are silly not to get yours” is not as effective as saying, “What are your concerns about vaccines? Let’s talk about them.”

Assure patients that recommendations are based on the best interest of their health and on the best available science. Listen to a patient’s concerns and acknowledge them in a nonconfrontational manner, allowing patients to express their concerns and thereby increase their willingness to listen.³² Saying that there is “absolutely no need to worry—vaccines are safe and you are silly not to get yours” is not as effective as saying, “What are your concerns regarding vaccines? Let’s talk about them.”

For the vaccine-hesitant group, building trust is essential through a respectful, nonjudgmental approach that aims to elicit and address specific concerns. For those who refuse vaccines, keep the consultation brief, keep the door open for further discussion, and provide appropriate resources if the patient wants them.³³

Increase use of new media

Mass communication through smartphones and other Internet-based tools such as Facebook and Twitter brings a new dimension to health care, allowing patients and health professionals to communicate about health issues and possibly improve health outcomes.³⁴ The number of people using social media increased by almost 570% worldwide between 2000 and 2012 and surpassed 2.75 billion in 2013.³⁵

Sixty-one percent of adults in the United States look online for health information.³⁶ In a survey conducted in September 2014, the Pew Research Center found that Facebook is the most popular social media site in the United States. Seventy-one percent of online-knowledgeable adults use Facebook, and multiplatform use is on the rise: 52% of adult Internet users now use 2 or more social media sites, a significant increase from 2013, when it stood at 42%. (Other platforms such as Twitter, Instagram, Pinterest, and LinkedIn saw significant increases over the past year in the proportion of online adults who use them).³⁷

One RCT showed that patient access to a personalized Web-based portal increased influenza vaccination rates.

Health information provided by social media can answer medical questions and concerns and enhance health promotion and education.³⁵ A recent review of 98 research studies provided evidence that social media can create a space to share, comment, and discuss health information.³⁴ Compared with traditional communication methods, the widespread availability of social media makes health information more accessible, broadening access to various population groups, regardless of age, education, race, ethnicity, and locale.

New media platforms are proving effective. The first systematic assessment of available evidence on the use of new media to increase vaccine uptake and immunization coverage (a review of 7 randomized controlled trials [RCTs], 5 non-RCTs, 3 cross-sectional studies, one case-control study and 3 operational research studies published between 2000-2013) found that text messaging, accessing immunization campaign Web sites, using patient-held Web-based portals, computerized reminders, and standing orders increased immunization coverage rates.³⁵ However, evidence was insufficient in this regard on the value of social networks, email communication, and smartphone applications.

One RCT showed that having access to a personalized Web-based portal where patients could manage health records as well as interact with both health care providers and other members of the community through social forums and messaging tools increased influenza vaccination rates.³⁵

CORRESPONDENCE
Pamela G. Rockwell, DO, Department of Family Medicine, University of Michigan, 24 Frank Lloyd Wright Drive, P.O. Box 431, Ann Arbor, MI 48106-0795; [email protected].

CASE › James A, age 68, presents to his family physician (FP) with anorexia, nausea, and vague upper abdominal pain that he’s had for 2 weeks. Mr. A has diabetes and hypertension, both of which are well controlled by medications. He also consumes more than 4 alcoholic beverages daily.

On examination, the FP notes icterus and tenderness in the right hypochondrium. Liver function testing reveals elevated liver enzyme levels: aspartate aminotransferase (AST), 864 IU/L (normal range: 10-40 IU/L); alanine aminotransferase (ALT), 1012 IU/L (normal range: 7-56 IU/L); serum bilirubin, 4.8 mg/dL (normal range: 0.3-1.9 mg/dL); and alkaline phosphatase (ALP), 200 IU/L (normal range: 44-147 IU/L). Mr. A’s coagulation profile is slightly abnormal. He is provisionally diagnosed with acute hepatitis. The FP sends blood samples to the lab to assess for viral markers, and starts symptomatic management.

If Mr. A were your patient, how would you proceed?

In the United States, drug-induced liver injury (DILI) is the most common cause of acute liver failure.^1,2 It can occur due to ingestion of any therapeutic drug, herbal product, or xenobiotic. Further complicating matters is the fact that it has an unpredictable and heterogeneous course, ranging from an asymptomatic rise in liver enzymes to acute liver failure. This article describes the risk factors, common causative agents, tools for early diagnosis, and effective management of DILI.

Two types of risk factors for DILI

Risk factors for DILI can be classified as drug-related (eg, dose, concomitant medications, polypharmacy) or host-related (eg, age, gender, alcohol intake, concomitant infections).^3-5

Drug-related factors. Hundreds of agents can lead to liver injury. In fact, the US National Library of Medicine and the National Institute of Diabetes and Digestive and Kidney Diseases have created LiverTox (http://www.livertox.nih.gov/), an online database that provides detailed information on more than 600 such agents.⁶ Antibiotics are the most common cause of DILI, followed by neuropsychiatric drugs, immunomodulatory agents, antihypertensives, analgesics, antineoplastic drugs, and lipid-lowering agents.²

Among antibiotics, the specific medication most often responsible for DILI varies by geographical region. Amoxicillin/clavulanic acid is the most common causative antibiotic in the United States, whereas anti-tuberculosis agents such as isoniazid, rifampin, and pyrazinamide are the most common causative drugs in developing countries such as India, where the prevalence of tuberculosis is still high.^7,8 Herbal and dietary supplements are emerging as an important cause of DILI.^5,9,10

The use of multiple drugs further increases the risk of developing DILI.¹⁰ Drugs with a recommended daily dose of <50 mg are rarely associated with DILI.¹¹

Host-related factors. Vulnerability to DILI is influenced by a patient’s age and sex.^3,12 Very young and very old patients have an increased risk of developing DILI, and a patient’s age may make him or her particularly susceptible to the effects of certain medications.^3,12,13 For example, children are more susceptible to DILI as a result of taking valproate or aspirin, whereas older patients are more likely to experience DILI brought on by amoxicillin/clavulanic acid.¹³ The pattern of liver injury also varies by age. Younger patients present most commonly with a hepatocellular pattern of injury, whereas older patients mostly present with a cholestatic pattern of liver injury.³

Some studies have found that women have a greater risk of developing DILI than men.¹³ The presence of chronic liver diseases, alcoholism, and nonalcoholic fatty liver disease (NAFLD) increase the risk of developing DILI.¹⁴ Diabetes is an independent risk factor for DILI.³

Clinical presentation of DILI varies widely

Some degree of liver injury may occur in any patient who ingests a drug that is metabolized in the liver. The clinical presentation of a patient with DILI can vary from an asymptomatic rise in liver enzymes to acute liver failure. Unexplained transaminitis should raise the possibility of DILI, especially when the patient has started a new drug in the preceding 3 months. However, in most patients, an asymptomatic rise in liver enzymes is due to hepatic adaptation or tolerance. In such cases, liver enzyme levels tend to normalize even if the patient continues to take the drug in the same dose.¹⁵

Apart from nonspecific symptoms such as anorexia, nausea, and vomiting, a patient with DILI may exhibit right upper quadrant pain, skin rash, or itching. A patient with severe DILI might exhibit jaundice, ascites, or encephalopathy.¹⁵