The growing elderly population varies widely in functional capacity and mental agility. Age by itself is not a reliable indicator of physiologic performance in patients with cardiovascular disease.¹

See related article

The concept of frailty helps to identify elderly patients most susceptible to adverse outcomes. Frailty is a powerful indicator of disability, loss of independence, hospitalization, and death. In a patient whose health is declining, frailty is an appropriate impetus for the clinician and patient to reevaluate the goals of care.

In this issue of the Journal, Mallery et al² address an important topic: the use of preventive lipid-lowering therapies in frail patients with limited life expectancy. For these patients, they recommend against lipid-lowering therapy for primary prevention, and only in extenuating circumstances for secondary prevention.

No trials have evaluated lipid-lowering therapy specifically in frail older adults, and therefore, these recommendations are based on an evidence-informed appraisal of the literature. Mallery et al² suggest that in the frail elderly, improvement in function and quality of life are more relevant end points than traditional cardiovascular outcomes. They conclude that available evidence does not support lipid-lowering therapy for most patients with advanced frailty.

POINTS TO CONSIDER

Mallery et al² effectively articulate the need for frailty-specific care. Multimorbidity, polypharmacy, and increased adverse drug effects require special attention in the frail elderly. The authors make a sound argument against lipid-lowering therapy for primary prevention in the severely frail elderly, in whom the evidence for short-term benefit is not compelling. They also recommend against nonstatin lipid-lowering medications, and against statin therapy for heart failure, which is consistent with major guidelines. In the modern era of reflexive testing and prescribing, the authors’ “less is more” approach provides needed encouragement for thoughtful care in these vulnerable patients.

However, certain points of contention deserve additional consideration, including the imprecise definition of frailty, potential benefits and harms of statin therapy in high-risk patients, and the importance of shared decision-making.

How should frailty be defined?

Frailty biology is a field of ongoing research, and there is a lack of consensus on how best to define the condition.³ Estimates of the prevalence of frailty among older adults with cardiovascular disease range from 10% to 60%, owing to considerable variability in the tools used for frailty assessment.⁴

Mallery et al² consider an individual to be severely frail if he or she requires assistance with basic activities of daily living as the result of any physical or cognitive deficit (derived from the Clinical Frailty Scale or Frailty Assessment for Care Planning Tool). While functional dependence may be a consequence of frailty, this generalized definition does not characterize the clinical phenotype, which includes slowness, weakness, low physical activity, exhaustion, and unintentional weight loss.

Furthermore, this definition offers no insight into the unique characteristics, causes, and clinical course related to frailty. Significant heterogeneity among “frail” patients precludes a uniform treatment approach in this population.

Do statins benefit frail patients at high risk?

Regarding secondary prevention, the authors highlight a meta-analysis by Afilalo et al,⁵ the most comprehensive assessment to date of statin therapy in elderly patients with documented coronary heart disease. This study included nearly 20,000 elderly patients in nine secondary prevention trials, including the secondary prevention subgroup of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial.⁶

Afilalo et al⁵ calculated that statin therapy reduced the rates of all-cause mortality by 22% and coronary death by 30%, with even greater reductions in the rates of nonfatal myocardial infarction, stroke, and revascularization. Furthermore, the absolute risk reduction was higher and the number needed to treat was lower in those over age 80. Overall, these data convincingly showed that high-risk patients ages 65 to 82 enrolled in clinical trials derive substantial benefit from statin therapy.

Mallery et al² contend that many of the secondary prevention statin trials evaluated composite outcomes over many years of follow-up and therefore are not generalizable to the frail elderly. However, the Afilalo meta-analysis⁵ does not provide patient-level data, and therefore the benefit for different clinical and demographic subgroups is unknown. It is only speculative to infer that those with frailty are unlikely to benefit. In fact, the improved outcomes observed with increasing age would argue against this notion.

Given the compelling data supporting statin therapy in the high-risk elderly population, some patients and clinicians may reasonably feel there is value in statin therapy—even in those with advanced frailty.

What about symptoms, disability, quality of life, and short-term benefits? Asymptomatic or “silent” myocardial infarction is associated with angina, congestive heart failure, and subsequent symptomatic myocardial infarction.^7,8 Dismissing the importance of these end points in clinical trials fails to recognize potential downstream effects that are directly relevant to a patient’s overall health status.

The Study Assessing Goals in the Elderly (SAGE) trial⁹ assessed the effect of statin therapy on ischemia burden in patients ages 65 to 85 with stable coronary disease. The results showed that both moderate and intensive statin dosing significantly reduced myocardial ischemia at 3 and 12 months, as detected by continuous electrocardiographic monitoring.

More research is needed to determine the effect of statin therapy on functional capacity and quality of life. Currently, it is premature to conclude that statins have no relevance to these important patient-centered outcomes.

What are the potential harms?

Mallery et al² cite numerous articles that emphasize the potential adverse effects of statin therapy in the elderly. Unfortunately, data supporting the safety of statin therapy in the elderly were not included. This should be stressed, given that older statin-eligible patients are often undertreated in contemporary practice.¹⁰

A 2015 systematic review and meta-analysis indicated that statin-related events are relatively rare in the elderly.¹¹ Another study showed elderly patients who started statin therapy after a myocardial infarction had no change in short-term cognitive or physical function.¹²

Older age and low body mass index are risk factors for statin myopathy, underscoring the need for close monitoring in frail patients. However, it is important to maintain an objective and balanced approach when considering potential harms.

Need for shared decision-making

Mallery et al² make no mention of shared decision-making. Best practice guidelines for the management of frailty support a holistic medical review to establish an individualized care plan for each patient.¹³ Firm recommendations based on indeterminate evidence undermine the patient-physician relationship and do not allow for personal preferences of care. In an environment of uncertain benefit and harm, the patient’s priorities and values should serve as the cornerstone for clinical decisions.

The growing elderly population varies widely in functional capacity and mental agility. Age by itself is not a reliable indicator of physiologic performance in patients with cardiovascular disease.¹

See related article

The concept of frailty helps to identify elderly patients most susceptible to adverse outcomes. Frailty is a powerful indicator of disability, loss of independence, hospitalization, and death. In a patient whose health is declining, frailty is an appropriate impetus for the clinician and patient to reevaluate the goals of care.

In this issue of the Journal, Mallery et al² address an important topic: the use of preventive lipid-lowering therapies in frail patients with limited life expectancy. For these patients, they recommend against lipid-lowering therapy for primary prevention, and only in extenuating circumstances for secondary prevention.

No trials have evaluated lipid-lowering therapy specifically in frail older adults, and therefore, these recommendations are based on an evidence-informed appraisal of the literature. Mallery et al² suggest that in the frail elderly, improvement in function and quality of life are more relevant end points than traditional cardiovascular outcomes. They conclude that available evidence does not support lipid-lowering therapy for most patients with advanced frailty.

POINTS TO CONSIDER

Mallery et al² effectively articulate the need for frailty-specific care. Multimorbidity, polypharmacy, and increased adverse drug effects require special attention in the frail elderly. The authors make a sound argument against lipid-lowering therapy for primary prevention in the severely frail elderly, in whom the evidence for short-term benefit is not compelling. They also recommend against nonstatin lipid-lowering medications, and against statin therapy for heart failure, which is consistent with major guidelines. In the modern era of reflexive testing and prescribing, the authors’ “less is more” approach provides needed encouragement for thoughtful care in these vulnerable patients.

However, certain points of contention deserve additional consideration, including the imprecise definition of frailty, potential benefits and harms of statin therapy in high-risk patients, and the importance of shared decision-making.

How should frailty be defined?

Frailty biology is a field of ongoing research, and there is a lack of consensus on how best to define the condition.³ Estimates of the prevalence of frailty among older adults with cardiovascular disease range from 10% to 60%, owing to considerable variability in the tools used for frailty assessment.⁴

Mallery et al² consider an individual to be severely frail if he or she requires assistance with basic activities of daily living as the result of any physical or cognitive deficit (derived from the Clinical Frailty Scale or Frailty Assessment for Care Planning Tool). While functional dependence may be a consequence of frailty, this generalized definition does not characterize the clinical phenotype, which includes slowness, weakness, low physical activity, exhaustion, and unintentional weight loss.

Furthermore, this definition offers no insight into the unique characteristics, causes, and clinical course related to frailty. Significant heterogeneity among “frail” patients precludes a uniform treatment approach in this population.

Do statins benefit frail patients at high risk?

Regarding secondary prevention, the authors highlight a meta-analysis by Afilalo et al,⁵ the most comprehensive assessment to date of statin therapy in elderly patients with documented coronary heart disease. This study included nearly 20,000 elderly patients in nine secondary prevention trials, including the secondary prevention subgroup of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial.⁶

Afilalo et al⁵ calculated that statin therapy reduced the rates of all-cause mortality by 22% and coronary death by 30%, with even greater reductions in the rates of nonfatal myocardial infarction, stroke, and revascularization. Furthermore, the absolute risk reduction was higher and the number needed to treat was lower in those over age 80. Overall, these data convincingly showed that high-risk patients ages 65 to 82 enrolled in clinical trials derive substantial benefit from statin therapy.

Mallery et al² contend that many of the secondary prevention statin trials evaluated composite outcomes over many years of follow-up and therefore are not generalizable to the frail elderly. However, the Afilalo meta-analysis⁵ does not provide patient-level data, and therefore the benefit for different clinical and demographic subgroups is unknown. It is only speculative to infer that those with frailty are unlikely to benefit. In fact, the improved outcomes observed with increasing age would argue against this notion.

Given the compelling data supporting statin therapy in the high-risk elderly population, some patients and clinicians may reasonably feel there is value in statin therapy—even in those with advanced frailty.

What about symptoms, disability, quality of life, and short-term benefits? Asymptomatic or “silent” myocardial infarction is associated with angina, congestive heart failure, and subsequent symptomatic myocardial infarction.^7,8 Dismissing the importance of these end points in clinical trials fails to recognize potential downstream effects that are directly relevant to a patient’s overall health status.

The Study Assessing Goals in the Elderly (SAGE) trial⁹ assessed the effect of statin therapy on ischemia burden in patients ages 65 to 85 with stable coronary disease. The results showed that both moderate and intensive statin dosing significantly reduced myocardial ischemia at 3 and 12 months, as detected by continuous electrocardiographic monitoring.

More research is needed to determine the effect of statin therapy on functional capacity and quality of life. Currently, it is premature to conclude that statins have no relevance to these important patient-centered outcomes.

What are the potential harms?

Mallery et al² cite numerous articles that emphasize the potential adverse effects of statin therapy in the elderly. Unfortunately, data supporting the safety of statin therapy in the elderly were not included. This should be stressed, given that older statin-eligible patients are often undertreated in contemporary practice.¹⁰

A 2015 systematic review and meta-analysis indicated that statin-related events are relatively rare in the elderly.¹¹ Another study showed elderly patients who started statin therapy after a myocardial infarction had no change in short-term cognitive or physical function.¹²

Older age and low body mass index are risk factors for statin myopathy, underscoring the need for close monitoring in frail patients. However, it is important to maintain an objective and balanced approach when considering potential harms.

Need for shared decision-making

Mallery et al² make no mention of shared decision-making. Best practice guidelines for the management of frailty support a holistic medical review to establish an individualized care plan for each patient.¹³ Firm recommendations based on indeterminate evidence undermine the patient-physician relationship and do not allow for personal preferences of care. In an environment of uncertain benefit and harm, the patient’s priorities and values should serve as the cornerstone for clinical decisions.

The growing elderly population varies widely in functional capacity and mental agility. Age by itself is not a reliable indicator of physiologic performance in patients with cardiovascular disease.¹

See related article

The concept of frailty helps to identify elderly patients most susceptible to adverse outcomes. Frailty is a powerful indicator of disability, loss of independence, hospitalization, and death. In a patient whose health is declining, frailty is an appropriate impetus for the clinician and patient to reevaluate the goals of care.

In this issue of the Journal, Mallery et al² address an important topic: the use of preventive lipid-lowering therapies in frail patients with limited life expectancy. For these patients, they recommend against lipid-lowering therapy for primary prevention, and only in extenuating circumstances for secondary prevention.

No trials have evaluated lipid-lowering therapy specifically in frail older adults, and therefore, these recommendations are based on an evidence-informed appraisal of the literature. Mallery et al² suggest that in the frail elderly, improvement in function and quality of life are more relevant end points than traditional cardiovascular outcomes. They conclude that available evidence does not support lipid-lowering therapy for most patients with advanced frailty.

POINTS TO CONSIDER

Mallery et al² effectively articulate the need for frailty-specific care. Multimorbidity, polypharmacy, and increased adverse drug effects require special attention in the frail elderly. The authors make a sound argument against lipid-lowering therapy for primary prevention in the severely frail elderly, in whom the evidence for short-term benefit is not compelling. They also recommend against nonstatin lipid-lowering medications, and against statin therapy for heart failure, which is consistent with major guidelines. In the modern era of reflexive testing and prescribing, the authors’ “less is more” approach provides needed encouragement for thoughtful care in these vulnerable patients.

However, certain points of contention deserve additional consideration, including the imprecise definition of frailty, potential benefits and harms of statin therapy in high-risk patients, and the importance of shared decision-making.

How should frailty be defined?

Frailty biology is a field of ongoing research, and there is a lack of consensus on how best to define the condition.³ Estimates of the prevalence of frailty among older adults with cardiovascular disease range from 10% to 60%, owing to considerable variability in the tools used for frailty assessment.⁴

Mallery et al² consider an individual to be severely frail if he or she requires assistance with basic activities of daily living as the result of any physical or cognitive deficit (derived from the Clinical Frailty Scale or Frailty Assessment for Care Planning Tool). While functional dependence may be a consequence of frailty, this generalized definition does not characterize the clinical phenotype, which includes slowness, weakness, low physical activity, exhaustion, and unintentional weight loss.

Furthermore, this definition offers no insight into the unique characteristics, causes, and clinical course related to frailty. Significant heterogeneity among “frail” patients precludes a uniform treatment approach in this population.

Do statins benefit frail patients at high risk?

Regarding secondary prevention, the authors highlight a meta-analysis by Afilalo et al,⁵ the most comprehensive assessment to date of statin therapy in elderly patients with documented coronary heart disease. This study included nearly 20,000 elderly patients in nine secondary prevention trials, including the secondary prevention subgroup of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial.⁶

Afilalo et al⁵ calculated that statin therapy reduced the rates of all-cause mortality by 22% and coronary death by 30%, with even greater reductions in the rates of nonfatal myocardial infarction, stroke, and revascularization. Furthermore, the absolute risk reduction was higher and the number needed to treat was lower in those over age 80. Overall, these data convincingly showed that high-risk patients ages 65 to 82 enrolled in clinical trials derive substantial benefit from statin therapy.

Mallery et al² contend that many of the secondary prevention statin trials evaluated composite outcomes over many years of follow-up and therefore are not generalizable to the frail elderly. However, the Afilalo meta-analysis⁵ does not provide patient-level data, and therefore the benefit for different clinical and demographic subgroups is unknown. It is only speculative to infer that those with frailty are unlikely to benefit. In fact, the improved outcomes observed with increasing age would argue against this notion.

Given the compelling data supporting statin therapy in the high-risk elderly population, some patients and clinicians may reasonably feel there is value in statin therapy—even in those with advanced frailty.

What about symptoms, disability, quality of life, and short-term benefits? Asymptomatic or “silent” myocardial infarction is associated with angina, congestive heart failure, and subsequent symptomatic myocardial infarction.^7,8 Dismissing the importance of these end points in clinical trials fails to recognize potential downstream effects that are directly relevant to a patient’s overall health status.

The Study Assessing Goals in the Elderly (SAGE) trial⁹ assessed the effect of statin therapy on ischemia burden in patients ages 65 to 85 with stable coronary disease. The results showed that both moderate and intensive statin dosing significantly reduced myocardial ischemia at 3 and 12 months, as detected by continuous electrocardiographic monitoring.

More research is needed to determine the effect of statin therapy on functional capacity and quality of life. Currently, it is premature to conclude that statins have no relevance to these important patient-centered outcomes.

What are the potential harms?

Mallery et al² cite numerous articles that emphasize the potential adverse effects of statin therapy in the elderly. Unfortunately, data supporting the safety of statin therapy in the elderly were not included. This should be stressed, given that older statin-eligible patients are often undertreated in contemporary practice.¹⁰

A 2015 systematic review and meta-analysis indicated that statin-related events are relatively rare in the elderly.¹¹ Another study showed elderly patients who started statin therapy after a myocardial infarction had no change in short-term cognitive or physical function.¹²

Older age and low body mass index are risk factors for statin myopathy, underscoring the need for close monitoring in frail patients. However, it is important to maintain an objective and balanced approach when considering potential harms.

Need for shared decision-making

Mallery et al² make no mention of shared decision-making. Best practice guidelines for the management of frailty support a holistic medical review to establish an individualized care plan for each patient.¹³ Firm recommendations based on indeterminate evidence undermine the patient-physician relationship and do not allow for personal preferences of care. In an environment of uncertain benefit and harm, the patient’s priorities and values should serve as the cornerstone for clinical decisions.

Our knowledge of the pathogenesis of thrombotic microangiopathies has greatly advanced in the last decade, improving the diagnosis and treatment of these diseases.

Many conditions involve thrombotic microangiopathies (Table 1). This article reviews the most common ones, ie, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, atypical hemolytic uremic syndrome, and antiphospholipid syndrome—their clinical features (focusing on the kidney), course, and management. Of note, although the diseases are similar, their pathogeneses and treatments differ.

DIFFERENT PATHWAYS TO MULTIORGAN THROMBOSIS

The thrombotic microangiopathies are multisystem disorders that can affect children and adults and often present with prominent renal and neurologic involvement. Endothelial injury is likely the inciting factor leading to thrombosis in the kidney and in many other organs. The causes variously include:

• Toxins from bacteria or drugs
• Abnormal complement activation, genetic or autoantibody-induced
• Procoagulant factors, eg, antiphospholipid antibodies
• Loss of anticoagulants, eg, from a defect of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13); ADAMTS13 is also known as von Willebrand factor-cleaving protease
• Severe hypertension.

The histopathologic features are similar in all the thrombotic microangiopathies. Laboratory findings include thrombocytopenia, microangiopathic hemolytic anemia (with schistocytes on the peripheral blood smear), and high serum lactate dehydrogenase (LDH) levels; these are also markers of treatment progress. Bilirubin may be elevated and haptoglobin absent. Renal biopsy reveals thrombi in the glomeruli and arterioles.

THROMBOTIC THROMBOCYTOPENIC PURPURA

A young woman with fever, bruising, and renal failure, then blindness

A 36-year-old black woman who had been previously healthy presents to her doctor with fever and bruising.

Her hematocrit is 28% (reference range 38%–46%), platelet count 15 x 10⁹/L (150–450), and prothrombin and partial thromboplastin times are normal. Her peripheral blood smear shows microangiopathic hemolytic anemia with schistocytes.

Over the next few days, her urine output declines and she develops sudden blindness followed by decreased mental acuity. Blood is drawn and sent for ADAMTS13 assay. Treatment is started at once with daily therapeutic plasma exchange. The assay results, when they arrive, show marked ADAMTS13 reduction (< 5%). Over the ensuing weeks, her mental acuity improves, her vision returns, and her renal function improves.

ADAMTS13 deficiency is definitive

Thrombotic thrombocytopenic purpura is characterized by:

• Neurologic abnormalities and acute renal failure
• Thrombocytopenia and microangiopathic hemolytic anemia
• Histologic evidence of thrombotic microangiopathy
• Deficiency of von Willebrand factor-cleaving protease (ADAMTS13 < 10%).

von Willebrand factor forms ultralarge multimers in the circulation that interact with platelets; these are normally cleaved by ADAMTS13. With ADAMTS13 deficiency (from either a genetic mutation or autoantibodies), the ultralarge multimers lead to coagulation as blood flows through small vessels.¹

In 2003, Tsai² evaluated 127 patients over age 10 who had thrombocytopenia and microangiopathic hemolysis with no plausible cause or features suggestive of hemolytic uremic syndrome. All were severely deficient in ADAMTS13. Subsequently, thrombotic thrombocytopenic purpura has been defined by a severe actual or effective deficiency of ADAMTS13.

Prompt plasma exchange is critical

Although the ADAMTS13 assay is important for diagnosing thrombotic thrombocytopenic purpura, in suspected cases daily plasma exchange should be started promptly, before test results return. Plasma exchange removes autoantibodies to ADAMTS13 from the blood, removes circulating ultralarge von Willebrand factor multimers, and replaces the missing ADAMTS13. Untreated, the disease is progressive, with irreversible renal failure, neurologic deterioration, and a 90% mortality rate. Plasma exchange reduces the mortality rate to less than 15%. If another diagnosis is confirmed, plasma exchange can be stopped.

Plasma exchange has been shown in clinical trials to be superior to plasma infusion in normalizing platelet counts and reducing mortality.^3,4 Mortality rates were comparable with different replacement fluids vs fresh-frozen plasma, including solvent or detergent-treated plasma, and cryo-poor (cryosupernatant) plasma.⁴ Antiplatelet therapy, platelet transfusions, and splenectomy are ineffective.

Glucocorticoids for early treatment

An appropriate strategy is to add a glucocorticoid to plasma-exchange therapy at once (oral prednisone 1 mg/kg per day or intravenous methylprednisolone 125 mg twice daily) and withdraw it after several days if it is determined that it is not needed. Steroids for suspected thrombotic thrombocytopenic purpura can be justified for several reasons:

• The results of the ADAMTS13 assay are usually delayed, so steroids provide coverage for other diagnoses.
• They are helpful if thrombotic thrombocytopenic purpura is idiopathic (which is true for most cases) and if the patient has a poor response to initial therapy with plasma exchange.
• They are indicated for patients whose platelet counts do not increase with several days of plasma exchange or whose thrombocytopenia recurs as plasma exchange is decreased.

Rituximab improves survival

Rituximab, a chimeric (half murine) monoclonal antibody against CD19 and CD20 B cells, suppresses antibody production by knocking out the precursors of antibody-producing cells.

Anecdotal reports and small studies involving a total of 42 patients have been published on the use of rituximab for thrombotic thrombocytopenic purpura. Courses of rituximab varied greatly, from 1 to 13 weekly doses at 375 mg/m², with 4 doses being the most common. Complete remission occurred in 90% of cases.^5,6 A typical study from 2014 involved 48 patients (30 of whom received rituximab) followed by severe ADAMTS13 deficiency during remission.⁷ Despite the small study size, the investigators found significantly improved relapse-free survival rates with rituximab treatment.

But rituximab can cost $25,000 for 2 doses of 1,000 mg, and this will most likely prohibit its routine use. The cost and insurance coverage vary with location and policies.

Based on such studies, a reasonable strategy is to treat thrombotic thrombocytopenic purpura with:

• Daily plasma exchange
• Steroids, at least until the diagnosis is certain
• Rituximab if warranted.

New targeted therapies

Caplacizumab, a humanized immunoglobulin that inhibits the interaction between ultralarge von Willebrand factor multimers and platelets, has the potential to change this strategy when it receives US Food and Drug Administration approval, which is expected soon.

Peyvandi et al⁸ randomized 75 patients with acquired thrombotic thrombocytopenic purpura to either subcutaneous caplacizumab 10 mg daily for 30 days or placebo. Both groups had daily plasma exchange. The treatment group had a 39% reduction in median time to normalization of platelets vs the placebo group, and 3 of 36 patients had exacerbations, compared with 11 of 39 patients in the placebo group. Although 8 patients relapsed within the first month after stopping caplacizumab, their cases were brought under control. There were also more bleeding episodes with caplacizumab (54% vs 38%), most being mild to moderate. Two patients in the placebo group died, but none in the treatment group.

The fact that platelet normalization occurred significantly faster with caplacizumab, even in some patients who had not yet had plasma exchange therapy initiated, has enormous clinical significance. The low platelet count in thrombotic thrombocytopenic purpura is a marker of susceptibility to rapid damage to the brain and kidneys, so correcting it quickly is critical.

Other strategies for new drug development include replacing the deficient ADAMTS13 with a recombinant molecule and blocking antibody production (the same mode of action as rituximab and glucocorticoids).⁹ Using all 3 strategies to treat thrombotic thrombocytopenic purpura may be the future standard of care.

HEMOLYTIC UREMIC SYNDROME

A child with sudden onset of bloody diarrhea and kidney failure

A 4-year-old girl plays with baby animals at a petting zoo and does not wash her hands immediately afterwards. Three days later, she develops fever, abdominal cramps, nausea, vomiting, and bloody diarrhea. Her pediatrician gives her antibiotics. On day 6, she develops ecchymoses on the extremities and lips, thrombocytopenia, low urine output, and seizures. Her stool tests positive for Escherichia coli O157:H7

Classic presentation: Young patient with bloody diarrhea

The classic presentation of hemolytic uremic syndrome is of a young patient with bloody diarrhea typically lasting 5 to 10 days. Kidney failure may follow, requiring dialysis in about 60% of patients for a mean of 10 days. About one-fourth of patients develop neurologic symptoms, and about the same fraction are left with long-term morbidity, eg, hypertension, proteinuria, and reduced glomerular filtration rate. The mortality rate is typically 4%^10,11 but varies with the outbreak.

Histologically, the kidneys look identical to those in thrombotic thrombocytopenic purpura, with thrombi in glomeruli and small vessels.

E coli is the most common culprit, but other bacteria, including Shigella dysenteriae, and viruses are sometimes the cause. Fewer than 10% of children infected with Shiga toxin-positive E coli, also known as enterohemorrhagic E coli (O157:H7, O104:H4), develop hemolytic uremic syndrome.

Lessons from outbreaks

Petting zoos are a common source of transmission of pathogenic bacteria. Disease can be extremely serious: in 15 cases linked to a Florida petting zoo, 3 children died.

Other outbreaks involving pathogenic E coli have been tied to fresh vegetables and to undercooked hamburger at fast-food chains.

In Germany in 2011, more than 3,000 people acquired Shiga toxin nonhemolytic uremic syndrome due to E coli, and 16 of them died. In addition, 845 acquired hemolytic uremic syndrome, and 36 died. This outbreak was associated with the more virulent and less common O104:H4 strain, which has acquired a Shiga toxin-encoding phage. Patients were treated with quinolone antibiotics, which actually increase toxin production in this strain.¹²

Unusual in the German epidemic was that more adults were affected (88%), especially women (68% of cases).¹³ The source of infection was eventually found to be alfalfa sprouts, the seeds of which had been contaminated by E coli. Women did not harbor any intrinsic factor making them more susceptible; rather, they were more likely to eat salads.¹³

Supportive management

Supportive care is most important. Transfusion with packed red blood cells is indicated for hemoglobin below 6 g/dL. Hypertension should be controlled and dialysis provided. For central nervous system involvement or severe disease, plasma exchange is sometimes used.

Eculizumab was tried for a time as therapy but did not prove to be of benefit. Shiga toxin-binding agents have been developed, but by the time they are given it is too late in the disease process to help.

Antibiotics may harm; it is possible that they kill beneficial bacteria, allowing the Shiga toxin-producing E coli to better proliferate. Antimotility agents also are contraindicated. Other agents not recommended include urokinase, heparin, dipyridamole, and vincristine. Splenectomy is not advised.

The most important way to control hemolytic uremic syndrome is to prevent it by thoroughly cooking meat, cleaning fresh produce, and having children wash their hands after petting animals.

ATYPICAL HEMOLYTIC UREMIC SYNDROME

A young man in renal failure

A 28-year-old man has a history of “thrombotic thrombocytopenic purpura-hemolytic uremic syndrome” at age 12. He slowly progresses to end-stage renal disease and receives a renal transplant from his mother at age 20 that fails after 3 months. The renal transplant biopsy report at the time reads “thrombotic microangiopathy.” The patient’s brother also requires dialysis.

The patient’s complement values are low, especially C3. His father is offering him a kidney at this time, and the patient wants to know whether to proceed.

Normal ADAMTS13, no diarrhea

Hemolytic uremic syndrome without diarrhea is now called atypical hemolytic uremic syndrome. Patients have normal levels of ADAMTS13, do not have diarrhea, and have no evidence of Shiga toxin-producing E coli.

Continuous complement pathway activation

The complement system is part of the innate immune system, which provides immediate defense against infection and does not evolve as does the adaptive immune system. The classic complement pathway is activated by the C1 antibody-antigen complex. The alternative complement pathway leads to the same pathway via C3.¹⁴ Both pathways lead to the formation of C5 through C9 membrane attack complexes, which form channels across the membranes of target cells, leading to cell lysis and death.

The alternate pathway does not require an antibody trigger so is always active at a low level. Inhibitory factors (factor H, factor I, membrane cofactor protein, factor H-related proteins) are naturally present and slow it down at various steps. People who are born with an abnormal factor or, more commonly, develop antibodies against one of the factors, have uninhibited complement activation. If this happens in the blood vessels, massive coagulation and atypical hemolytic uremic syndrome ensues. The endothelial damage and clotting in the brain, kidney, and other organs are identical to that of hemolytic uremic syndrome caused by Shiga toxin.

Treat with eculizumab

Historically, atypical hemolytic uremic syndrome was treated with plasma exchange, which replaces defective complement regulatory proteins and removes inhibitory antibodies.

Understanding the complement pathways is key to developing drugs that target atypical hemolytic uremic syndrome, and about 60 are in the pipeline. The only one currently approved in the United States for atypical hemolytic uremic syndrome is eculizumab, a humanized monoclonal antibody that binds with high affinity to C5, blocking the end of the complement cascade and preventing formation of the membrane attack complex.^15–18

The effects of eculizumab on atypical hemolytic uremic syndrome were studied in 2 prospective trials.¹⁹ Platelet counts rose rapidly within weeks of starting treatment, and kidney function improved. Benefits continued throughout the 64 weeks studied. There were no deaths among the 37 patients enrolled, and although these were single-arm trials, they provide evidence of dramatic benefit considering the high mortality risk of this disease.

Eculizumab is now considered the treatment of choice. It may be used empirically for patients with hemolytic uremic syndrome who test negative for Shiga toxin and antiphospholipid antibody, and who do not have a very low level of ADAMTS13. The big drawback of eculizumab is its high price,^20–22 which varies by amount used, location, and pharmacy negotiation, but can be in the hundreds of thousands of dollars.

For a patient with atypical hemolytic uremic syndrome on dialysis, treatment with eculizumab should continue for 4 to 6 months if there are no extrarenal manifestations. But many patients continue to have the defect in the complement system, so the problem may recur.

Case revisited

For our patient considering a kidney transplant, many experts feel that a transplant can be done as long as platelet counts are monitored and treatment with eculizumab is restarted if needed. One can also make the case for waiting a few years for new oral drugs to become available before offering transplant.

ANTIPHOSPHOLIPID SYNDROME

A young woman with a history of thrombosis and miscarriages

A 27-year-old woman presents with arthralgias, low-grade fever, and malaise. She has a history of 3 spontaneous abortions and Raynaud phenomenon. Two years ago, she had deep vein thrombosis of the right calf after a long automobile trip.

She now has swollen metacarpophalangeal and proximal interphalangeal joints, livedo reticularis (a mottled venous pattern of the skin best seen under fluorescent light) of the legs and arms, and ankle edema (2-cm indentation).

Her blood pressure is 152/92 mm Hg. Laboratory values:

• White blood cell count 3.6 × 10⁹/L (reference range 4.5–11.0)
• Hematocrit 24% (36%–47%)
• Platelet count 89 × 10⁹/L (150–450)
• Urinalysis: protein 4+, heme 3+, red blood cells 8–15 per high-power field (< 3), red blood cell casts present
• Blood urea nitrogen 43 mg/dL (10–20)
• Creatinine 2.6 mg/dL (0.5–1.1).
• Prothrombin time 14.6 s (10–14)
• Partial thromboplastin time 85 s (25–35)
• Antinuclear antibody positive at 1:160
• Anti-double-stranded DNA and serum complement normal
• Syphilis serologic screening (VDRL) positive.

The patient has leukopenia, anemia, thrombocytopenia, hematuria, proteinuria, high blood urea nitrogen, and markedly elevated partial thromboplastin time. Although she has a positive antinuclear antibody test and renal dysfunction, her anti-dsDNA and serum complement tests are normal, making the diagnosis of systemic lupus erythematosus unlikely.

Consider antiphospholipid syndrome

In any patient with multiple pregnancy losses, lupus, or a history of thrombosis, antiphospholipid syndrome should be considered.

In a series of patients with antiphospholipid antibody who underwent kidney biopsy, more than half were men, indicating that, unlike lupus, this is not primarily a disease of young women.

Diagnosis based on specific criteria

Clinical criteria require at least one of the following in the patient’s history²³:

• One or more episodes of arterial, venous, or small-vessel thrombosis
• Unexplained pregnancy morbidity (death of a fetus or neonate with normal morphology or 3 or more spontaneous abortions).

Serologic criteria for any of the following antiphospholipid antibodies require that at least one of the following tests be positive at least twice and at least 12 weeks apart:

• Anticardiolipin antibodies—high-titer immunoglobulin (Ig) G or IgM
• Autoantibodies for beta 2-glycoprotein
• Lupus anticoagulant—autoantibodies that increase clotting time in vitro and target beta 2-glycoprotein I and prothrombin (despite its name and actions in vitro, lupus anticoagulant functions as a coagulant).

As with the other thrombotic microangiopathies, patients with anticardiolipin syndrome have microthrombi in the glomeruli and blood vessels that are evident on kidney biopsy.

Suspect condition in likely groups

Antiphospholipid syndrome is surprisingly common.²⁴ In a case-control study, de Groot et al²⁵ found that 3.1% of patients under age 70 with a first episode of venous thrombosis and no known cancer were positive for lupus anticoagulant vs 0.9% of controls. In another case-control study, Urbanus et al²⁶ found that 17% of women under age 50 with a stroke tested positive for lupus anticoagulant compared with less than 1% of controls. Because of such studies, it has become routine to test for anticardiolipin and lupus anticoagulant in young patients presenting with a stroke.

About 1% of women trying to have children have recurrent miscarriages, and of these, 10% to 15% have antiphospholipid antibody present.^27–30

Pathogenesis

Patients with antiphospholipid syndrome have a much higher proportion of plasma beta 2-glycoprotein in the oxidized form than do healthy controls. The level is also higher than in patients with a different autoimmune disease whether or not they have antibodies against beta 2-glycoprotein 1. Although about 40% of patients with lupus have an anticardiolipin antibody, only a small percentage develop antiphospholipid syndrome with clotting.

It is thought that antiphospholipid syndrome involves initial injury to the endothelium, then potentiation of thrombus formation. Oxidized beta 2-glycoprotein complexes may bind to the endothelial cell surface, causing it to become the target of antibodies. The exact relationships between the factors are not yet understood.

The risk of a thrombotic event in an asymp­tomatic patient positive for all 3 factors—lupus anticoagulant, anticardiolipin antibody, and anti-beta 2-glycoprotein I antibody—is more than 5% per year.³¹

Manage thrombosis with anticoagulation

Khamashta et al,³² in a 1995 study, retrospectively studied patients with antiphospholipid antibodies and a history of thrombosis. Of 147 patients, 66 had idiopathic primary disease, 62 had systemic lupus, and 19 had “lupus-like” disease. Almost 70% (101 patients) had a recurrence of thrombosis, totaling 186 events. The mean time to recurrence was 12 months (range 2 weeks to 12 years). Recurrence rates were 0.01 events per patient per year with high-dose warfarin, 0.23 with low-dose warfarin, and 0.18 with aspirin. But the highest bleeding rates were in the 6 months after warfarin withdrawal; 29 patients had bleeding events, one-fourth of which were severe.

Standard therapy has become anticoagulation, starting with heparin or enoxaparin, then warfarin. There is inadequate evidence for the role of newer oral anticoagulant therapy.

A very high INR is not generally better than a moderately elevated level

For a time, it was thought that the international normalized ratio (INR) should be kept on the very high side to prevent thrombosis.

Crowther et al³³ conducted a randomized, double-blind trial comparing moderate warfarin therapy (INR 2.0–3.0) and high-intensity warfarin therapy (INR 3.1–4.0) in antiphospholipid syndrome. Thrombosis actually recurred more frequently in the high-intensity therapy group (10.7% vs 3.4%), with no significant difference in major bleeding events.

A reasonable strategy is to keep the INR between 2.5 and 3.0, keeping in mind that values fluctuate in any individual patient. A higher goal often leads to excessive anticoagulation and bleeding. If the goal is too low, recurrent thrombosis becomes more likely. There are fewer data on the newer oral anticoagulants, but their role is likely to increase as reversal agents are developed.

Recommendations published in 2003 for treating antiphospholipid syndrome include³⁴:

• Warfarin (INR 2.0–3.0) after the first thrombotic event
• Warfarin (INR 3.0–4.0) if a clot develops despite warfarin
• Warfarin (INR > 3.0) for an arterial event.

For the rare but catastrophic antiphospholipid syndrome in which thrombosis occurs in multiple organs, recommendations are for heparin plus steroids, with or without intravenous immunoglobulin and plasmapheresis. This approach has not always been successful, and the mortality rate is high.

Treatment of asymptomatic carriers is uncertain

Treatment of asymptomatic carriers of the antiphospholipid antibody is controversial. Evidence for management is scarce; some experts recommend aspirin therapy, but benefit has yet to be proven in clinical trials.

Canaud et al³⁵ documented the role of activation of the kinase mammalian target of rapamycin (mTOR) in the vascular changes characteristic of antiphospholipid nephropathy. Postkidney transplant surveillance biopsies of patients with antiphospholipid antibodies showed vascular damage occurring over time (despite patients being asymptomatic) compared with other renal transplant patients. Patients with antiphospholipid antibodies who were treated with the immunosuppressive drug sirolimus were protected from developing these changes. Twelve years after transplant, 70% of patients with antiphospholipid antibodies taking sirolimus still had a functioning graft compared with 11% of untreated patients.

Our knowledge of the pathogenesis of thrombotic microangiopathies has greatly advanced in the last decade, improving the diagnosis and treatment of these diseases.

Many conditions involve thrombotic microangiopathies (Table 1). This article reviews the most common ones, ie, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, atypical hemolytic uremic syndrome, and antiphospholipid syndrome—their clinical features (focusing on the kidney), course, and management. Of note, although the diseases are similar, their pathogeneses and treatments differ.

DIFFERENT PATHWAYS TO MULTIORGAN THROMBOSIS

The thrombotic microangiopathies are multisystem disorders that can affect children and adults and often present with prominent renal and neurologic involvement. Endothelial injury is likely the inciting factor leading to thrombosis in the kidney and in many other organs. The causes variously include:

• Toxins from bacteria or drugs
• Abnormal complement activation, genetic or autoantibody-induced
• Procoagulant factors, eg, antiphospholipid antibodies
• Loss of anticoagulants, eg, from a defect of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13); ADAMTS13 is also known as von Willebrand factor-cleaving protease
• Severe hypertension.

The histopathologic features are similar in all the thrombotic microangiopathies. Laboratory findings include thrombocytopenia, microangiopathic hemolytic anemia (with schistocytes on the peripheral blood smear), and high serum lactate dehydrogenase (LDH) levels; these are also markers of treatment progress. Bilirubin may be elevated and haptoglobin absent. Renal biopsy reveals thrombi in the glomeruli and arterioles.

THROMBOTIC THROMBOCYTOPENIC PURPURA

A young woman with fever, bruising, and renal failure, then blindness

A 36-year-old black woman who had been previously healthy presents to her doctor with fever and bruising.

Her hematocrit is 28% (reference range 38%–46%), platelet count 15 x 10⁹/L (150–450), and prothrombin and partial thromboplastin times are normal. Her peripheral blood smear shows microangiopathic hemolytic anemia with schistocytes.

Over the next few days, her urine output declines and she develops sudden blindness followed by decreased mental acuity. Blood is drawn and sent for ADAMTS13 assay. Treatment is started at once with daily therapeutic plasma exchange. The assay results, when they arrive, show marked ADAMTS13 reduction (< 5%). Over the ensuing weeks, her mental acuity improves, her vision returns, and her renal function improves.

ADAMTS13 deficiency is definitive

Thrombotic thrombocytopenic purpura is characterized by:

• Neurologic abnormalities and acute renal failure
• Thrombocytopenia and microangiopathic hemolytic anemia
• Histologic evidence of thrombotic microangiopathy
• Deficiency of von Willebrand factor-cleaving protease (ADAMTS13 < 10%).

von Willebrand factor forms ultralarge multimers in the circulation that interact with platelets; these are normally cleaved by ADAMTS13. With ADAMTS13 deficiency (from either a genetic mutation or autoantibodies), the ultralarge multimers lead to coagulation as blood flows through small vessels.¹

In 2003, Tsai² evaluated 127 patients over age 10 who had thrombocytopenia and microangiopathic hemolysis with no plausible cause or features suggestive of hemolytic uremic syndrome. All were severely deficient in ADAMTS13. Subsequently, thrombotic thrombocytopenic purpura has been defined by a severe actual or effective deficiency of ADAMTS13.

Prompt plasma exchange is critical

Although the ADAMTS13 assay is important for diagnosing thrombotic thrombocytopenic purpura, in suspected cases daily plasma exchange should be started promptly, before test results return. Plasma exchange removes autoantibodies to ADAMTS13 from the blood, removes circulating ultralarge von Willebrand factor multimers, and replaces the missing ADAMTS13. Untreated, the disease is progressive, with irreversible renal failure, neurologic deterioration, and a 90% mortality rate. Plasma exchange reduces the mortality rate to less than 15%. If another diagnosis is confirmed, plasma exchange can be stopped.

Plasma exchange has been shown in clinical trials to be superior to plasma infusion in normalizing platelet counts and reducing mortality.^3,4 Mortality rates were comparable with different replacement fluids vs fresh-frozen plasma, including solvent or detergent-treated plasma, and cryo-poor (cryosupernatant) plasma.⁴ Antiplatelet therapy, platelet transfusions, and splenectomy are ineffective.

Glucocorticoids for early treatment

An appropriate strategy is to add a glucocorticoid to plasma-exchange therapy at once (oral prednisone 1 mg/kg per day or intravenous methylprednisolone 125 mg twice daily) and withdraw it after several days if it is determined that it is not needed. Steroids for suspected thrombotic thrombocytopenic purpura can be justified for several reasons:

• The results of the ADAMTS13 assay are usually delayed, so steroids provide coverage for other diagnoses.
• They are helpful if thrombotic thrombocytopenic purpura is idiopathic (which is true for most cases) and if the patient has a poor response to initial therapy with plasma exchange.
• They are indicated for patients whose platelet counts do not increase with several days of plasma exchange or whose thrombocytopenia recurs as plasma exchange is decreased.

Rituximab improves survival

Rituximab, a chimeric (half murine) monoclonal antibody against CD19 and CD20 B cells, suppresses antibody production by knocking out the precursors of antibody-producing cells.

Anecdotal reports and small studies involving a total of 42 patients have been published on the use of rituximab for thrombotic thrombocytopenic purpura. Courses of rituximab varied greatly, from 1 to 13 weekly doses at 375 mg/m², with 4 doses being the most common. Complete remission occurred in 90% of cases.^5,6 A typical study from 2014 involved 48 patients (30 of whom received rituximab) followed by severe ADAMTS13 deficiency during remission.⁷ Despite the small study size, the investigators found significantly improved relapse-free survival rates with rituximab treatment.

But rituximab can cost $25,000 for 2 doses of 1,000 mg, and this will most likely prohibit its routine use. The cost and insurance coverage vary with location and policies.

Based on such studies, a reasonable strategy is to treat thrombotic thrombocytopenic purpura with:

• Daily plasma exchange
• Steroids, at least until the diagnosis is certain
• Rituximab if warranted.

New targeted therapies

Caplacizumab, a humanized immunoglobulin that inhibits the interaction between ultralarge von Willebrand factor multimers and platelets, has the potential to change this strategy when it receives US Food and Drug Administration approval, which is expected soon.

Peyvandi et al⁸ randomized 75 patients with acquired thrombotic thrombocytopenic purpura to either subcutaneous caplacizumab 10 mg daily for 30 days or placebo. Both groups had daily plasma exchange. The treatment group had a 39% reduction in median time to normalization of platelets vs the placebo group, and 3 of 36 patients had exacerbations, compared with 11 of 39 patients in the placebo group. Although 8 patients relapsed within the first month after stopping caplacizumab, their cases were brought under control. There were also more bleeding episodes with caplacizumab (54% vs 38%), most being mild to moderate. Two patients in the placebo group died, but none in the treatment group.

The fact that platelet normalization occurred significantly faster with caplacizumab, even in some patients who had not yet had plasma exchange therapy initiated, has enormous clinical significance. The low platelet count in thrombotic thrombocytopenic purpura is a marker of susceptibility to rapid damage to the brain and kidneys, so correcting it quickly is critical.

Other strategies for new drug development include replacing the deficient ADAMTS13 with a recombinant molecule and blocking antibody production (the same mode of action as rituximab and glucocorticoids).⁹ Using all 3 strategies to treat thrombotic thrombocytopenic purpura may be the future standard of care.

HEMOLYTIC UREMIC SYNDROME

A child with sudden onset of bloody diarrhea and kidney failure

A 4-year-old girl plays with baby animals at a petting zoo and does not wash her hands immediately afterwards. Three days later, she develops fever, abdominal cramps, nausea, vomiting, and bloody diarrhea. Her pediatrician gives her antibiotics. On day 6, she develops ecchymoses on the extremities and lips, thrombocytopenia, low urine output, and seizures. Her stool tests positive for Escherichia coli O157:H7

Classic presentation: Young patient with bloody diarrhea

The classic presentation of hemolytic uremic syndrome is of a young patient with bloody diarrhea typically lasting 5 to 10 days. Kidney failure may follow, requiring dialysis in about 60% of patients for a mean of 10 days. About one-fourth of patients develop neurologic symptoms, and about the same fraction are left with long-term morbidity, eg, hypertension, proteinuria, and reduced glomerular filtration rate. The mortality rate is typically 4%^10,11 but varies with the outbreak.

Histologically, the kidneys look identical to those in thrombotic thrombocytopenic purpura, with thrombi in glomeruli and small vessels.

E coli is the most common culprit, but other bacteria, including Shigella dysenteriae, and viruses are sometimes the cause. Fewer than 10% of children infected with Shiga toxin-positive E coli, also known as enterohemorrhagic E coli (O157:H7, O104:H4), develop hemolytic uremic syndrome.

Lessons from outbreaks

Petting zoos are a common source of transmission of pathogenic bacteria. Disease can be extremely serious: in 15 cases linked to a Florida petting zoo, 3 children died.

Other outbreaks involving pathogenic E coli have been tied to fresh vegetables and to undercooked hamburger at fast-food chains.

In Germany in 2011, more than 3,000 people acquired Shiga toxin nonhemolytic uremic syndrome due to E coli, and 16 of them died. In addition, 845 acquired hemolytic uremic syndrome, and 36 died. This outbreak was associated with the more virulent and less common O104:H4 strain, which has acquired a Shiga toxin-encoding phage. Patients were treated with quinolone antibiotics, which actually increase toxin production in this strain.¹²

Unusual in the German epidemic was that more adults were affected (88%), especially women (68% of cases).¹³ The source of infection was eventually found to be alfalfa sprouts, the seeds of which had been contaminated by E coli. Women did not harbor any intrinsic factor making them more susceptible; rather, they were more likely to eat salads.¹³

Supportive management

Supportive care is most important. Transfusion with packed red blood cells is indicated for hemoglobin below 6 g/dL. Hypertension should be controlled and dialysis provided. For central nervous system involvement or severe disease, plasma exchange is sometimes used.

Eculizumab was tried for a time as therapy but did not prove to be of benefit. Shiga toxin-binding agents have been developed, but by the time they are given it is too late in the disease process to help.

Antibiotics may harm; it is possible that they kill beneficial bacteria, allowing the Shiga toxin-producing E coli to better proliferate. Antimotility agents also are contraindicated. Other agents not recommended include urokinase, heparin, dipyridamole, and vincristine. Splenectomy is not advised.

The most important way to control hemolytic uremic syndrome is to prevent it by thoroughly cooking meat, cleaning fresh produce, and having children wash their hands after petting animals.

ATYPICAL HEMOLYTIC UREMIC SYNDROME

A young man in renal failure

A 28-year-old man has a history of “thrombotic thrombocytopenic purpura-hemolytic uremic syndrome” at age 12. He slowly progresses to end-stage renal disease and receives a renal transplant from his mother at age 20 that fails after 3 months. The renal transplant biopsy report at the time reads “thrombotic microangiopathy.” The patient’s brother also requires dialysis.

The patient’s complement values are low, especially C3. His father is offering him a kidney at this time, and the patient wants to know whether to proceed.

Normal ADAMTS13, no diarrhea

Hemolytic uremic syndrome without diarrhea is now called atypical hemolytic uremic syndrome. Patients have normal levels of ADAMTS13, do not have diarrhea, and have no evidence of Shiga toxin-producing E coli.

Continuous complement pathway activation

The complement system is part of the innate immune system, which provides immediate defense against infection and does not evolve as does the adaptive immune system. The classic complement pathway is activated by the C1 antibody-antigen complex. The alternative complement pathway leads to the same pathway via C3.¹⁴ Both pathways lead to the formation of C5 through C9 membrane attack complexes, which form channels across the membranes of target cells, leading to cell lysis and death.

The alternate pathway does not require an antibody trigger so is always active at a low level. Inhibitory factors (factor H, factor I, membrane cofactor protein, factor H-related proteins) are naturally present and slow it down at various steps. People who are born with an abnormal factor or, more commonly, develop antibodies against one of the factors, have uninhibited complement activation. If this happens in the blood vessels, massive coagulation and atypical hemolytic uremic syndrome ensues. The endothelial damage and clotting in the brain, kidney, and other organs are identical to that of hemolytic uremic syndrome caused by Shiga toxin.

Treat with eculizumab

Historically, atypical hemolytic uremic syndrome was treated with plasma exchange, which replaces defective complement regulatory proteins and removes inhibitory antibodies.

Understanding the complement pathways is key to developing drugs that target atypical hemolytic uremic syndrome, and about 60 are in the pipeline. The only one currently approved in the United States for atypical hemolytic uremic syndrome is eculizumab, a humanized monoclonal antibody that binds with high affinity to C5, blocking the end of the complement cascade and preventing formation of the membrane attack complex.^15–18

The effects of eculizumab on atypical hemolytic uremic syndrome were studied in 2 prospective trials.¹⁹ Platelet counts rose rapidly within weeks of starting treatment, and kidney function improved. Benefits continued throughout the 64 weeks studied. There were no deaths among the 37 patients enrolled, and although these were single-arm trials, they provide evidence of dramatic benefit considering the high mortality risk of this disease.

Eculizumab is now considered the treatment of choice. It may be used empirically for patients with hemolytic uremic syndrome who test negative for Shiga toxin and antiphospholipid antibody, and who do not have a very low level of ADAMTS13. The big drawback of eculizumab is its high price,^20–22 which varies by amount used, location, and pharmacy negotiation, but can be in the hundreds of thousands of dollars.

For a patient with atypical hemolytic uremic syndrome on dialysis, treatment with eculizumab should continue for 4 to 6 months if there are no extrarenal manifestations. But many patients continue to have the defect in the complement system, so the problem may recur.

Case revisited

For our patient considering a kidney transplant, many experts feel that a transplant can be done as long as platelet counts are monitored and treatment with eculizumab is restarted if needed. One can also make the case for waiting a few years for new oral drugs to become available before offering transplant.

ANTIPHOSPHOLIPID SYNDROME

A young woman with a history of thrombosis and miscarriages

A 27-year-old woman presents with arthralgias, low-grade fever, and malaise. She has a history of 3 spontaneous abortions and Raynaud phenomenon. Two years ago, she had deep vein thrombosis of the right calf after a long automobile trip.

She now has swollen metacarpophalangeal and proximal interphalangeal joints, livedo reticularis (a mottled venous pattern of the skin best seen under fluorescent light) of the legs and arms, and ankle edema (2-cm indentation).

Her blood pressure is 152/92 mm Hg. Laboratory values:

• White blood cell count 3.6 × 10⁹/L (reference range 4.5–11.0)
• Hematocrit 24% (36%–47%)
• Platelet count 89 × 10⁹/L (150–450)
• Urinalysis: protein 4+, heme 3+, red blood cells 8–15 per high-power field (< 3), red blood cell casts present
• Blood urea nitrogen 43 mg/dL (10–20)
• Creatinine 2.6 mg/dL (0.5–1.1).
• Prothrombin time 14.6 s (10–14)
• Partial thromboplastin time 85 s (25–35)
• Antinuclear antibody positive at 1:160
• Anti-double-stranded DNA and serum complement normal
• Syphilis serologic screening (VDRL) positive.

The patient has leukopenia, anemia, thrombocytopenia, hematuria, proteinuria, high blood urea nitrogen, and markedly elevated partial thromboplastin time. Although she has a positive antinuclear antibody test and renal dysfunction, her anti-dsDNA and serum complement tests are normal, making the diagnosis of systemic lupus erythematosus unlikely.

Consider antiphospholipid syndrome

In any patient with multiple pregnancy losses, lupus, or a history of thrombosis, antiphospholipid syndrome should be considered.

In a series of patients with antiphospholipid antibody who underwent kidney biopsy, more than half were men, indicating that, unlike lupus, this is not primarily a disease of young women.

Diagnosis based on specific criteria

Clinical criteria require at least one of the following in the patient’s history²³:

• One or more episodes of arterial, venous, or small-vessel thrombosis
• Unexplained pregnancy morbidity (death of a fetus or neonate with normal morphology or 3 or more spontaneous abortions).

Serologic criteria for any of the following antiphospholipid antibodies require that at least one of the following tests be positive at least twice and at least 12 weeks apart:

• Anticardiolipin antibodies—high-titer immunoglobulin (Ig) G or IgM
• Autoantibodies for beta 2-glycoprotein
• Lupus anticoagulant—autoantibodies that increase clotting time in vitro and target beta 2-glycoprotein I and prothrombin (despite its name and actions in vitro, lupus anticoagulant functions as a coagulant).

As with the other thrombotic microangiopathies, patients with anticardiolipin syndrome have microthrombi in the glomeruli and blood vessels that are evident on kidney biopsy.

Suspect condition in likely groups

Antiphospholipid syndrome is surprisingly common.²⁴ In a case-control study, de Groot et al²⁵ found that 3.1% of patients under age 70 with a first episode of venous thrombosis and no known cancer were positive for lupus anticoagulant vs 0.9% of controls. In another case-control study, Urbanus et al²⁶ found that 17% of women under age 50 with a stroke tested positive for lupus anticoagulant compared with less than 1% of controls. Because of such studies, it has become routine to test for anticardiolipin and lupus anticoagulant in young patients presenting with a stroke.

About 1% of women trying to have children have recurrent miscarriages, and of these, 10% to 15% have antiphospholipid antibody present.^27–30

Pathogenesis

Patients with antiphospholipid syndrome have a much higher proportion of plasma beta 2-glycoprotein in the oxidized form than do healthy controls. The level is also higher than in patients with a different autoimmune disease whether or not they have antibodies against beta 2-glycoprotein 1. Although about 40% of patients with lupus have an anticardiolipin antibody, only a small percentage develop antiphospholipid syndrome with clotting.

It is thought that antiphospholipid syndrome involves initial injury to the endothelium, then potentiation of thrombus formation. Oxidized beta 2-glycoprotein complexes may bind to the endothelial cell surface, causing it to become the target of antibodies. The exact relationships between the factors are not yet understood.

The risk of a thrombotic event in an asymp­tomatic patient positive for all 3 factors—lupus anticoagulant, anticardiolipin antibody, and anti-beta 2-glycoprotein I antibody—is more than 5% per year.³¹

Manage thrombosis with anticoagulation

Khamashta et al,³² in a 1995 study, retrospectively studied patients with antiphospholipid antibodies and a history of thrombosis. Of 147 patients, 66 had idiopathic primary disease, 62 had systemic lupus, and 19 had “lupus-like” disease. Almost 70% (101 patients) had a recurrence of thrombosis, totaling 186 events. The mean time to recurrence was 12 months (range 2 weeks to 12 years). Recurrence rates were 0.01 events per patient per year with high-dose warfarin, 0.23 with low-dose warfarin, and 0.18 with aspirin. But the highest bleeding rates were in the 6 months after warfarin withdrawal; 29 patients had bleeding events, one-fourth of which were severe.

Standard therapy has become anticoagulation, starting with heparin or enoxaparin, then warfarin. There is inadequate evidence for the role of newer oral anticoagulant therapy.

A very high INR is not generally better than a moderately elevated level

For a time, it was thought that the international normalized ratio (INR) should be kept on the very high side to prevent thrombosis.

Crowther et al³³ conducted a randomized, double-blind trial comparing moderate warfarin therapy (INR 2.0–3.0) and high-intensity warfarin therapy (INR 3.1–4.0) in antiphospholipid syndrome. Thrombosis actually recurred more frequently in the high-intensity therapy group (10.7% vs 3.4%), with no significant difference in major bleeding events.

A reasonable strategy is to keep the INR between 2.5 and 3.0, keeping in mind that values fluctuate in any individual patient. A higher goal often leads to excessive anticoagulation and bleeding. If the goal is too low, recurrent thrombosis becomes more likely. There are fewer data on the newer oral anticoagulants, but their role is likely to increase as reversal agents are developed.

Recommendations published in 2003 for treating antiphospholipid syndrome include³⁴:

• Warfarin (INR 2.0–3.0) after the first thrombotic event
• Warfarin (INR 3.0–4.0) if a clot develops despite warfarin
• Warfarin (INR > 3.0) for an arterial event.

For the rare but catastrophic antiphospholipid syndrome in which thrombosis occurs in multiple organs, recommendations are for heparin plus steroids, with or without intravenous immunoglobulin and plasmapheresis. This approach has not always been successful, and the mortality rate is high.

Treatment of asymptomatic carriers is uncertain

Treatment of asymptomatic carriers of the antiphospholipid antibody is controversial. Evidence for management is scarce; some experts recommend aspirin therapy, but benefit has yet to be proven in clinical trials.

Canaud et al³⁵ documented the role of activation of the kinase mammalian target of rapamycin (mTOR) in the vascular changes characteristic of antiphospholipid nephropathy. Postkidney transplant surveillance biopsies of patients with antiphospholipid antibodies showed vascular damage occurring over time (despite patients being asymptomatic) compared with other renal transplant patients. Patients with antiphospholipid antibodies who were treated with the immunosuppressive drug sirolimus were protected from developing these changes. Twelve years after transplant, 70% of patients with antiphospholipid antibodies taking sirolimus still had a functioning graft compared with 11% of untreated patients.

Our knowledge of the pathogenesis of thrombotic microangiopathies has greatly advanced in the last decade, improving the diagnosis and treatment of these diseases.

Many conditions involve thrombotic microangiopathies (Table 1). This article reviews the most common ones, ie, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, atypical hemolytic uremic syndrome, and antiphospholipid syndrome—their clinical features (focusing on the kidney), course, and management. Of note, although the diseases are similar, their pathogeneses and treatments differ.

DIFFERENT PATHWAYS TO MULTIORGAN THROMBOSIS

The thrombotic microangiopathies are multisystem disorders that can affect children and adults and often present with prominent renal and neurologic involvement. Endothelial injury is likely the inciting factor leading to thrombosis in the kidney and in many other organs. The causes variously include:

• Toxins from bacteria or drugs
• Abnormal complement activation, genetic or autoantibody-induced
• Procoagulant factors, eg, antiphospholipid antibodies
• Loss of anticoagulants, eg, from a defect of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13); ADAMTS13 is also known as von Willebrand factor-cleaving protease
• Severe hypertension.

The histopathologic features are similar in all the thrombotic microangiopathies. Laboratory findings include thrombocytopenia, microangiopathic hemolytic anemia (with schistocytes on the peripheral blood smear), and high serum lactate dehydrogenase (LDH) levels; these are also markers of treatment progress. Bilirubin may be elevated and haptoglobin absent. Renal biopsy reveals thrombi in the glomeruli and arterioles.

THROMBOTIC THROMBOCYTOPENIC PURPURA

A young woman with fever, bruising, and renal failure, then blindness

A 36-year-old black woman who had been previously healthy presents to her doctor with fever and bruising.

Her hematocrit is 28% (reference range 38%–46%), platelet count 15 x 10⁹/L (150–450), and prothrombin and partial thromboplastin times are normal. Her peripheral blood smear shows microangiopathic hemolytic anemia with schistocytes.

Over the next few days, her urine output declines and she develops sudden blindness followed by decreased mental acuity. Blood is drawn and sent for ADAMTS13 assay. Treatment is started at once with daily therapeutic plasma exchange. The assay results, when they arrive, show marked ADAMTS13 reduction (< 5%). Over the ensuing weeks, her mental acuity improves, her vision returns, and her renal function improves.

ADAMTS13 deficiency is definitive

Thrombotic thrombocytopenic purpura is characterized by:

• Neurologic abnormalities and acute renal failure
• Thrombocytopenia and microangiopathic hemolytic anemia
• Histologic evidence of thrombotic microangiopathy
• Deficiency of von Willebrand factor-cleaving protease (ADAMTS13 < 10%).

von Willebrand factor forms ultralarge multimers in the circulation that interact with platelets; these are normally cleaved by ADAMTS13. With ADAMTS13 deficiency (from either a genetic mutation or autoantibodies), the ultralarge multimers lead to coagulation as blood flows through small vessels.¹

In 2003, Tsai² evaluated 127 patients over age 10 who had thrombocytopenia and microangiopathic hemolysis with no plausible cause or features suggestive of hemolytic uremic syndrome. All were severely deficient in ADAMTS13. Subsequently, thrombotic thrombocytopenic purpura has been defined by a severe actual or effective deficiency of ADAMTS13.

Prompt plasma exchange is critical

Although the ADAMTS13 assay is important for diagnosing thrombotic thrombocytopenic purpura, in suspected cases daily plasma exchange should be started promptly, before test results return. Plasma exchange removes autoantibodies to ADAMTS13 from the blood, removes circulating ultralarge von Willebrand factor multimers, and replaces the missing ADAMTS13. Untreated, the disease is progressive, with irreversible renal failure, neurologic deterioration, and a 90% mortality rate. Plasma exchange reduces the mortality rate to less than 15%. If another diagnosis is confirmed, plasma exchange can be stopped.

Plasma exchange has been shown in clinical trials to be superior to plasma infusion in normalizing platelet counts and reducing mortality.^3,4 Mortality rates were comparable with different replacement fluids vs fresh-frozen plasma, including solvent or detergent-treated plasma, and cryo-poor (cryosupernatant) plasma.⁴ Antiplatelet therapy, platelet transfusions, and splenectomy are ineffective.

Glucocorticoids for early treatment

An appropriate strategy is to add a glucocorticoid to plasma-exchange therapy at once (oral prednisone 1 mg/kg per day or intravenous methylprednisolone 125 mg twice daily) and withdraw it after several days if it is determined that it is not needed. Steroids for suspected thrombotic thrombocytopenic purpura can be justified for several reasons:

• The results of the ADAMTS13 assay are usually delayed, so steroids provide coverage for other diagnoses.
• They are helpful if thrombotic thrombocytopenic purpura is idiopathic (which is true for most cases) and if the patient has a poor response to initial therapy with plasma exchange.
• They are indicated for patients whose platelet counts do not increase with several days of plasma exchange or whose thrombocytopenia recurs as plasma exchange is decreased.

Rituximab improves survival

Rituximab, a chimeric (half murine) monoclonal antibody against CD19 and CD20 B cells, suppresses antibody production by knocking out the precursors of antibody-producing cells.

Anecdotal reports and small studies involving a total of 42 patients have been published on the use of rituximab for thrombotic thrombocytopenic purpura. Courses of rituximab varied greatly, from 1 to 13 weekly doses at 375 mg/m², with 4 doses being the most common. Complete remission occurred in 90% of cases.^5,6 A typical study from 2014 involved 48 patients (30 of whom received rituximab) followed by severe ADAMTS13 deficiency during remission.⁷ Despite the small study size, the investigators found significantly improved relapse-free survival rates with rituximab treatment.

But rituximab can cost $25,000 for 2 doses of 1,000 mg, and this will most likely prohibit its routine use. The cost and insurance coverage vary with location and policies.

Based on such studies, a reasonable strategy is to treat thrombotic thrombocytopenic purpura with:

• Daily plasma exchange
• Steroids, at least until the diagnosis is certain
• Rituximab if warranted.

New targeted therapies

Caplacizumab, a humanized immunoglobulin that inhibits the interaction between ultralarge von Willebrand factor multimers and platelets, has the potential to change this strategy when it receives US Food and Drug Administration approval, which is expected soon.

Peyvandi et al⁸ randomized 75 patients with acquired thrombotic thrombocytopenic purpura to either subcutaneous caplacizumab 10 mg daily for 30 days or placebo. Both groups had daily plasma exchange. The treatment group had a 39% reduction in median time to normalization of platelets vs the placebo group, and 3 of 36 patients had exacerbations, compared with 11 of 39 patients in the placebo group. Although 8 patients relapsed within the first month after stopping caplacizumab, their cases were brought under control. There were also more bleeding episodes with caplacizumab (54% vs 38%), most being mild to moderate. Two patients in the placebo group died, but none in the treatment group.

The fact that platelet normalization occurred significantly faster with caplacizumab, even in some patients who had not yet had plasma exchange therapy initiated, has enormous clinical significance. The low platelet count in thrombotic thrombocytopenic purpura is a marker of susceptibility to rapid damage to the brain and kidneys, so correcting it quickly is critical.

Other strategies for new drug development include replacing the deficient ADAMTS13 with a recombinant molecule and blocking antibody production (the same mode of action as rituximab and glucocorticoids).⁹ Using all 3 strategies to treat thrombotic thrombocytopenic purpura may be the future standard of care.

HEMOLYTIC UREMIC SYNDROME

A child with sudden onset of bloody diarrhea and kidney failure

A 4-year-old girl plays with baby animals at a petting zoo and does not wash her hands immediately afterwards. Three days later, she develops fever, abdominal cramps, nausea, vomiting, and bloody diarrhea. Her pediatrician gives her antibiotics. On day 6, she develops ecchymoses on the extremities and lips, thrombocytopenia, low urine output, and seizures. Her stool tests positive for Escherichia coli O157:H7

Classic presentation: Young patient with bloody diarrhea

The classic presentation of hemolytic uremic syndrome is of a young patient with bloody diarrhea typically lasting 5 to 10 days. Kidney failure may follow, requiring dialysis in about 60% of patients for a mean of 10 days. About one-fourth of patients develop neurologic symptoms, and about the same fraction are left with long-term morbidity, eg, hypertension, proteinuria, and reduced glomerular filtration rate. The mortality rate is typically 4%^10,11 but varies with the outbreak.

Histologically, the kidneys look identical to those in thrombotic thrombocytopenic purpura, with thrombi in glomeruli and small vessels.

E coli is the most common culprit, but other bacteria, including Shigella dysenteriae, and viruses are sometimes the cause. Fewer than 10% of children infected with Shiga toxin-positive E coli, also known as enterohemorrhagic E coli (O157:H7, O104:H4), develop hemolytic uremic syndrome.

Lessons from outbreaks

Petting zoos are a common source of transmission of pathogenic bacteria. Disease can be extremely serious: in 15 cases linked to a Florida petting zoo, 3 children died.

Other outbreaks involving pathogenic E coli have been tied to fresh vegetables and to undercooked hamburger at fast-food chains.

In Germany in 2011, more than 3,000 people acquired Shiga toxin nonhemolytic uremic syndrome due to E coli, and 16 of them died. In addition, 845 acquired hemolytic uremic syndrome, and 36 died. This outbreak was associated with the more virulent and less common O104:H4 strain, which has acquired a Shiga toxin-encoding phage. Patients were treated with quinolone antibiotics, which actually increase toxin production in this strain.¹²

Unusual in the German epidemic was that more adults were affected (88%), especially women (68% of cases).¹³ The source of infection was eventually found to be alfalfa sprouts, the seeds of which had been contaminated by E coli. Women did not harbor any intrinsic factor making them more susceptible; rather, they were more likely to eat salads.¹³

Supportive management

Supportive care is most important. Transfusion with packed red blood cells is indicated for hemoglobin below 6 g/dL. Hypertension should be controlled and dialysis provided. For central nervous system involvement or severe disease, plasma exchange is sometimes used.

Eculizumab was tried for a time as therapy but did not prove to be of benefit. Shiga toxin-binding agents have been developed, but by the time they are given it is too late in the disease process to help.

Antibiotics may harm; it is possible that they kill beneficial bacteria, allowing the Shiga toxin-producing E coli to better proliferate. Antimotility agents also are contraindicated. Other agents not recommended include urokinase, heparin, dipyridamole, and vincristine. Splenectomy is not advised.

The most important way to control hemolytic uremic syndrome is to prevent it by thoroughly cooking meat, cleaning fresh produce, and having children wash their hands after petting animals.

ATYPICAL HEMOLYTIC UREMIC SYNDROME

A young man in renal failure

A 28-year-old man has a history of “thrombotic thrombocytopenic purpura-hemolytic uremic syndrome” at age 12. He slowly progresses to end-stage renal disease and receives a renal transplant from his mother at age 20 that fails after 3 months. The renal transplant biopsy report at the time reads “thrombotic microangiopathy.” The patient’s brother also requires dialysis.

The patient’s complement values are low, especially C3. His father is offering him a kidney at this time, and the patient wants to know whether to proceed.

Normal ADAMTS13, no diarrhea

Hemolytic uremic syndrome without diarrhea is now called atypical hemolytic uremic syndrome. Patients have normal levels of ADAMTS13, do not have diarrhea, and have no evidence of Shiga toxin-producing E coli.

Continuous complement pathway activation

The complement system is part of the innate immune system, which provides immediate defense against infection and does not evolve as does the adaptive immune system. The classic complement pathway is activated by the C1 antibody-antigen complex. The alternative complement pathway leads to the same pathway via C3.¹⁴ Both pathways lead to the formation of C5 through C9 membrane attack complexes, which form channels across the membranes of target cells, leading to cell lysis and death.

The alternate pathway does not require an antibody trigger so is always active at a low level. Inhibitory factors (factor H, factor I, membrane cofactor protein, factor H-related proteins) are naturally present and slow it down at various steps. People who are born with an abnormal factor or, more commonly, develop antibodies against one of the factors, have uninhibited complement activation. If this happens in the blood vessels, massive coagulation and atypical hemolytic uremic syndrome ensues. The endothelial damage and clotting in the brain, kidney, and other organs are identical to that of hemolytic uremic syndrome caused by Shiga toxin.

Treat with eculizumab

Historically, atypical hemolytic uremic syndrome was treated with plasma exchange, which replaces defective complement regulatory proteins and removes inhibitory antibodies.

Understanding the complement pathways is key to developing drugs that target atypical hemolytic uremic syndrome, and about 60 are in the pipeline. The only one currently approved in the United States for atypical hemolytic uremic syndrome is eculizumab, a humanized monoclonal antibody that binds with high affinity to C5, blocking the end of the complement cascade and preventing formation of the membrane attack complex.^15–18

The effects of eculizumab on atypical hemolytic uremic syndrome were studied in 2 prospective trials.¹⁹ Platelet counts rose rapidly within weeks of starting treatment, and kidney function improved. Benefits continued throughout the 64 weeks studied. There were no deaths among the 37 patients enrolled, and although these were single-arm trials, they provide evidence of dramatic benefit considering the high mortality risk of this disease.

Eculizumab is now considered the treatment of choice. It may be used empirically for patients with hemolytic uremic syndrome who test negative for Shiga toxin and antiphospholipid antibody, and who do not have a very low level of ADAMTS13. The big drawback of eculizumab is its high price,^20–22 which varies by amount used, location, and pharmacy negotiation, but can be in the hundreds of thousands of dollars.

For a patient with atypical hemolytic uremic syndrome on dialysis, treatment with eculizumab should continue for 4 to 6 months if there are no extrarenal manifestations. But many patients continue to have the defect in the complement system, so the problem may recur.

Case revisited

For our patient considering a kidney transplant, many experts feel that a transplant can be done as long as platelet counts are monitored and treatment with eculizumab is restarted if needed. One can also make the case for waiting a few years for new oral drugs to become available before offering transplant.

ANTIPHOSPHOLIPID SYNDROME

A young woman with a history of thrombosis and miscarriages

A 27-year-old woman presents with arthralgias, low-grade fever, and malaise. She has a history of 3 spontaneous abortions and Raynaud phenomenon. Two years ago, she had deep vein thrombosis of the right calf after a long automobile trip.

She now has swollen metacarpophalangeal and proximal interphalangeal joints, livedo reticularis (a mottled venous pattern of the skin best seen under fluorescent light) of the legs and arms, and ankle edema (2-cm indentation).

Her blood pressure is 152/92 mm Hg. Laboratory values:

• White blood cell count 3.6 × 10⁹/L (reference range 4.5–11.0)
• Hematocrit 24% (36%–47%)
• Platelet count 89 × 10⁹/L (150–450)
• Urinalysis: protein 4+, heme 3+, red blood cells 8–15 per high-power field (< 3), red blood cell casts present
• Blood urea nitrogen 43 mg/dL (10–20)
• Creatinine 2.6 mg/dL (0.5–1.1).
• Prothrombin time 14.6 s (10–14)
• Partial thromboplastin time 85 s (25–35)
• Antinuclear antibody positive at 1:160
• Anti-double-stranded DNA and serum complement normal
• Syphilis serologic screening (VDRL) positive.

The patient has leukopenia, anemia, thrombocytopenia, hematuria, proteinuria, high blood urea nitrogen, and markedly elevated partial thromboplastin time. Although she has a positive antinuclear antibody test and renal dysfunction, her anti-dsDNA and serum complement tests are normal, making the diagnosis of systemic lupus erythematosus unlikely.

Consider antiphospholipid syndrome

In any patient with multiple pregnancy losses, lupus, or a history of thrombosis, antiphospholipid syndrome should be considered.

In a series of patients with antiphospholipid antibody who underwent kidney biopsy, more than half were men, indicating that, unlike lupus, this is not primarily a disease of young women.

Diagnosis based on specific criteria

Clinical criteria require at least one of the following in the patient’s history²³:

• One or more episodes of arterial, venous, or small-vessel thrombosis
• Unexplained pregnancy morbidity (death of a fetus or neonate with normal morphology or 3 or more spontaneous abortions).

Serologic criteria for any of the following antiphospholipid antibodies require that at least one of the following tests be positive at least twice and at least 12 weeks apart:

• Anticardiolipin antibodies—high-titer immunoglobulin (Ig) G or IgM
• Autoantibodies for beta 2-glycoprotein
• Lupus anticoagulant—autoantibodies that increase clotting time in vitro and target beta 2-glycoprotein I and prothrombin (despite its name and actions in vitro, lupus anticoagulant functions as a coagulant).

As with the other thrombotic microangiopathies, patients with anticardiolipin syndrome have microthrombi in the glomeruli and blood vessels that are evident on kidney biopsy.

Suspect condition in likely groups

Antiphospholipid syndrome is surprisingly common.²⁴ In a case-control study, de Groot et al²⁵ found that 3.1% of patients under age 70 with a first episode of venous thrombosis and no known cancer were positive for lupus anticoagulant vs 0.9% of controls. In another case-control study, Urbanus et al²⁶ found that 17% of women under age 50 with a stroke tested positive for lupus anticoagulant compared with less than 1% of controls. Because of such studies, it has become routine to test for anticardiolipin and lupus anticoagulant in young patients presenting with a stroke.

About 1% of women trying to have children have recurrent miscarriages, and of these, 10% to 15% have antiphospholipid antibody present.^27–30

Pathogenesis

Patients with antiphospholipid syndrome have a much higher proportion of plasma beta 2-glycoprotein in the oxidized form than do healthy controls. The level is also higher than in patients with a different autoimmune disease whether or not they have antibodies against beta 2-glycoprotein 1. Although about 40% of patients with lupus have an anticardiolipin antibody, only a small percentage develop antiphospholipid syndrome with clotting.

It is thought that antiphospholipid syndrome involves initial injury to the endothelium, then potentiation of thrombus formation. Oxidized beta 2-glycoprotein complexes may bind to the endothelial cell surface, causing it to become the target of antibodies. The exact relationships between the factors are not yet understood.

The risk of a thrombotic event in an asymp­tomatic patient positive for all 3 factors—lupus anticoagulant, anticardiolipin antibody, and anti-beta 2-glycoprotein I antibody—is more than 5% per year.³¹

Manage thrombosis with anticoagulation

Khamashta et al,³² in a 1995 study, retrospectively studied patients with antiphospholipid antibodies and a history of thrombosis. Of 147 patients, 66 had idiopathic primary disease, 62 had systemic lupus, and 19 had “lupus-like” disease. Almost 70% (101 patients) had a recurrence of thrombosis, totaling 186 events. The mean time to recurrence was 12 months (range 2 weeks to 12 years). Recurrence rates were 0.01 events per patient per year with high-dose warfarin, 0.23 with low-dose warfarin, and 0.18 with aspirin. But the highest bleeding rates were in the 6 months after warfarin withdrawal; 29 patients had bleeding events, one-fourth of which were severe.

Standard therapy has become anticoagulation, starting with heparin or enoxaparin, then warfarin. There is inadequate evidence for the role of newer oral anticoagulant therapy.

A very high INR is not generally better than a moderately elevated level

For a time, it was thought that the international normalized ratio (INR) should be kept on the very high side to prevent thrombosis.

Crowther et al³³ conducted a randomized, double-blind trial comparing moderate warfarin therapy (INR 2.0–3.0) and high-intensity warfarin therapy (INR 3.1–4.0) in antiphospholipid syndrome. Thrombosis actually recurred more frequently in the high-intensity therapy group (10.7% vs 3.4%), with no significant difference in major bleeding events.

A reasonable strategy is to keep the INR between 2.5 and 3.0, keeping in mind that values fluctuate in any individual patient. A higher goal often leads to excessive anticoagulation and bleeding. If the goal is too low, recurrent thrombosis becomes more likely. There are fewer data on the newer oral anticoagulants, but their role is likely to increase as reversal agents are developed.

Recommendations published in 2003 for treating antiphospholipid syndrome include³⁴:

• Warfarin (INR 2.0–3.0) after the first thrombotic event
• Warfarin (INR 3.0–4.0) if a clot develops despite warfarin
• Warfarin (INR > 3.0) for an arterial event.

For the rare but catastrophic antiphospholipid syndrome in which thrombosis occurs in multiple organs, recommendations are for heparin plus steroids, with or without intravenous immunoglobulin and plasmapheresis. This approach has not always been successful, and the mortality rate is high.

Treatment of asymptomatic carriers is uncertain

Treatment of asymptomatic carriers of the antiphospholipid antibody is controversial. Evidence for management is scarce; some experts recommend aspirin therapy, but benefit has yet to be proven in clinical trials.

Canaud et al³⁵ documented the role of activation of the kinase mammalian target of rapamycin (mTOR) in the vascular changes characteristic of antiphospholipid nephropathy. Postkidney transplant surveillance biopsies of patients with antiphospholipid antibodies showed vascular damage occurring over time (despite patients being asymptomatic) compared with other renal transplant patients. Patients with antiphospholipid antibodies who were treated with the immunosuppressive drug sirolimus were protected from developing these changes. Twelve years after transplant, 70% of patients with antiphospholipid antibodies taking sirolimus still had a functioning graft compared with 11% of untreated patients.

A 39-year-old woman with a history of human immunodeficiency virus (HIV) and hepatitis B virus infection was brought to the emergency department for evaluation of seizures, which had started a few days earlier. She was born and raised in a state bordering the Ohio River, an area where Histoplasma capsulatum is endemic. She denied any recent travel.

Her vital signs and neurologic examination were normal. Computed tomography of the head showed two areas of increased attenuation anterior to the frontal horns. To better characterize those lesions, magnetic resonance imaging (MRI) with contrast was done, which showed about a dozen 1-cm ring-enhancing lesions in the right cerebellum and both cerebral hemispheres (Figure 1).

Results of a complete blood cell count, metabolic profile, and chest radiography were normal. Her CD4 count was 428/μL (reference range 533–1,674) and 20% (60%–89%); her HIV viral load was 326,000 copies/mL.

She was initially treated empirically with sulfadiazine, pyrimethamine, and leukovorin for possible toxoplasmosis, which is the most common cause of ring-enhancing brain lesions in HIV patients. In the meantime, cerebrospinal fluid, blood, and urine were sent for a detailed workup for fungi, including Histoplasma. Results of the Histoplasma antibody and antigen studies of the serum, urine, and cerebrospinal fluid were positive, while cerebrospinal fluid testing for Toxoplasma by polymerase chain reaction testing was negative. Empirical treatment for toxoplasmosis was stopped and amphotericin B was started to treat disseminated histoplasmosis.

During her hospital course, she underwent brain biopsy via right frontotemporal craniotomy with resection of right frontal lesions. Pathologic study showed partially organizing abscesses with central necrosis (Figure 2), microscopy with Grocott-Gomori methenamine silver stain was positive for budding yeast forms consistent with H capsulatum (Figure 3), and special stain for acid-fast bacilli was negative for mycobacteria. Cultures of the brain biopsy specimen, blood, and cerebrospinal fluid for fungi, acid-fast bacilli, and bacteria did not reveal any growth after 28 days.

The patient was discharged home with instructions to take amphotericin B for a total of 6 weeks and then itraconazole. About 1 year later, she remained free of symptoms, although repeat MRI did not show any significant change in the size or number of histoplasmomas.

She did not comply well with her HIV treatment, and her immune status did not improve, so we decided to continue her itraconazole treatment for more than 1 year.

CEREBRAL HISTOPLASMOMA

The term “histoplasmoma” was introduced by Shapiro et al¹ in 1955, when they first described numerous focal areas of softening, up to 1 cm in diameter, scattered throughout the brain at autopsy in a 41-year-old man who had died of disseminated histoplasmosis. They coined the word to describe these discrete areas of necrosis that might resemble tumors on the basis of their size, location, and capability of causing increased intracranial pressure.

Central nervous system involvement can either be a manifestation of disseminated disease or present as an isolated illness.² It occurs in 5% to 10% of cases of disseminated histoplasmosis.³ Histoplasmosis of the central nervous system can have different manifestations; the most common presentation is chronic meningitis.⁴

Laboratory diagnosis is based on detecting H capsulatum antigen and antibody in the urine, blood, and cerebrospinal fluid. Tissue biopsy (histopathology) as well as cultures of tissue samples or body fluids may also establish the diagnosis.⁴

Toxoplasmosis and primary central nervous system lymphoma are the most common causes of brain ring-enhancing lesions in HIV patients in developed countries, while in the developing world neurocysticercosis and tuberculomas are more common.^5,6 Much less common causes include brain abscesses secondary to bacterial infections (pyogenic abscess),⁷ cryptococcomas,⁸ syphilitic cerebral gummata,⁹ primary brain tumors (gliomas), and metastases.¹⁰

Compared with other forms of the disease, histoplasmosis of the central nervous system has higher rates of treatment failure and relapse, so treatment should be prolonged and aggressive.^2,3 The cure rate with amphotericin B ranges from 33% to 61%, and higher doses produce better response rates.³

Current treatment recommendations are based on 2007 guidelines of the Infectious Diseases Society of America.¹¹ Liposomal amphotericin B is the drug of choice because it achieves higher concentrations in the central nervous system than other drugs and is less toxic. It is given for 4 to 6 weeks, followed by itraconazole for at least 1 year and until the cerebrospinal fluid Histoplasma antigen test is negative and other cerebrospinal fluid abnormalities are resolved.

In patients who have primary disseminated histoplasmosis that includes the central nervous system, itraconazole can be given for more than 1 year or until immune recovery is achieved—or lifelong if necessary.^2,12 Long-term suppressive antifungal therapy also should be considered in patients for whom appropriate initial therapy fails.²

Nephrotoxicity (acute kidney injury, hypokalemia, and hypomagnesemia), infusion-related drug reactions, and rash are among the well-described side effects of amphotericin B. Maintenance of intravascular volume and replacement of electrolytes should be an integral part of the amphotericin B treatment regimen.¹³

TAKE-AWAY POINTS

• Histoplasmomas should be considered in the differential diagnosis of ring-enhancing lesions of the central nervous system, along with toxoplasmosis and primary central nervous system lymphoma. This will allow timely initiation of the diagnostic workup, avoiding unnecessary and potentially risky interventions and delays in starting targeted antifungal therapy.
• There is no single gold standard test for central nervous system histoplasmosis. Rather, the final diagnosis is based on the combination of clinical, laboratory, and radiologic findings.

Acknowledgment: Library research assistance provided by HSHS St. John’s Hospital Health Sciences Library staff.

A 39-year-old woman with a history of human immunodeficiency virus (HIV) and hepatitis B virus infection was brought to the emergency department for evaluation of seizures, which had started a few days earlier. She was born and raised in a state bordering the Ohio River, an area where Histoplasma capsulatum is endemic. She denied any recent travel.

Her vital signs and neurologic examination were normal. Computed tomography of the head showed two areas of increased attenuation anterior to the frontal horns. To better characterize those lesions, magnetic resonance imaging (MRI) with contrast was done, which showed about a dozen 1-cm ring-enhancing lesions in the right cerebellum and both cerebral hemispheres (Figure 1).

Results of a complete blood cell count, metabolic profile, and chest radiography were normal. Her CD4 count was 428/μL (reference range 533–1,674) and 20% (60%–89%); her HIV viral load was 326,000 copies/mL.

She was initially treated empirically with sulfadiazine, pyrimethamine, and leukovorin for possible toxoplasmosis, which is the most common cause of ring-enhancing brain lesions in HIV patients. In the meantime, cerebrospinal fluid, blood, and urine were sent for a detailed workup for fungi, including Histoplasma. Results of the Histoplasma antibody and antigen studies of the serum, urine, and cerebrospinal fluid were positive, while cerebrospinal fluid testing for Toxoplasma by polymerase chain reaction testing was negative. Empirical treatment for toxoplasmosis was stopped and amphotericin B was started to treat disseminated histoplasmosis.

During her hospital course, she underwent brain biopsy via right frontotemporal craniotomy with resection of right frontal lesions. Pathologic study showed partially organizing abscesses with central necrosis (Figure 2), microscopy with Grocott-Gomori methenamine silver stain was positive for budding yeast forms consistent with H capsulatum (Figure 3), and special stain for acid-fast bacilli was negative for mycobacteria. Cultures of the brain biopsy specimen, blood, and cerebrospinal fluid for fungi, acid-fast bacilli, and bacteria did not reveal any growth after 28 days.

The patient was discharged home with instructions to take amphotericin B for a total of 6 weeks and then itraconazole. About 1 year later, she remained free of symptoms, although repeat MRI did not show any significant change in the size or number of histoplasmomas.

She did not comply well with her HIV treatment, and her immune status did not improve, so we decided to continue her itraconazole treatment for more than 1 year.

CEREBRAL HISTOPLASMOMA

The term “histoplasmoma” was introduced by Shapiro et al¹ in 1955, when they first described numerous focal areas of softening, up to 1 cm in diameter, scattered throughout the brain at autopsy in a 41-year-old man who had died of disseminated histoplasmosis. They coined the word to describe these discrete areas of necrosis that might resemble tumors on the basis of their size, location, and capability of causing increased intracranial pressure.

Central nervous system involvement can either be a manifestation of disseminated disease or present as an isolated illness.² It occurs in 5% to 10% of cases of disseminated histoplasmosis.³ Histoplasmosis of the central nervous system can have different manifestations; the most common presentation is chronic meningitis.⁴

Laboratory diagnosis is based on detecting H capsulatum antigen and antibody in the urine, blood, and cerebrospinal fluid. Tissue biopsy (histopathology) as well as cultures of tissue samples or body fluids may also establish the diagnosis.⁴

Toxoplasmosis and primary central nervous system lymphoma are the most common causes of brain ring-enhancing lesions in HIV patients in developed countries, while in the developing world neurocysticercosis and tuberculomas are more common.^5,6 Much less common causes include brain abscesses secondary to bacterial infections (pyogenic abscess),⁷ cryptococcomas,⁸ syphilitic cerebral gummata,⁹ primary brain tumors (gliomas), and metastases.¹⁰

Compared with other forms of the disease, histoplasmosis of the central nervous system has higher rates of treatment failure and relapse, so treatment should be prolonged and aggressive.^2,3 The cure rate with amphotericin B ranges from 33% to 61%, and higher doses produce better response rates.³

Current treatment recommendations are based on 2007 guidelines of the Infectious Diseases Society of America.¹¹ Liposomal amphotericin B is the drug of choice because it achieves higher concentrations in the central nervous system than other drugs and is less toxic. It is given for 4 to 6 weeks, followed by itraconazole for at least 1 year and until the cerebrospinal fluid Histoplasma antigen test is negative and other cerebrospinal fluid abnormalities are resolved.

In patients who have primary disseminated histoplasmosis that includes the central nervous system, itraconazole can be given for more than 1 year or until immune recovery is achieved—or lifelong if necessary.^2,12 Long-term suppressive antifungal therapy also should be considered in patients for whom appropriate initial therapy fails.²

Nephrotoxicity (acute kidney injury, hypokalemia, and hypomagnesemia), infusion-related drug reactions, and rash are among the well-described side effects of amphotericin B. Maintenance of intravascular volume and replacement of electrolytes should be an integral part of the amphotericin B treatment regimen.¹³

TAKE-AWAY POINTS

• Histoplasmomas should be considered in the differential diagnosis of ring-enhancing lesions of the central nervous system, along with toxoplasmosis and primary central nervous system lymphoma. This will allow timely initiation of the diagnostic workup, avoiding unnecessary and potentially risky interventions and delays in starting targeted antifungal therapy.
• There is no single gold standard test for central nervous system histoplasmosis. Rather, the final diagnosis is based on the combination of clinical, laboratory, and radiologic findings.

Acknowledgment: Library research assistance provided by HSHS St. John’s Hospital Health Sciences Library staff.

A 39-year-old woman with a history of human immunodeficiency virus (HIV) and hepatitis B virus infection was brought to the emergency department for evaluation of seizures, which had started a few days earlier. She was born and raised in a state bordering the Ohio River, an area where Histoplasma capsulatum is endemic. She denied any recent travel.

Her vital signs and neurologic examination were normal. Computed tomography of the head showed two areas of increased attenuation anterior to the frontal horns. To better characterize those lesions, magnetic resonance imaging (MRI) with contrast was done, which showed about a dozen 1-cm ring-enhancing lesions in the right cerebellum and both cerebral hemispheres (Figure 1).

Results of a complete blood cell count, metabolic profile, and chest radiography were normal. Her CD4 count was 428/μL (reference range 533–1,674) and 20% (60%–89%); her HIV viral load was 326,000 copies/mL.

She was initially treated empirically with sulfadiazine, pyrimethamine, and leukovorin for possible toxoplasmosis, which is the most common cause of ring-enhancing brain lesions in HIV patients. In the meantime, cerebrospinal fluid, blood, and urine were sent for a detailed workup for fungi, including Histoplasma. Results of the Histoplasma antibody and antigen studies of the serum, urine, and cerebrospinal fluid were positive, while cerebrospinal fluid testing for Toxoplasma by polymerase chain reaction testing was negative. Empirical treatment for toxoplasmosis was stopped and amphotericin B was started to treat disseminated histoplasmosis.

During her hospital course, she underwent brain biopsy via right frontotemporal craniotomy with resection of right frontal lesions. Pathologic study showed partially organizing abscesses with central necrosis (Figure 2), microscopy with Grocott-Gomori methenamine silver stain was positive for budding yeast forms consistent with H capsulatum (Figure 3), and special stain for acid-fast bacilli was negative for mycobacteria. Cultures of the brain biopsy specimen, blood, and cerebrospinal fluid for fungi, acid-fast bacilli, and bacteria did not reveal any growth after 28 days.

The patient was discharged home with instructions to take amphotericin B for a total of 6 weeks and then itraconazole. About 1 year later, she remained free of symptoms, although repeat MRI did not show any significant change in the size or number of histoplasmomas.

She did not comply well with her HIV treatment, and her immune status did not improve, so we decided to continue her itraconazole treatment for more than 1 year.

CEREBRAL HISTOPLASMOMA

The term “histoplasmoma” was introduced by Shapiro et al¹ in 1955, when they first described numerous focal areas of softening, up to 1 cm in diameter, scattered throughout the brain at autopsy in a 41-year-old man who had died of disseminated histoplasmosis. They coined the word to describe these discrete areas of necrosis that might resemble tumors on the basis of their size, location, and capability of causing increased intracranial pressure.

Central nervous system involvement can either be a manifestation of disseminated disease or present as an isolated illness.² It occurs in 5% to 10% of cases of disseminated histoplasmosis.³ Histoplasmosis of the central nervous system can have different manifestations; the most common presentation is chronic meningitis.⁴

Laboratory diagnosis is based on detecting H capsulatum antigen and antibody in the urine, blood, and cerebrospinal fluid. Tissue biopsy (histopathology) as well as cultures of tissue samples or body fluids may also establish the diagnosis.⁴

Toxoplasmosis and primary central nervous system lymphoma are the most common causes of brain ring-enhancing lesions in HIV patients in developed countries, while in the developing world neurocysticercosis and tuberculomas are more common.^5,6 Much less common causes include brain abscesses secondary to bacterial infections (pyogenic abscess),⁷ cryptococcomas,⁸ syphilitic cerebral gummata,⁹ primary brain tumors (gliomas), and metastases.¹⁰

Compared with other forms of the disease, histoplasmosis of the central nervous system has higher rates of treatment failure and relapse, so treatment should be prolonged and aggressive.^2,3 The cure rate with amphotericin B ranges from 33% to 61%, and higher doses produce better response rates.³

Current treatment recommendations are based on 2007 guidelines of the Infectious Diseases Society of America.¹¹ Liposomal amphotericin B is the drug of choice because it achieves higher concentrations in the central nervous system than other drugs and is less toxic. It is given for 4 to 6 weeks, followed by itraconazole for at least 1 year and until the cerebrospinal fluid Histoplasma antigen test is negative and other cerebrospinal fluid abnormalities are resolved.

In patients who have primary disseminated histoplasmosis that includes the central nervous system, itraconazole can be given for more than 1 year or until immune recovery is achieved—or lifelong if necessary.^2,12 Long-term suppressive antifungal therapy also should be considered in patients for whom appropriate initial therapy fails.²

Nephrotoxicity (acute kidney injury, hypokalemia, and hypomagnesemia), infusion-related drug reactions, and rash are among the well-described side effects of amphotericin B. Maintenance of intravascular volume and replacement of electrolytes should be an integral part of the amphotericin B treatment regimen.¹³

TAKE-AWAY POINTS

• Histoplasmomas should be considered in the differential diagnosis of ring-enhancing lesions of the central nervous system, along with toxoplasmosis and primary central nervous system lymphoma. This will allow timely initiation of the diagnostic workup, avoiding unnecessary and potentially risky interventions and delays in starting targeted antifungal therapy.
• There is no single gold standard test for central nervous system histoplasmosis. Rather, the final diagnosis is based on the combination of clinical, laboratory, and radiologic findings.

Acknowledgment: Library research assistance provided by HSHS St. John’s Hospital Health Sciences Library staff.

Despite advances in therapy, more than 10% of patients with acute bacterial meningitis still die of it, and more suffer significant morbidity, including cognitive dysfunction and deafness. Well-defined protocols that include empiric antibiotics and systemic corticosteroids have improved the outcomes of patients with meningitis. But, as with other closed-space infections such as septic arthritis, any delay in providing appropriate antibiotic treatment is associated with a worse prognosis. In the case of bacterial meningitis, a retrospective analysis concluded that each hour of delay in delivering antibiotics and a corticosteroid can be associated with a relative (not absolute) increase in mortality of 13%.¹

The precise diagnosis of bacterial meningitis depends entirely on obtaining cerebrospinal fluid for analysis, including culture and antibiotic sensitivity testing. But that simple statement belies several current and historical complexities. From my experience, getting a prompt diagnostic lumbar puncture is not as simple as it once was.

Many hospitals have imposed patient safety initiatives, which overall have been beneficial but have had the effect that medical residents and probably even hospitalists in some medical centers are less frequently the ones doing interventional procedures. Some procedures, such as placement of pulmonary arterial catheters in the medical intensive care unit, have been shown to be less useful and to pose more risk than once believed. The tasks of placing other central lines and performing thoracenteses have been relegated to special procedure teams trained in using ultrasound guidance. Interventional radiologists now often do the visceral biopsies and lumbar punctures, and as a result, it is hoped that procedural complication rates will decline. On the other hand, these changes mean that medical residents and future staff are less experienced in performing these procedures, even though there are times that they are the only ones available to perform them. The result is a potential delay in performing a necessary lumbar puncture.

Another reason that a lumbar puncture may be delayed is concern over iatrogenic herniation if the procedure is done in a patient who has elevated intracranial pressure. We do not know precisely how often this occurs if there is an undiagnosed brain mass lesion such as an abscess, which can mimic bacterial meningitis, or a malignancy, and meningitis itself may be associated with herniation. Yet, for years physicians have hesitated to perform lumbar punctures in some patients without first ruling out a brain mass by computed tomography (CT), a diagnostic flow algorithm that often introduces at least an hour of delay in performing the procedure and in obtaining cultures before starting antibiotics.

When I was in training, we were perhaps more cavalier, appropriately or not. If the history and examination did not suggest a brain mass and the patient had retinal vein pulsations without papilledema, we did the lumbar puncture. It was a different time, and there was a different perspective on risks and benefits. More recently, the trend has been to obtain a CT scan before a lumbar puncture in several subsets of patients.

A 2015 analysis from Sweden¹ showed that we can probably do a lumbar puncture for suspected bacterial meningitis without first doing a CT scan in most patients, even in patients with moderately impaired mentation. Perhaps some other concerns can also be assuaged if evaluated, but we don’t have data. Mirrakhimov et al, in this issue of the Journal, review the current evidence on when to do CT before a lumbar puncture, even if it may significantly delay the procedure and the timely delivery of antibiotics. A perfect algorithm that balances the risks of delaying treatment, initiating less-than-ideal empiric antibiotics potentially without definitive culture, and inducing complications from a procedure done promptly may well be impossible to develop. Evidence helps us refine the diagnostic approach, but with limited data, some important decisions unfortunately remain within the “art” rather than the science of medicine.

Despite advances in therapy, more than 10% of patients with acute bacterial meningitis still die of it, and more suffer significant morbidity, including cognitive dysfunction and deafness. Well-defined protocols that include empiric antibiotics and systemic corticosteroids have improved the outcomes of patients with meningitis. But, as with other closed-space infections such as septic arthritis, any delay in providing appropriate antibiotic treatment is associated with a worse prognosis. In the case of bacterial meningitis, a retrospective analysis concluded that each hour of delay in delivering antibiotics and a corticosteroid can be associated with a relative (not absolute) increase in mortality of 13%.¹

The precise diagnosis of bacterial meningitis depends entirely on obtaining cerebrospinal fluid for analysis, including culture and antibiotic sensitivity testing. But that simple statement belies several current and historical complexities. From my experience, getting a prompt diagnostic lumbar puncture is not as simple as it once was.

Many hospitals have imposed patient safety initiatives, which overall have been beneficial but have had the effect that medical residents and probably even hospitalists in some medical centers are less frequently the ones doing interventional procedures. Some procedures, such as placement of pulmonary arterial catheters in the medical intensive care unit, have been shown to be less useful and to pose more risk than once believed. The tasks of placing other central lines and performing thoracenteses have been relegated to special procedure teams trained in using ultrasound guidance. Interventional radiologists now often do the visceral biopsies and lumbar punctures, and as a result, it is hoped that procedural complication rates will decline. On the other hand, these changes mean that medical residents and future staff are less experienced in performing these procedures, even though there are times that they are the only ones available to perform them. The result is a potential delay in performing a necessary lumbar puncture.

Another reason that a lumbar puncture may be delayed is concern over iatrogenic herniation if the procedure is done in a patient who has elevated intracranial pressure. We do not know precisely how often this occurs if there is an undiagnosed brain mass lesion such as an abscess, which can mimic bacterial meningitis, or a malignancy, and meningitis itself may be associated with herniation. Yet, for years physicians have hesitated to perform lumbar punctures in some patients without first ruling out a brain mass by computed tomography (CT), a diagnostic flow algorithm that often introduces at least an hour of delay in performing the procedure and in obtaining cultures before starting antibiotics.

When I was in training, we were perhaps more cavalier, appropriately or not. If the history and examination did not suggest a brain mass and the patient had retinal vein pulsations without papilledema, we did the lumbar puncture. It was a different time, and there was a different perspective on risks and benefits. More recently, the trend has been to obtain a CT scan before a lumbar puncture in several subsets of patients.

A 2015 analysis from Sweden¹ showed that we can probably do a lumbar puncture for suspected bacterial meningitis without first doing a CT scan in most patients, even in patients with moderately impaired mentation. Perhaps some other concerns can also be assuaged if evaluated, but we don’t have data. Mirrakhimov et al, in this issue of the Journal, review the current evidence on when to do CT before a lumbar puncture, even if it may significantly delay the procedure and the timely delivery of antibiotics. A perfect algorithm that balances the risks of delaying treatment, initiating less-than-ideal empiric antibiotics potentially without definitive culture, and inducing complications from a procedure done promptly may well be impossible to develop. Evidence helps us refine the diagnostic approach, but with limited data, some important decisions unfortunately remain within the “art” rather than the science of medicine.

Despite advances in therapy, more than 10% of patients with acute bacterial meningitis still die of it, and more suffer significant morbidity, including cognitive dysfunction and deafness. Well-defined protocols that include empiric antibiotics and systemic corticosteroids have improved the outcomes of patients with meningitis. But, as with other closed-space infections such as septic arthritis, any delay in providing appropriate antibiotic treatment is associated with a worse prognosis. In the case of bacterial meningitis, a retrospective analysis concluded that each hour of delay in delivering antibiotics and a corticosteroid can be associated with a relative (not absolute) increase in mortality of 13%.¹

The precise diagnosis of bacterial meningitis depends entirely on obtaining cerebrospinal fluid for analysis, including culture and antibiotic sensitivity testing. But that simple statement belies several current and historical complexities. From my experience, getting a prompt diagnostic lumbar puncture is not as simple as it once was.

Many hospitals have imposed patient safety initiatives, which overall have been beneficial but have had the effect that medical residents and probably even hospitalists in some medical centers are less frequently the ones doing interventional procedures. Some procedures, such as placement of pulmonary arterial catheters in the medical intensive care unit, have been shown to be less useful and to pose more risk than once believed. The tasks of placing other central lines and performing thoracenteses have been relegated to special procedure teams trained in using ultrasound guidance. Interventional radiologists now often do the visceral biopsies and lumbar punctures, and as a result, it is hoped that procedural complication rates will decline. On the other hand, these changes mean that medical residents and future staff are less experienced in performing these procedures, even though there are times that they are the only ones available to perform them. The result is a potential delay in performing a necessary lumbar puncture.

Another reason that a lumbar puncture may be delayed is concern over iatrogenic herniation if the procedure is done in a patient who has elevated intracranial pressure. We do not know precisely how often this occurs if there is an undiagnosed brain mass lesion such as an abscess, which can mimic bacterial meningitis, or a malignancy, and meningitis itself may be associated with herniation. Yet, for years physicians have hesitated to perform lumbar punctures in some patients without first ruling out a brain mass by computed tomography (CT), a diagnostic flow algorithm that often introduces at least an hour of delay in performing the procedure and in obtaining cultures before starting antibiotics.

When I was in training, we were perhaps more cavalier, appropriately or not. If the history and examination did not suggest a brain mass and the patient had retinal vein pulsations without papilledema, we did the lumbar puncture. It was a different time, and there was a different perspective on risks and benefits. More recently, the trend has been to obtain a CT scan before a lumbar puncture in several subsets of patients.

A 2015 analysis from Sweden¹ showed that we can probably do a lumbar puncture for suspected bacterial meningitis without first doing a CT scan in most patients, even in patients with moderately impaired mentation. Perhaps some other concerns can also be assuaged if evaluated, but we don’t have data. Mirrakhimov et al, in this issue of the Journal, review the current evidence on when to do CT before a lumbar puncture, even if it may significantly delay the procedure and the timely delivery of antibiotics. A perfect algorithm that balances the risks of delaying treatment, initiating less-than-ideal empiric antibiotics potentially without definitive culture, and inducing complications from a procedure done promptly may well be impossible to develop. Evidence helps us refine the diagnostic approach, but with limited data, some important decisions unfortunately remain within the “art” rather than the science of medicine.

Urinary incontinence—the loss of bladder control—affects 15 million American women. Many endure it in silence, thinking that it is a normal part of aging or that no medical urinary incontinence treatments exist. But in many cases it can be managed through exercise, lifestyle changes, pelvic stimulation, and sometimes medicines or other treatments.

Types of urinary incontinence

Urgency incontinence causes an urgent desire to urinate (void), which is followed by involuntary loss of urine. This condition can be caused by an “overactive” bladder, or OAB. Normally, strong muscles (sphincters) control the flow of urine from the bladder. In OAB, the muscles contract or spasm with enough force to override the sphincter muscles of the urethra and allow urine to pass out of the bladder.

Stress incontinence occurs when an activity such as a coughing or sneezing increases pressure on the bladder. Typically, a small amount of urine leaks from the urethra. This problem can be caused by weak muscles of the pelvic floor, a weak sphincter muscle, or a problem with the way the sphincter muscle opens and closes. Women who have given birth are more likely to have stress incontinence.

Women with mixed incontinence have symptoms of both urgency and stress incontinence.

Treatment options

For urge incontinence, doctors generally recommend:

• Bladder training. You would complete a bladder diary to determine how often you urinate and then try to lengthen the time between voids.
• Kegel exercises. These help strengthen the pelvic muscles, improving pelvic support and the bladder’s ability to hold urine. When you try to stop the flow of urine or try not to pass gas, you are contracting the muscles of the pelvic floor. This is what happens when you do Kegel exercises. When doing the exercises, try not to move your legs, buttocks, or abdominal muscles. In fact, no one should be able to see that you are doing them. Do 5 sets of Kegel exercises a day. Each time you contract the muscles of the pelvic floor, hold for a slow count of 5 and then relax. Repeat this 10 times for 1 set of Kegels.
• Medications such as antidepressant drugs may be prescribed to relax the bladder. Other drugs, called anticholinergic drugs, help control muscle spasms in the bladder.

For stress incontinence, doctors generally recommend:

• Bladder training and Kegel exercises, as described above.
• Bulking agents, which are injected into the lining of the urethra. They increase the thickness of the lining of the urethra, which creates resistance against the flow of urine. Collagen is one bulking agent commonly used.

Treatments for either type of urinary incontinence include:

• Vaginal estrogen—this is used by women who are going through menopause or who are postmenopausal. Vaginal estrogen is provided in the form of creams, tablets, or a ring inserted into the vagina. It works in part by thickening the vaginal tissue, which increases pelvic support, and by relieving tissue irritation.
• Pelvic stimulation. Mild electrical impulses stimulate contractions of the pelvic floor muscles, and this eventually strengthens them. Some devices require a prescription and monthly office visits and are connected to biofeedback. Others, such as the Automatic Pelvic Exerciser (APEX M), are available over the counter.
• Biofeedback therapy with a physical therapist can help you learn how to perform Kegel exercises by letting you know if you are contracting your pelvic muscles correctly. Sensors are placed on the body or within the anus or vagina and provide feedback on a computer screen or through audio tones.
• Weight loss. Being overweight or obese can lead to urinary incontinence by increasing pressure in the abdomen. Losing even 5 pounds can make a big difference in bladder control.

This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It does not replace your physician’s medical assessment and judgment.

This page may be reproduced noncommercially. For information on hundreds of health topics, see my.clevelandclinic.org/health.

Urinary incontinence—the loss of bladder control—affects 15 million American women. Many endure it in silence, thinking that it is a normal part of aging or that no medical urinary incontinence treatments exist. But in many cases it can be managed through exercise, lifestyle changes, pelvic stimulation, and sometimes medicines or other treatments.

Types of urinary incontinence

Urgency incontinence causes an urgent desire to urinate (void), which is followed by involuntary loss of urine. This condition can be caused by an “overactive” bladder, or OAB. Normally, strong muscles (sphincters) control the flow of urine from the bladder. In OAB, the muscles contract or spasm with enough force to override the sphincter muscles of the urethra and allow urine to pass out of the bladder.

Stress incontinence occurs when an activity such as a coughing or sneezing increases pressure on the bladder. Typically, a small amount of urine leaks from the urethra. This problem can be caused by weak muscles of the pelvic floor, a weak sphincter muscle, or a problem with the way the sphincter muscle opens and closes. Women who have given birth are more likely to have stress incontinence.

Women with mixed incontinence have symptoms of both urgency and stress incontinence.

Treatment options

For urge incontinence, doctors generally recommend:

• Bladder training. You would complete a bladder diary to determine how often you urinate and then try to lengthen the time between voids.
• Kegel exercises. These help strengthen the pelvic muscles, improving pelvic support and the bladder’s ability to hold urine. When you try to stop the flow of urine or try not to pass gas, you are contracting the muscles of the pelvic floor. This is what happens when you do Kegel exercises. When doing the exercises, try not to move your legs, buttocks, or abdominal muscles. In fact, no one should be able to see that you are doing them. Do 5 sets of Kegel exercises a day. Each time you contract the muscles of the pelvic floor, hold for a slow count of 5 and then relax. Repeat this 10 times for 1 set of Kegels.
• Medications such as antidepressant drugs may be prescribed to relax the bladder. Other drugs, called anticholinergic drugs, help control muscle spasms in the bladder.

For stress incontinence, doctors generally recommend:

• Bladder training and Kegel exercises, as described above.
• Bulking agents, which are injected into the lining of the urethra. They increase the thickness of the lining of the urethra, which creates resistance against the flow of urine. Collagen is one bulking agent commonly used.

Treatments for either type of urinary incontinence include:

• Vaginal estrogen—this is used by women who are going through menopause or who are postmenopausal. Vaginal estrogen is provided in the form of creams, tablets, or a ring inserted into the vagina. It works in part by thickening the vaginal tissue, which increases pelvic support, and by relieving tissue irritation.
• Pelvic stimulation. Mild electrical impulses stimulate contractions of the pelvic floor muscles, and this eventually strengthens them. Some devices require a prescription and monthly office visits and are connected to biofeedback. Others, such as the Automatic Pelvic Exerciser (APEX M), are available over the counter.
• Biofeedback therapy with a physical therapist can help you learn how to perform Kegel exercises by letting you know if you are contracting your pelvic muscles correctly. Sensors are placed on the body or within the anus or vagina and provide feedback on a computer screen or through audio tones.
• Weight loss. Being overweight or obese can lead to urinary incontinence by increasing pressure in the abdomen. Losing even 5 pounds can make a big difference in bladder control.

This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It does not replace your physician’s medical assessment and judgment.

This page may be reproduced noncommercially. For information on hundreds of health topics, see my.clevelandclinic.org/health.

Urinary incontinence—the loss of bladder control—affects 15 million American women. Many endure it in silence, thinking that it is a normal part of aging or that no medical urinary incontinence treatments exist. But in many cases it can be managed through exercise, lifestyle changes, pelvic stimulation, and sometimes medicines or other treatments.

Types of urinary incontinence

Urgency incontinence causes an urgent desire to urinate (void), which is followed by involuntary loss of urine. This condition can be caused by an “overactive” bladder, or OAB. Normally, strong muscles (sphincters) control the flow of urine from the bladder. In OAB, the muscles contract or spasm with enough force to override the sphincter muscles of the urethra and allow urine to pass out of the bladder.

Stress incontinence occurs when an activity such as a coughing or sneezing increases pressure on the bladder. Typically, a small amount of urine leaks from the urethra. This problem can be caused by weak muscles of the pelvic floor, a weak sphincter muscle, or a problem with the way the sphincter muscle opens and closes. Women who have given birth are more likely to have stress incontinence.

Women with mixed incontinence have symptoms of both urgency and stress incontinence.

Treatment options

For urge incontinence, doctors generally recommend:

• Bladder training. You would complete a bladder diary to determine how often you urinate and then try to lengthen the time between voids.
• Kegel exercises. These help strengthen the pelvic muscles, improving pelvic support and the bladder’s ability to hold urine. When you try to stop the flow of urine or try not to pass gas, you are contracting the muscles of the pelvic floor. This is what happens when you do Kegel exercises. When doing the exercises, try not to move your legs, buttocks, or abdominal muscles. In fact, no one should be able to see that you are doing them. Do 5 sets of Kegel exercises a day. Each time you contract the muscles of the pelvic floor, hold for a slow count of 5 and then relax. Repeat this 10 times for 1 set of Kegels.
• Medications such as antidepressant drugs may be prescribed to relax the bladder. Other drugs, called anticholinergic drugs, help control muscle spasms in the bladder.

For stress incontinence, doctors generally recommend:

• Bladder training and Kegel exercises, as described above.
• Bulking agents, which are injected into the lining of the urethra. They increase the thickness of the lining of the urethra, which creates resistance against the flow of urine. Collagen is one bulking agent commonly used.

Treatments for either type of urinary incontinence include:

• Vaginal estrogen—this is used by women who are going through menopause or who are postmenopausal. Vaginal estrogen is provided in the form of creams, tablets, or a ring inserted into the vagina. It works in part by thickening the vaginal tissue, which increases pelvic support, and by relieving tissue irritation.
• Pelvic stimulation. Mild electrical impulses stimulate contractions of the pelvic floor muscles, and this eventually strengthens them. Some devices require a prescription and monthly office visits and are connected to biofeedback. Others, such as the Automatic Pelvic Exerciser (APEX M), are available over the counter.
• Biofeedback therapy with a physical therapist can help you learn how to perform Kegel exercises by letting you know if you are contracting your pelvic muscles correctly. Sensors are placed on the body or within the anus or vagina and provide feedback on a computer screen or through audio tones.
• Weight loss. Being overweight or obese can lead to urinary incontinence by increasing pressure in the abdomen. Losing even 5 pounds can make a big difference in bladder control.

This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It does not replace your physician’s medical assessment and judgment.

This page may be reproduced noncommercially. For information on hundreds of health topics, see my.clevelandclinic.org/health.

Urinary incontinence can lead to a cascade of symptomatic burden on the patient, causing distress, embarrassment, and suffering.

See related patient information

Traditionally, incontinence has been treated by surgeons, and surgery remains an option. However, more patients are now being managed by medical clinicians, who can offer a number of newer therapies. Ideally, a medical physician can initiate the evaluation and treatment and even effectively cure some forms of urinary incontinence.

In 2014, the American College of Physicians (ACP) published recommendations on the medical treatment of urinary incontinence in women (Table 1).¹

This review describes the medical management of urinary incontinence in women, emphasizing the ACP recommendations¹ and newer over-the-counter options.

COMMON AND UNDERREPORTED

Many women erroneously believe that urinary incontinence is an inevitable consequence of aging and allow it to lessen their quality of life without seeking medical attention.

Indeed, it is common. The 2005–2006 National Health and Nutritional Examination Survey² found the prevalence of urinary incontinence in US women to be 15.7%. The prevalence increases with age from 6.9% in women ages 20 through 29 to 31.7% in those age 80 and older. A separate analysis of the same data found that 25.0% of women age 20 and older had 1 or more pelvic floor disorders.³ Some estimates are even higher. Wu et al⁴ reported a prevalence of urinary incontinence of 51.1% in women ages 31 through 54.

Too few of these women are identified and treated, for many reasons, including embarrassment and inadequate screening. Half of women with urinary incontinence do not report their symptoms because of humiliation or anxiety.⁵

The burden of urinary incontinence extends beyond the individual and into society. The total cost of overactive bladder and urgency urinary incontinence in the United States was estimated to be $65.9 billion in 2007 and is projected to reach $82.6 billion in 2020.⁶

THREE TYPES

There are 3 types of urinary incontinence: stress, urgency, and mixed.

Stress urinary incontinence is involuntary loss of urine associated with physical exertion or increased abdominal pressure, eg, with coughing or sneezing.

Urgency urinary incontinence is involuntary loss of urine associated with the sudden need to void. Many patients experience these symptoms simultaneously, making the distinction difficult.

Mixed urinary incontinence is loss of urine with both urgency and increased abdominal pressure or physical exertion.

Overactive bladder, a related problem, is defined as urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence, in the absence of a urinary tract infection or other obvious disease.⁷

Nongenitourinary causes such as neurologic disorders or even malignancy can present with urinary incontinence, and thus it is critical to perform a thorough initial evaluation.

A 2014 study revealed that by age 80, 20% of women may need to undergo surgery for stress urinary incontinence or pelvic organ prolapse. This statistic should motivate healthcare providers to focus on prevention and offer conservative medical management for these conditions first.⁸

QUESTIONS TO ASK

When doing a pelvic examination, once could inquire about urinary incontinence with questions such as:

Do you leak urine when you cough, sneeze, laugh, or jump or during sexual climax?

Do you have to get up more than once at night to urinate?

Do you feel the urge to urinate frequently?

BEHAVIORAL MODIFICATION AND BLADDER TRAINING

Bladder training is a conservative behavioral treatment for urinary incontinence that primary care physicians can teach. It is primarily used for urgency urinary incontinence but can also be useful in stress urinary incontinence.

After completing a bladder diary and gaining awareness of their daily voiding patterns, patients can learn scheduled voiding to train the bladder, gradually extending the urges to longer intervals.

Clinicians should instruct patients on how to train the bladder, using methods first described by Wyman and Fantl.⁹ (See Training the bladder.)

There is evidence that bladder training improves urinary incontinence compared with usual care.^10,11

The ACP recommends bladder training for women who have urgency urinary incontinence, but grades this recommendation as weak with low-quality evidence.

PELVIC FLOOR MUSCLE TRAINING

Introduced in 1948 by Dr. Arnold Kegel, pelvic floor muscle training has become widely adopted.¹²

The pelvic floor consists of a group of muscles, resembling a hammock, that support the pelvic viscera. These muscles include the coccygeus and the layers of the levator ani (Figure 1). A weak pelvic floor is one of many risk factors for developing stress urinary incontinence. Like other muscle groups, a weak pelvic floor can be rehabilitated through various techniques, often guided by a physical therapist.

Compared with those who received no treatment, women with stress urinary incontinence who performed pelvic floor muscle training were 8 times more likely to report being cured and 17 times more likely to report cure or improvement.¹³

To perform a Kegel exercise, a woman consciously contracts her pelvic floor muscles as if stopping the flow of urine.

The Knack maneuver can be used to prevent leakage during anticipated events that increase intra-abdominal pressure. For example, when a cough or sneeze is imminent, patients can preemptively contract their pelvic floor and hold the contraction through the cough or sneeze.

Although many protocols have been compared, no specific pelvic floor exercise strategy has proven superior. A systematic review assessed variations in pelvic floor interventions, exercises, and delivery and found that there was insufficient evidence to make any recommendations about the best approach. However, the benefit was greater with regular supervision during pelvic floor muscle training than with little or no supervision.¹⁴

Pelvic floor muscle training strengthens the pelvic floor, which better supports the bladder neck and anatomically compensates for defects in stress urinary incontinence. In urgency urinary incontinence, a strong pelvic floor created by muscle training prevents leaking induced by the involuntary contractions of the detrusor muscle.

Recommendation

The ACP recommends pelvic floor muscle training as first-line treatment for stress urinary incontinence and mixed urinary incontinence, and grades this recommendation as strong with high-quality evidence.

BIOFEEDBACK AND PELVIC STIMULATION

Although pelvic floor exercises are effective in urinary incontinence, 30% of patients perform them incorrectly.¹⁵

Biofeedback therapy uses visual, verbal, and acoustic signals to give the patient immediate feedback and a greater awareness of her muscular activity. A commonly used technique employs a vaginal probe to measure and display pressure changes as the patient contracts her levator ani muscles.

Women who received biofeedback in addition to traditional pelvic floor physical therapy had greater improvement in urinary incontinence than those who received pelvic physical therapy alone (risk ratio 0.75, 95% confidence interval 0.66–0.86).¹⁶

Pelvic stimulation can be used separately or in conjunction with biofeedback in both urgency and stress urinary incontinence. When pelvic stimulation is used alone, 9 women need to be treated to achieve continence in 1, and 6 women need to be treated to improve continence in 1.¹⁶ 

Traditionally delivered by a pelvic floor physical therapist, pelvic stimulation and biofeedback have also been validated for home use.^17,18 Several pelvic stimulation devices have been approved by the US Food and Drug Administration (FDA) for treating stress, urgency, and mixed urinary incontinence. These devices deliver stimulation to the pelvic floor at single or multiple frequencies. Although the mechanisms are not clearly understood, lower frequencies are used to treat urgency incontinence, while higher frequencies are used for stress incontinence. A theory is that higher-frequency stimulation strengthens the pelvic floor in stress urinary incontinence while lower frequency stimulation calms the detrusor muscle in urgency urinary incontinence.

The Apex and Apex M devices are both available over the counter, the former to treat stress urinary incontinence and the latter to treat mixed urinary incontinence, using pelvic stimulation alone. Other available devices, including the InTone and a smaller version, the InTone MV, are available by prescription and combine pelvic stimulation with biofeedback.¹⁸

Women who wish to avoid surgery, botulinum toxin injections, and daily oral medications, particularly those who are highly motivated, are ideal candidates for these over-the-counter automatic neuromuscular pelvic exercising devices.

PESSARIES AND OTHER DEVICES

Pessaries are commonly used to treat pelvic organ prolapse but can also be designed to help correct the anatomic defect responsible for stress urinary incontinence. Continence pessaries support the bladder neck so that the urethrovesicular junction is stabilized rather than hypermobile during the increased intra-abdominal pressure that occurs with coughing, sneezing, or physical exertion (Figure 2). In theory, this should decrease leakage.

A systematic review concluded that the value of pessaries in the management of incontinence remains uncertain. However, there are inherent challenges in conducting trials of such devices.¹⁹ A pessary needs to be fitted by an appropriately trained healthcare provider. The Ambulatory Treatments for Leakage Associated With Stress Incontinence (ATLAS) trial²⁰ reported that behavioral therapy was more effective than a pessary at 3 months, but the treatments were equivalent at 12 months.

The FDA has approved a disposable, over-the-counter silicone intravaginal device for treating stress urinary incontinence. Patients initially purchase a sizing kit and subsequently insert the nonabsorbent temporary intravaginal bladder supportive device, which is worn for up to 8 hours.

Women may elect to use regular tampons to do the job of a pessary, as they are easy to use and low in cost. No large randomized trials have compared tampons and pessaries, and currently no one device is known to be superior to another.

Overall, these devices are temporizing measures that have few serious adverse effects.

WEIGHT LOSS AND DIETARY CHANGES

Obesity has become a national epidemic, with more than 68% of Americans found to be overweight or obese according to the National Institutes of Health.²¹

Several studies found obesity to be an independent risk factor for urinary incontinence. As early as 1946, the British Birth Cohort study found that women ages 48 through 54 who were obese earlier in life had a higher risk of urinary incontinence in middle age, and those who were obese by age 20 were more likely to report severe incontinence.²² Likewise, the Nurses’ Health Study showed that women with a body mass index (BMI) more than 30 kg/m² had 3.1 times the risk of severe incontinence compared with women with a normal BMI. Also, the Study of Women’s Health Across the Nation and the Leicestershire Medical Research Council (MRC) incontinence study both showed that a higher BMI and weight gain are strongly correlated with urinary incontinence.^23,24

Increased intra-abdominal pressure may be the causative mechanism of stress urinary incontinence in obesity. The Korean National Health and Nutrition Examination Survey showed that central adiposity correlated with urgency incontinence.^25,26

The MRC study was one of the largest to evaluate the effect of diet on urinary symptoms. Consuming a diet dense in vegetables, bread, and chicken was found to reduce the risk of urinary incontinence, while carbonated drinks were associated with a higher risk.²⁵ These studies and others may point to reducing calories, and thus BMI, as a conservative treatment for urinary incontinence.

Newer data show bariatric surgery is associated with a strong reduction in urinary incontinence, demonstrated in a study that followed patients for 3 years after surgery.²⁷ This encouraging result is but one of several positive health outcomes from bariatric surgery.

Recommendation

The ACP recommends both weight loss and exercise for overweight women with urinary incontinence, and grades this as strong with moderate-quality evidence.

DRUG THERAPY

The bladder neck is rich with sympathetic alpha-adrenergic receptors, and the bladder dome is dense with parasympathetic muscarinic receptors and sympathetic beta-adrenergic receptors. When the parasympathetic system is stimulated, the muscarinic receptors are activated, causing detrusor contraction and ultimately bladder emptying.

Agonism of beta-alpha adrenergic receptors and inhibition of parasympathetic receptors are both strategies of drug treatment of urinary incontinence.

Anticholinergic drugs

Anticholinergic medications function by blocking the muscarinic receptor, thereby inhibiting detrusor contraction.

Six oral anticholinergic medications are available: oxybutynin, tolterodine, fesoterodine, solifenacin, trospium, and darifenacin. These drugs have about the same effectiveness in treating urgency urinary incontinence, as measured by achieving continence and improving quality of life.²⁸ Given their similarity in effectiveness, the choice of agent typically relies on the side-effect profile. Extended-release formulations have a more favorable side-effect profile, with fewer cases of dry mouth compared with immediate-release formulations.²⁹

Overall, however, the benefit of these medications is small, with fewer than 200 patients achieving continence per 1,000 treated.²⁸

Other limitations of these medications include their adverse effects and contraindications, and patients’ poor adherence to therapy. The most commonly reported adverse effect is dry mouth, but other common side effects include constipation, abdominal pain, dyspepsia, fatigue, dry eye, and dry skin. Transdermal oxybutynin therapy has been associated with fewer anticholinergic side effects than oral therapy.³⁰

Contraindications to these medications include gastric retention, urinary retention, and angle-closure glaucoma.

Long-term adherence to anticholinergics is low, reported between 14% to 35% after 12 months, with the highest rates of adherence with solifenacin.³¹ The most commonly cited reason for discontinuation is lack of effect.³²

Caution is urged when considering starting anticholinergic medications in older adults because of the central nervous system side effects, including drowsiness, hallucinations, cognitive impairment, and dementia. After 3 weeks, oxybutynin caused a memory decline as measured by delayed recall that was comparable to the decline seen over 10 years in normal aging.³³ There is evidence suggesting trospium may cause less cognitive impairment, and therefore may be a better option for older patients.³⁴

Beta-3 adrenoreceptor agonists

Activation of beta-3 adrenergic receptors through the sympathetic nervous system relaxes the detrusor muscle, allowing the bladder to store urine.

Mirabegron is a selective beta-3 adrenoreceptor agonist that effectively relaxes the bladder and increases bladder capacity. It improves continence, treatment satisfaction, and quality of life.^35,36 There are fewer reports of dry mouth and constipation with this drug than with the anticholinergics; however, beta-3 adrenoreceptor agonists may be associated with greater risk of hypertension, nasopharyngitis, headache, and urinary tract infection.³⁷

Duloxetine

Duloxetine, an antidepressant, blocks the reuptake of both serotonin and norepinephrine. Consequently, it decreases parasympathetic activity and increases sympathetic and somatic activity in the urinary system.³⁸ While urine is stored, this cascade of neural activity is thought to collectively increase pudendal nerve activity and improve closure of the urethra.

Although duloxetine is approved to treat stress urinary incontinence in Europe, this is an off-label use in the United States.

A meta-analysis³⁹ found that duloxetine improved quality of life in patients with stress urinary incontinence and that subjective cure rates were 10.8% with duloxetine vs 7.7% with placebo (P = .04). However the rate of adverse events is high, with nausea most common. Given its modest benefit and high rate of side effects, physicians may consider starting duloxetine only if there are psychiatric comorbidities such as depression, anxiety, or fibromyalgia.

Recommendations

The ACP recommends against systemic pharmacologic therapy for stress urinary incontinence. For urgency urinary incontinence, pharmacologic therapy is recommended if bladder training fails, and should be individualized based on the patient’s preference and medical comorbidities and the drug’s tolerability, cost, and ease of use.

Hormone therapy

In 2014, the North American Menopause Society recommended replacing the term “vulvovaginal atrophy” with the term genitourinary syndrome of menopause, which better encompasses the postmenopausal changes to the female genital system.⁴⁰

Estrogen therapy is commercially available in both systemic and local preparations. The effect of exogenous estrogen on urinary incontinence may depend on whether it is given locally or systemically.

A systematic review⁴¹ definitively concluded that all commercially prepared local vaginal estrogen preparations can effectively relieve the genitourinary syndrome of menopause, including not only the common complaints of dryness, burning, and irritation but also urinary complaints of frequency, urgency, and urgency urinary incontinence.⁴¹ Additionally, the estradiol vaginal ring for vaginal atrophy (Estring) may have dual effects, functioning like an incontinence pessary by supporting the bladder neck while simultaneously providing local estrogen to the atrophied vaginal tissue.

However, in the Women’s Health Initiative,⁴² continent women who received either systemic estrogen therapy alone or systemic estrogen combined with progestin actually had a higher risk of developing urinary incontinence, and those already experiencing incontinence developed a worsening of their symptoms on systemic hormone therapy. The mechanism by which systemic hormone therapy causes urinary incontinence is unclear; however, previous studies showed that hormone therapy leads to a reduction in periurethral collagen and increased bladder contractility.^43,44

TAKE-HOME POINTS

• Half of women with symptomatic urinary incontinence never report their symptoms.
• Bladder training is recommended for urgency incontinence and pelvic floor muscle training for stress incontinence.
• Thirty percent of women perform pelvic floor exercises incorrectly.
• Devices can be considered, including automatic pelvic exercise devices for stress and urgency incontinence and incontinence pessaries and disposable intravaginal bladder support devices for stress incontinence.
• Higher BMIs are strongly correlated with urinary incontinence.
• Anticholinergic medications are recommended for urgency but not stress incontinence.
• Vaginal estrogen cream may help with symptoms of urinary urgency, recurrent bladder infections, and nocturia in addition to incontinence.

Urinary incontinence can lead to a cascade of symptomatic burden on the patient, causing distress, embarrassment, and suffering.

See related patient information

Traditionally, incontinence has been treated by surgeons, and surgery remains an option. However, more patients are now being managed by medical clinicians, who can offer a number of newer therapies. Ideally, a medical physician can initiate the evaluation and treatment and even effectively cure some forms of urinary incontinence.

In 2014, the American College of Physicians (ACP) published recommendations on the medical treatment of urinary incontinence in women (Table 1).¹

This review describes the medical management of urinary incontinence in women, emphasizing the ACP recommendations¹ and newer over-the-counter options.

COMMON AND UNDERREPORTED

Many women erroneously believe that urinary incontinence is an inevitable consequence of aging and allow it to lessen their quality of life without seeking medical attention.

Indeed, it is common. The 2005–2006 National Health and Nutritional Examination Survey² found the prevalence of urinary incontinence in US women to be 15.7%. The prevalence increases with age from 6.9% in women ages 20 through 29 to 31.7% in those age 80 and older. A separate analysis of the same data found that 25.0% of women age 20 and older had 1 or more pelvic floor disorders.³ Some estimates are even higher. Wu et al⁴ reported a prevalence of urinary incontinence of 51.1% in women ages 31 through 54.

Too few of these women are identified and treated, for many reasons, including embarrassment and inadequate screening. Half of women with urinary incontinence do not report their symptoms because of humiliation or anxiety.⁵

The burden of urinary incontinence extends beyond the individual and into society. The total cost of overactive bladder and urgency urinary incontinence in the United States was estimated to be $65.9 billion in 2007 and is projected to reach $82.6 billion in 2020.⁶

THREE TYPES

There are 3 types of urinary incontinence: stress, urgency, and mixed.

Stress urinary incontinence is involuntary loss of urine associated with physical exertion or increased abdominal pressure, eg, with coughing or sneezing.

Urgency urinary incontinence is involuntary loss of urine associated with the sudden need to void. Many patients experience these symptoms simultaneously, making the distinction difficult.

Mixed urinary incontinence is loss of urine with both urgency and increased abdominal pressure or physical exertion.

Overactive bladder, a related problem, is defined as urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence, in the absence of a urinary tract infection or other obvious disease.⁷

Nongenitourinary causes such as neurologic disorders or even malignancy can present with urinary incontinence, and thus it is critical to perform a thorough initial evaluation.

A 2014 study revealed that by age 80, 20% of women may need to undergo surgery for stress urinary incontinence or pelvic organ prolapse. This statistic should motivate healthcare providers to focus on prevention and offer conservative medical management for these conditions first.⁸

QUESTIONS TO ASK

When doing a pelvic examination, once could inquire about urinary incontinence with questions such as:

Do you leak urine when you cough, sneeze, laugh, or jump or during sexual climax?

Do you have to get up more than once at night to urinate?

Do you feel the urge to urinate frequently?

BEHAVIORAL MODIFICATION AND BLADDER TRAINING

Bladder training is a conservative behavioral treatment for urinary incontinence that primary care physicians can teach. It is primarily used for urgency urinary incontinence but can also be useful in stress urinary incontinence.

After completing a bladder diary and gaining awareness of their daily voiding patterns, patients can learn scheduled voiding to train the bladder, gradually extending the urges to longer intervals.

Clinicians should instruct patients on how to train the bladder, using methods first described by Wyman and Fantl.⁹ (See Training the bladder.)

There is evidence that bladder training improves urinary incontinence compared with usual care.^10,11

The ACP recommends bladder training for women who have urgency urinary incontinence, but grades this recommendation as weak with low-quality evidence.

PELVIC FLOOR MUSCLE TRAINING

Introduced in 1948 by Dr. Arnold Kegel, pelvic floor muscle training has become widely adopted.¹²

The pelvic floor consists of a group of muscles, resembling a hammock, that support the pelvic viscera. These muscles include the coccygeus and the layers of the levator ani (Figure 1). A weak pelvic floor is one of many risk factors for developing stress urinary incontinence. Like other muscle groups, a weak pelvic floor can be rehabilitated through various techniques, often guided by a physical therapist.

Compared with those who received no treatment, women with stress urinary incontinence who performed pelvic floor muscle training were 8 times more likely to report being cured and 17 times more likely to report cure or improvement.¹³

To perform a Kegel exercise, a woman consciously contracts her pelvic floor muscles as if stopping the flow of urine.

The Knack maneuver can be used to prevent leakage during anticipated events that increase intra-abdominal pressure. For example, when a cough or sneeze is imminent, patients can preemptively contract their pelvic floor and hold the contraction through the cough or sneeze.

Although many protocols have been compared, no specific pelvic floor exercise strategy has proven superior. A systematic review assessed variations in pelvic floor interventions, exercises, and delivery and found that there was insufficient evidence to make any recommendations about the best approach. However, the benefit was greater with regular supervision during pelvic floor muscle training than with little or no supervision.¹⁴

Pelvic floor muscle training strengthens the pelvic floor, which better supports the bladder neck and anatomically compensates for defects in stress urinary incontinence. In urgency urinary incontinence, a strong pelvic floor created by muscle training prevents leaking induced by the involuntary contractions of the detrusor muscle.

Recommendation

The ACP recommends pelvic floor muscle training as first-line treatment for stress urinary incontinence and mixed urinary incontinence, and grades this recommendation as strong with high-quality evidence.

BIOFEEDBACK AND PELVIC STIMULATION

Although pelvic floor exercises are effective in urinary incontinence, 30% of patients perform them incorrectly.¹⁵

Biofeedback therapy uses visual, verbal, and acoustic signals to give the patient immediate feedback and a greater awareness of her muscular activity. A commonly used technique employs a vaginal probe to measure and display pressure changes as the patient contracts her levator ani muscles.

Women who received biofeedback in addition to traditional pelvic floor physical therapy had greater improvement in urinary incontinence than those who received pelvic physical therapy alone (risk ratio 0.75, 95% confidence interval 0.66–0.86).¹⁶

Pelvic stimulation can be used separately or in conjunction with biofeedback in both urgency and stress urinary incontinence. When pelvic stimulation is used alone, 9 women need to be treated to achieve continence in 1, and 6 women need to be treated to improve continence in 1.¹⁶ 

Traditionally delivered by a pelvic floor physical therapist, pelvic stimulation and biofeedback have also been validated for home use.^17,18 Several pelvic stimulation devices have been approved by the US Food and Drug Administration (FDA) for treating stress, urgency, and mixed urinary incontinence. These devices deliver stimulation to the pelvic floor at single or multiple frequencies. Although the mechanisms are not clearly understood, lower frequencies are used to treat urgency incontinence, while higher frequencies are used for stress incontinence. A theory is that higher-frequency stimulation strengthens the pelvic floor in stress urinary incontinence while lower frequency stimulation calms the detrusor muscle in urgency urinary incontinence.

The Apex and Apex M devices are both available over the counter, the former to treat stress urinary incontinence and the latter to treat mixed urinary incontinence, using pelvic stimulation alone. Other available devices, including the InTone and a smaller version, the InTone MV, are available by prescription and combine pelvic stimulation with biofeedback.¹⁸

Women who wish to avoid surgery, botulinum toxin injections, and daily oral medications, particularly those who are highly motivated, are ideal candidates for these over-the-counter automatic neuromuscular pelvic exercising devices.

PESSARIES AND OTHER DEVICES

Pessaries are commonly used to treat pelvic organ prolapse but can also be designed to help correct the anatomic defect responsible for stress urinary incontinence. Continence pessaries support the bladder neck so that the urethrovesicular junction is stabilized rather than hypermobile during the increased intra-abdominal pressure that occurs with coughing, sneezing, or physical exertion (Figure 2). In theory, this should decrease leakage.

A systematic review concluded that the value of pessaries in the management of incontinence remains uncertain. However, there are inherent challenges in conducting trials of such devices.¹⁹ A pessary needs to be fitted by an appropriately trained healthcare provider. The Ambulatory Treatments for Leakage Associated With Stress Incontinence (ATLAS) trial²⁰ reported that behavioral therapy was more effective than a pessary at 3 months, but the treatments were equivalent at 12 months.

The FDA has approved a disposable, over-the-counter silicone intravaginal device for treating stress urinary incontinence. Patients initially purchase a sizing kit and subsequently insert the nonabsorbent temporary intravaginal bladder supportive device, which is worn for up to 8 hours.

Women may elect to use regular tampons to do the job of a pessary, as they are easy to use and low in cost. No large randomized trials have compared tampons and pessaries, and currently no one device is known to be superior to another.

Overall, these devices are temporizing measures that have few serious adverse effects.

WEIGHT LOSS AND DIETARY CHANGES

Obesity has become a national epidemic, with more than 68% of Americans found to be overweight or obese according to the National Institutes of Health.²¹

Several studies found obesity to be an independent risk factor for urinary incontinence. As early as 1946, the British Birth Cohort study found that women ages 48 through 54 who were obese earlier in life had a higher risk of urinary incontinence in middle age, and those who were obese by age 20 were more likely to report severe incontinence.²² Likewise, the Nurses’ Health Study showed that women with a body mass index (BMI) more than 30 kg/m² had 3.1 times the risk of severe incontinence compared with women with a normal BMI. Also, the Study of Women’s Health Across the Nation and the Leicestershire Medical Research Council (MRC) incontinence study both showed that a higher BMI and weight gain are strongly correlated with urinary incontinence.^23,24

Increased intra-abdominal pressure may be the causative mechanism of stress urinary incontinence in obesity. The Korean National Health and Nutrition Examination Survey showed that central adiposity correlated with urgency incontinence.^25,26

The MRC study was one of the largest to evaluate the effect of diet on urinary symptoms. Consuming a diet dense in vegetables, bread, and chicken was found to reduce the risk of urinary incontinence, while carbonated drinks were associated with a higher risk.²⁵ These studies and others may point to reducing calories, and thus BMI, as a conservative treatment for urinary incontinence.

Newer data show bariatric surgery is associated with a strong reduction in urinary incontinence, demonstrated in a study that followed patients for 3 years after surgery.²⁷ This encouraging result is but one of several positive health outcomes from bariatric surgery.

Recommendation

The ACP recommends both weight loss and exercise for overweight women with urinary incontinence, and grades this as strong with moderate-quality evidence.

DRUG THERAPY

The bladder neck is rich with sympathetic alpha-adrenergic receptors, and the bladder dome is dense with parasympathetic muscarinic receptors and sympathetic beta-adrenergic receptors. When the parasympathetic system is stimulated, the muscarinic receptors are activated, causing detrusor contraction and ultimately bladder emptying.

Agonism of beta-alpha adrenergic receptors and inhibition of parasympathetic receptors are both strategies of drug treatment of urinary incontinence.

Anticholinergic drugs

Anticholinergic medications function by blocking the muscarinic receptor, thereby inhibiting detrusor contraction.

Six oral anticholinergic medications are available: oxybutynin, tolterodine, fesoterodine, solifenacin, trospium, and darifenacin. These drugs have about the same effectiveness in treating urgency urinary incontinence, as measured by achieving continence and improving quality of life.²⁸ Given their similarity in effectiveness, the choice of agent typically relies on the side-effect profile. Extended-release formulations have a more favorable side-effect profile, with fewer cases of dry mouth compared with immediate-release formulations.²⁹

Overall, however, the benefit of these medications is small, with fewer than 200 patients achieving continence per 1,000 treated.²⁸

Other limitations of these medications include their adverse effects and contraindications, and patients’ poor adherence to therapy. The most commonly reported adverse effect is dry mouth, but other common side effects include constipation, abdominal pain, dyspepsia, fatigue, dry eye, and dry skin. Transdermal oxybutynin therapy has been associated with fewer anticholinergic side effects than oral therapy.³⁰

Contraindications to these medications include gastric retention, urinary retention, and angle-closure glaucoma.

Long-term adherence to anticholinergics is low, reported between 14% to 35% after 12 months, with the highest rates of adherence with solifenacin.³¹ The most commonly cited reason for discontinuation is lack of effect.³²

Caution is urged when considering starting anticholinergic medications in older adults because of the central nervous system side effects, including drowsiness, hallucinations, cognitive impairment, and dementia. After 3 weeks, oxybutynin caused a memory decline as measured by delayed recall that was comparable to the decline seen over 10 years in normal aging.³³ There is evidence suggesting trospium may cause less cognitive impairment, and therefore may be a better option for older patients.³⁴

Beta-3 adrenoreceptor agonists

Activation of beta-3 adrenergic receptors through the sympathetic nervous system relaxes the detrusor muscle, allowing the bladder to store urine.

Mirabegron is a selective beta-3 adrenoreceptor agonist that effectively relaxes the bladder and increases bladder capacity. It improves continence, treatment satisfaction, and quality of life.^35,36 There are fewer reports of dry mouth and constipation with this drug than with the anticholinergics; however, beta-3 adrenoreceptor agonists may be associated with greater risk of hypertension, nasopharyngitis, headache, and urinary tract infection.³⁷

Duloxetine

Duloxetine, an antidepressant, blocks the reuptake of both serotonin and norepinephrine. Consequently, it decreases parasympathetic activity and increases sympathetic and somatic activity in the urinary system.³⁸ While urine is stored, this cascade of neural activity is thought to collectively increase pudendal nerve activity and improve closure of the urethra.

Although duloxetine is approved to treat stress urinary incontinence in Europe, this is an off-label use in the United States.

A meta-analysis³⁹ found that duloxetine improved quality of life in patients with stress urinary incontinence and that subjective cure rates were 10.8% with duloxetine vs 7.7% with placebo (P = .04). However the rate of adverse events is high, with nausea most common. Given its modest benefit and high rate of side effects, physicians may consider starting duloxetine only if there are psychiatric comorbidities such as depression, anxiety, or fibromyalgia.

Recommendations

The ACP recommends against systemic pharmacologic therapy for stress urinary incontinence. For urgency urinary incontinence, pharmacologic therapy is recommended if bladder training fails, and should be individualized based on the patient’s preference and medical comorbidities and the drug’s tolerability, cost, and ease of use.

Hormone therapy

In 2014, the North American Menopause Society recommended replacing the term “vulvovaginal atrophy” with the term genitourinary syndrome of menopause, which better encompasses the postmenopausal changes to the female genital system.⁴⁰

Estrogen therapy is commercially available in both systemic and local preparations. The effect of exogenous estrogen on urinary incontinence may depend on whether it is given locally or systemically.

A systematic review⁴¹ definitively concluded that all commercially prepared local vaginal estrogen preparations can effectively relieve the genitourinary syndrome of menopause, including not only the common complaints of dryness, burning, and irritation but also urinary complaints of frequency, urgency, and urgency urinary incontinence.⁴¹ Additionally, the estradiol vaginal ring for vaginal atrophy (Estring) may have dual effects, functioning like an incontinence pessary by supporting the bladder neck while simultaneously providing local estrogen to the atrophied vaginal tissue.

However, in the Women’s Health Initiative,⁴² continent women who received either systemic estrogen therapy alone or systemic estrogen combined with progestin actually had a higher risk of developing urinary incontinence, and those already experiencing incontinence developed a worsening of their symptoms on systemic hormone therapy. The mechanism by which systemic hormone therapy causes urinary incontinence is unclear; however, previous studies showed that hormone therapy leads to a reduction in periurethral collagen and increased bladder contractility.^43,44

TAKE-HOME POINTS

• Half of women with symptomatic urinary incontinence never report their symptoms.
• Bladder training is recommended for urgency incontinence and pelvic floor muscle training for stress incontinence.
• Thirty percent of women perform pelvic floor exercises incorrectly.
• Devices can be considered, including automatic pelvic exercise devices for stress and urgency incontinence and incontinence pessaries and disposable intravaginal bladder support devices for stress incontinence.
• Higher BMIs are strongly correlated with urinary incontinence.
• Anticholinergic medications are recommended for urgency but not stress incontinence.
• Vaginal estrogen cream may help with symptoms of urinary urgency, recurrent bladder infections, and nocturia in addition to incontinence.

Urinary incontinence can lead to a cascade of symptomatic burden on the patient, causing distress, embarrassment, and suffering.

See related patient information

Traditionally, incontinence has been treated by surgeons, and surgery remains an option. However, more patients are now being managed by medical clinicians, who can offer a number of newer therapies. Ideally, a medical physician can initiate the evaluation and treatment and even effectively cure some forms of urinary incontinence.

In 2014, the American College of Physicians (ACP) published recommendations on the medical treatment of urinary incontinence in women (Table 1).¹

This review describes the medical management of urinary incontinence in women, emphasizing the ACP recommendations¹ and newer over-the-counter options.

COMMON AND UNDERREPORTED

Many women erroneously believe that urinary incontinence is an inevitable consequence of aging and allow it to lessen their quality of life without seeking medical attention.

Indeed, it is common. The 2005–2006 National Health and Nutritional Examination Survey² found the prevalence of urinary incontinence in US women to be 15.7%. The prevalence increases with age from 6.9% in women ages 20 through 29 to 31.7% in those age 80 and older. A separate analysis of the same data found that 25.0% of women age 20 and older had 1 or more pelvic floor disorders.³ Some estimates are even higher. Wu et al⁴ reported a prevalence of urinary incontinence of 51.1% in women ages 31 through 54.

Too few of these women are identified and treated, for many reasons, including embarrassment and inadequate screening. Half of women with urinary incontinence do not report their symptoms because of humiliation or anxiety.⁵

The burden of urinary incontinence extends beyond the individual and into society. The total cost of overactive bladder and urgency urinary incontinence in the United States was estimated to be $65.9 billion in 2007 and is projected to reach $82.6 billion in 2020.⁶

THREE TYPES

There are 3 types of urinary incontinence: stress, urgency, and mixed.

Stress urinary incontinence is involuntary loss of urine associated with physical exertion or increased abdominal pressure, eg, with coughing or sneezing.

Urgency urinary incontinence is involuntary loss of urine associated with the sudden need to void. Many patients experience these symptoms simultaneously, making the distinction difficult.

Mixed urinary incontinence is loss of urine with both urgency and increased abdominal pressure or physical exertion.

Overactive bladder, a related problem, is defined as urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence, in the absence of a urinary tract infection or other obvious disease.⁷

Nongenitourinary causes such as neurologic disorders or even malignancy can present with urinary incontinence, and thus it is critical to perform a thorough initial evaluation.

A 2014 study revealed that by age 80, 20% of women may need to undergo surgery for stress urinary incontinence or pelvic organ prolapse. This statistic should motivate healthcare providers to focus on prevention and offer conservative medical management for these conditions first.⁸

QUESTIONS TO ASK

When doing a pelvic examination, once could inquire about urinary incontinence with questions such as:

Do you leak urine when you cough, sneeze, laugh, or jump or during sexual climax?

Do you have to get up more than once at night to urinate?

Do you feel the urge to urinate frequently?

BEHAVIORAL MODIFICATION AND BLADDER TRAINING

Bladder training is a conservative behavioral treatment for urinary incontinence that primary care physicians can teach. It is primarily used for urgency urinary incontinence but can also be useful in stress urinary incontinence.

After completing a bladder diary and gaining awareness of their daily voiding patterns, patients can learn scheduled voiding to train the bladder, gradually extending the urges to longer intervals.

Clinicians should instruct patients on how to train the bladder, using methods first described by Wyman and Fantl.⁹ (See Training the bladder.)

There is evidence that bladder training improves urinary incontinence compared with usual care.^10,11

The ACP recommends bladder training for women who have urgency urinary incontinence, but grades this recommendation as weak with low-quality evidence.

PELVIC FLOOR MUSCLE TRAINING

Introduced in 1948 by Dr. Arnold Kegel, pelvic floor muscle training has become widely adopted.¹²

The pelvic floor consists of a group of muscles, resembling a hammock, that support the pelvic viscera. These muscles include the coccygeus and the layers of the levator ani (Figure 1). A weak pelvic floor is one of many risk factors for developing stress urinary incontinence. Like other muscle groups, a weak pelvic floor can be rehabilitated through various techniques, often guided by a physical therapist.

Compared with those who received no treatment, women with stress urinary incontinence who performed pelvic floor muscle training were 8 times more likely to report being cured and 17 times more likely to report cure or improvement.¹³

To perform a Kegel exercise, a woman consciously contracts her pelvic floor muscles as if stopping the flow of urine.

The Knack maneuver can be used to prevent leakage during anticipated events that increase intra-abdominal pressure. For example, when a cough or sneeze is imminent, patients can preemptively contract their pelvic floor and hold the contraction through the cough or sneeze.

Although many protocols have been compared, no specific pelvic floor exercise strategy has proven superior. A systematic review assessed variations in pelvic floor interventions, exercises, and delivery and found that there was insufficient evidence to make any recommendations about the best approach. However, the benefit was greater with regular supervision during pelvic floor muscle training than with little or no supervision.¹⁴

Pelvic floor muscle training strengthens the pelvic floor, which better supports the bladder neck and anatomically compensates for defects in stress urinary incontinence. In urgency urinary incontinence, a strong pelvic floor created by muscle training prevents leaking induced by the involuntary contractions of the detrusor muscle.

Recommendation

The ACP recommends pelvic floor muscle training as first-line treatment for stress urinary incontinence and mixed urinary incontinence, and grades this recommendation as strong with high-quality evidence.

BIOFEEDBACK AND PELVIC STIMULATION

Although pelvic floor exercises are effective in urinary incontinence, 30% of patients perform them incorrectly.¹⁵

Biofeedback therapy uses visual, verbal, and acoustic signals to give the patient immediate feedback and a greater awareness of her muscular activity. A commonly used technique employs a vaginal probe to measure and display pressure changes as the patient contracts her levator ani muscles.

Women who received biofeedback in addition to traditional pelvic floor physical therapy had greater improvement in urinary incontinence than those who received pelvic physical therapy alone (risk ratio 0.75, 95% confidence interval 0.66–0.86).¹⁶

Pelvic stimulation can be used separately or in conjunction with biofeedback in both urgency and stress urinary incontinence. When pelvic stimulation is used alone, 9 women need to be treated to achieve continence in 1, and 6 women need to be treated to improve continence in 1.¹⁶ 

Traditionally delivered by a pelvic floor physical therapist, pelvic stimulation and biofeedback have also been validated for home use.^17,18 Several pelvic stimulation devices have been approved by the US Food and Drug Administration (FDA) for treating stress, urgency, and mixed urinary incontinence. These devices deliver stimulation to the pelvic floor at single or multiple frequencies. Although the mechanisms are not clearly understood, lower frequencies are used to treat urgency incontinence, while higher frequencies are used for stress incontinence. A theory is that higher-frequency stimulation strengthens the pelvic floor in stress urinary incontinence while lower frequency stimulation calms the detrusor muscle in urgency urinary incontinence.

The Apex and Apex M devices are both available over the counter, the former to treat stress urinary incontinence and the latter to treat mixed urinary incontinence, using pelvic stimulation alone. Other available devices, including the InTone and a smaller version, the InTone MV, are available by prescription and combine pelvic stimulation with biofeedback.¹⁸

Women who wish to avoid surgery, botulinum toxin injections, and daily oral medications, particularly those who are highly motivated, are ideal candidates for these over-the-counter automatic neuromuscular pelvic exercising devices.

PESSARIES AND OTHER DEVICES

Pessaries are commonly used to treat pelvic organ prolapse but can also be designed to help correct the anatomic defect responsible for stress urinary incontinence. Continence pessaries support the bladder neck so that the urethrovesicular junction is stabilized rather than hypermobile during the increased intra-abdominal pressure that occurs with coughing, sneezing, or physical exertion (Figure 2). In theory, this should decrease leakage.

A systematic review concluded that the value of pessaries in the management of incontinence remains uncertain. However, there are inherent challenges in conducting trials of such devices.¹⁹ A pessary needs to be fitted by an appropriately trained healthcare provider. The Ambulatory Treatments for Leakage Associated With Stress Incontinence (ATLAS) trial²⁰ reported that behavioral therapy was more effective than a pessary at 3 months, but the treatments were equivalent at 12 months.

The FDA has approved a disposable, over-the-counter silicone intravaginal device for treating stress urinary incontinence. Patients initially purchase a sizing kit and subsequently insert the nonabsorbent temporary intravaginal bladder supportive device, which is worn for up to 8 hours.

Women may elect to use regular tampons to do the job of a pessary, as they are easy to use and low in cost. No large randomized trials have compared tampons and pessaries, and currently no one device is known to be superior to another.

Overall, these devices are temporizing measures that have few serious adverse effects.

WEIGHT LOSS AND DIETARY CHANGES

Obesity has become a national epidemic, with more than 68% of Americans found to be overweight or obese according to the National Institutes of Health.²¹

Several studies found obesity to be an independent risk factor for urinary incontinence. As early as 1946, the British Birth Cohort study found that women ages 48 through 54 who were obese earlier in life had a higher risk of urinary incontinence in middle age, and those who were obese by age 20 were more likely to report severe incontinence.²² Likewise, the Nurses’ Health Study showed that women with a body mass index (BMI) more than 30 kg/m² had 3.1 times the risk of severe incontinence compared with women with a normal BMI. Also, the Study of Women’s Health Across the Nation and the Leicestershire Medical Research Council (MRC) incontinence study both showed that a higher BMI and weight gain are strongly correlated with urinary incontinence.^23,24

Increased intra-abdominal pressure may be the causative mechanism of stress urinary incontinence in obesity. The Korean National Health and Nutrition Examination Survey showed that central adiposity correlated with urgency incontinence.^25,26

The MRC study was one of the largest to evaluate the effect of diet on urinary symptoms. Consuming a diet dense in vegetables, bread, and chicken was found to reduce the risk of urinary incontinence, while carbonated drinks were associated with a higher risk.²⁵ These studies and others may point to reducing calories, and thus BMI, as a conservative treatment for urinary incontinence.

Newer data show bariatric surgery is associated with a strong reduction in urinary incontinence, demonstrated in a study that followed patients for 3 years after surgery.²⁷ This encouraging result is but one of several positive health outcomes from bariatric surgery.

Recommendation

The ACP recommends both weight loss and exercise for overweight women with urinary incontinence, and grades this as strong with moderate-quality evidence.

DRUG THERAPY

The bladder neck is rich with sympathetic alpha-adrenergic receptors, and the bladder dome is dense with parasympathetic muscarinic receptors and sympathetic beta-adrenergic receptors. When the parasympathetic system is stimulated, the muscarinic receptors are activated, causing detrusor contraction and ultimately bladder emptying.

Agonism of beta-alpha adrenergic receptors and inhibition of parasympathetic receptors are both strategies of drug treatment of urinary incontinence.

Anticholinergic drugs

Anticholinergic medications function by blocking the muscarinic receptor, thereby inhibiting detrusor contraction.

Six oral anticholinergic medications are available: oxybutynin, tolterodine, fesoterodine, solifenacin, trospium, and darifenacin. These drugs have about the same effectiveness in treating urgency urinary incontinence, as measured by achieving continence and improving quality of life.²⁸ Given their similarity in effectiveness, the choice of agent typically relies on the side-effect profile. Extended-release formulations have a more favorable side-effect profile, with fewer cases of dry mouth compared with immediate-release formulations.²⁹

Overall, however, the benefit of these medications is small, with fewer than 200 patients achieving continence per 1,000 treated.²⁸

Other limitations of these medications include their adverse effects and contraindications, and patients’ poor adherence to therapy. The most commonly reported adverse effect is dry mouth, but other common side effects include constipation, abdominal pain, dyspepsia, fatigue, dry eye, and dry skin. Transdermal oxybutynin therapy has been associated with fewer anticholinergic side effects than oral therapy.³⁰

Contraindications to these medications include gastric retention, urinary retention, and angle-closure glaucoma.

Long-term adherence to anticholinergics is low, reported between 14% to 35% after 12 months, with the highest rates of adherence with solifenacin.³¹ The most commonly cited reason for discontinuation is lack of effect.³²

Caution is urged when considering starting anticholinergic medications in older adults because of the central nervous system side effects, including drowsiness, hallucinations, cognitive impairment, and dementia. After 3 weeks, oxybutynin caused a memory decline as measured by delayed recall that was comparable to the decline seen over 10 years in normal aging.³³ There is evidence suggesting trospium may cause less cognitive impairment, and therefore may be a better option for older patients.³⁴

Beta-3 adrenoreceptor agonists

Activation of beta-3 adrenergic receptors through the sympathetic nervous system relaxes the detrusor muscle, allowing the bladder to store urine.

Mirabegron is a selective beta-3 adrenoreceptor agonist that effectively relaxes the bladder and increases bladder capacity. It improves continence, treatment satisfaction, and quality of life.^35,36 There are fewer reports of dry mouth and constipation with this drug than with the anticholinergics; however, beta-3 adrenoreceptor agonists may be associated with greater risk of hypertension, nasopharyngitis, headache, and urinary tract infection.³⁷

Duloxetine

Duloxetine, an antidepressant, blocks the reuptake of both serotonin and norepinephrine. Consequently, it decreases parasympathetic activity and increases sympathetic and somatic activity in the urinary system.³⁸ While urine is stored, this cascade of neural activity is thought to collectively increase pudendal nerve activity and improve closure of the urethra.

Although duloxetine is approved to treat stress urinary incontinence in Europe, this is an off-label use in the United States.

A meta-analysis³⁹ found that duloxetine improved quality of life in patients with stress urinary incontinence and that subjective cure rates were 10.8% with duloxetine vs 7.7% with placebo (P = .04). However the rate of adverse events is high, with nausea most common. Given its modest benefit and high rate of side effects, physicians may consider starting duloxetine only if there are psychiatric comorbidities such as depression, anxiety, or fibromyalgia.

Recommendations

The ACP recommends against systemic pharmacologic therapy for stress urinary incontinence. For urgency urinary incontinence, pharmacologic therapy is recommended if bladder training fails, and should be individualized based on the patient’s preference and medical comorbidities and the drug’s tolerability, cost, and ease of use.

Hormone therapy

In 2014, the North American Menopause Society recommended replacing the term “vulvovaginal atrophy” with the term genitourinary syndrome of menopause, which better encompasses the postmenopausal changes to the female genital system.⁴⁰

Estrogen therapy is commercially available in both systemic and local preparations. The effect of exogenous estrogen on urinary incontinence may depend on whether it is given locally or systemically.

A systematic review⁴¹ definitively concluded that all commercially prepared local vaginal estrogen preparations can effectively relieve the genitourinary syndrome of menopause, including not only the common complaints of dryness, burning, and irritation but also urinary complaints of frequency, urgency, and urgency urinary incontinence.⁴¹ Additionally, the estradiol vaginal ring for vaginal atrophy (Estring) may have dual effects, functioning like an incontinence pessary by supporting the bladder neck while simultaneously providing local estrogen to the atrophied vaginal tissue.

However, in the Women’s Health Initiative,⁴² continent women who received either systemic estrogen therapy alone or systemic estrogen combined with progestin actually had a higher risk of developing urinary incontinence, and those already experiencing incontinence developed a worsening of their symptoms on systemic hormone therapy. The mechanism by which systemic hormone therapy causes urinary incontinence is unclear; however, previous studies showed that hormone therapy leads to a reduction in periurethral collagen and increased bladder contractility.^43,44

TAKE-HOME POINTS

• Half of women with symptomatic urinary incontinence never report their symptoms.
• Bladder training is recommended for urgency incontinence and pelvic floor muscle training for stress incontinence.
• Thirty percent of women perform pelvic floor exercises incorrectly.
• Devices can be considered, including automatic pelvic exercise devices for stress and urgency incontinence and incontinence pessaries and disposable intravaginal bladder support devices for stress incontinence.
• Higher BMIs are strongly correlated with urinary incontinence.
• Anticholinergic medications are recommended for urgency but not stress incontinence.
• Vaginal estrogen cream may help with symptoms of urinary urgency, recurrent bladder infections, and nocturia in addition to incontinence.

To the Editor: I enjoyed Dr. Galicia-Castillo’s article about long-term opioid therapy in older adults,¹ which reaffirmed the imperative to “start low and go slow” to minimize the risk of addiction. However, the article missed an opportunity to raise awareness regarding another extremely important side effect of chronic prescription opioid consumption, that of ingestion prior to sleep, with consequent cessation of breathing leading to death.

According to the Drug Enforcement Administration,² most narcotic deaths are a result of respiratory depression. And the American Pain Society has stated, “No patient has succumbed to [opioid] respiratory depression while awake.”³

Dr. Galicia-Castillo noted that the prevalence of central sleep apnea in chronic opioid users is 24%, based on a review by Correa et al.⁴ As alarming as this number is, other investigators have estimated it to be even higher—as high as 50% to 90%.⁵

Walker et al,⁶ in a study of 60 patients, found that the higher the opioid dose the patients were on, the more episodes of obstructive sleep apnea and central sleep apnea per hour they had. Yet prescribing a low dose does not adequately protect the chronic opioid user. Farney et al⁷ reported that oxygen saturation dropped precipitously—from 98% to 70%—15 minutes after a patient took just 7.5 mg of hydrocodone in the middle of the night. Mogri et al⁸ reported that a patient had 91 apnea events within 1 hour of taking 15 mg of oxycodone at 2 am.

Opioids, benzodiazepines, barbiturates, and ethanol individually and additively suppress medullary reflex ventilatory drive during sleep, especially during non–rapid-eye-movement (non-REM) sleep.⁶ During waking hours, in contrast, there is redundant backup of cerebral cortical drive, ensuring that we keep breathing. Therefore, people are most vulnerable to dying of opioid ingestion during sleep.

Moreover, oxygen desaturation during episodes of sleep apnea may precipitate seizures (which may be lethal) or coronary vasospasm with consequent malignant arrhythmias and myocardial ischemia.

Continuous positive airway pressure protects against obstructive sleep apnea, but not against central sleep apnea.⁹

Patients need to be aware of the danger, and physicians need to consider the pharmacokinetic profiles of the opioid preparations they prescribe. If patients are taking an opioid that has a short half-life, such as immediate-release oxycodone, they should not take it within 5 hours of sleep. Longer-lasting preparations need a longer interval, and some, such as extended-release tramadol, may need to be taken only on awakening.

Safe sleep can be facilitated by medications that are sedating but do not compromise ventilation. Optimal agents also enhance restorative REM and stage III and IV deep-sleep duration, and some may have the additional benefit of reducing the risk of cancer.^10,11 Such agents may include baclofen, cyproheptadine, gabapentin, mirtazepine, and melatonin. Nonpharmacologic measures include sleep hygiene, aerobic exercise, and cognitive behavioral therapy.

A retrospective study¹² found that 301 (60.4%) of 498 patients who died while on opioid therapy and whose death was judged to be related to the opioid were also taking benzodiazepines. Patients who take opioids should avoid taking benzodiazepines, barbiturates, or alcohol before going to sleep, and physicians should be extremely cautious about prescribing benzodiazepines and barbiturates to patients who are on opioids. 

To the Editor: I enjoyed Dr. Galicia-Castillo’s article about long-term opioid therapy in older adults,¹ which reaffirmed the imperative to “start low and go slow” to minimize the risk of addiction. However, the article missed an opportunity to raise awareness regarding another extremely important side effect of chronic prescription opioid consumption, that of ingestion prior to sleep, with consequent cessation of breathing leading to death.

According to the Drug Enforcement Administration,² most narcotic deaths are a result of respiratory depression. And the American Pain Society has stated, “No patient has succumbed to [opioid] respiratory depression while awake.”³

Dr. Galicia-Castillo noted that the prevalence of central sleep apnea in chronic opioid users is 24%, based on a review by Correa et al.⁴ As alarming as this number is, other investigators have estimated it to be even higher—as high as 50% to 90%.⁵

Walker et al,⁶ in a study of 60 patients, found that the higher the opioid dose the patients were on, the more episodes of obstructive sleep apnea and central sleep apnea per hour they had. Yet prescribing a low dose does not adequately protect the chronic opioid user. Farney et al⁷ reported that oxygen saturation dropped precipitously—from 98% to 70%—15 minutes after a patient took just 7.5 mg of hydrocodone in the middle of the night. Mogri et al⁸ reported that a patient had 91 apnea events within 1 hour of taking 15 mg of oxycodone at 2 am.

Opioids, benzodiazepines, barbiturates, and ethanol individually and additively suppress medullary reflex ventilatory drive during sleep, especially during non–rapid-eye-movement (non-REM) sleep.⁶ During waking hours, in contrast, there is redundant backup of cerebral cortical drive, ensuring that we keep breathing. Therefore, people are most vulnerable to dying of opioid ingestion during sleep.

Moreover, oxygen desaturation during episodes of sleep apnea may precipitate seizures (which may be lethal) or coronary vasospasm with consequent malignant arrhythmias and myocardial ischemia.

Continuous positive airway pressure protects against obstructive sleep apnea, but not against central sleep apnea.⁹

Patients need to be aware of the danger, and physicians need to consider the pharmacokinetic profiles of the opioid preparations they prescribe. If patients are taking an opioid that has a short half-life, such as immediate-release oxycodone, they should not take it within 5 hours of sleep. Longer-lasting preparations need a longer interval, and some, such as extended-release tramadol, may need to be taken only on awakening.

Safe sleep can be facilitated by medications that are sedating but do not compromise ventilation. Optimal agents also enhance restorative REM and stage III and IV deep-sleep duration, and some may have the additional benefit of reducing the risk of cancer.^10,11 Such agents may include baclofen, cyproheptadine, gabapentin, mirtazepine, and melatonin. Nonpharmacologic measures include sleep hygiene, aerobic exercise, and cognitive behavioral therapy.

A retrospective study¹² found that 301 (60.4%) of 498 patients who died while on opioid therapy and whose death was judged to be related to the opioid were also taking benzodiazepines. Patients who take opioids should avoid taking benzodiazepines, barbiturates, or alcohol before going to sleep, and physicians should be extremely cautious about prescribing benzodiazepines and barbiturates to patients who are on opioids. 

To the Editor: I enjoyed Dr. Galicia-Castillo’s article about long-term opioid therapy in older adults,¹ which reaffirmed the imperative to “start low and go slow” to minimize the risk of addiction. However, the article missed an opportunity to raise awareness regarding another extremely important side effect of chronic prescription opioid consumption, that of ingestion prior to sleep, with consequent cessation of breathing leading to death.

According to the Drug Enforcement Administration,² most narcotic deaths are a result of respiratory depression. And the American Pain Society has stated, “No patient has succumbed to [opioid] respiratory depression while awake.”³

Dr. Galicia-Castillo noted that the prevalence of central sleep apnea in chronic opioid users is 24%, based on a review by Correa et al.⁴ As alarming as this number is, other investigators have estimated it to be even higher—as high as 50% to 90%.⁵

Walker et al,⁶ in a study of 60 patients, found that the higher the opioid dose the patients were on, the more episodes of obstructive sleep apnea and central sleep apnea per hour they had. Yet prescribing a low dose does not adequately protect the chronic opioid user. Farney et al⁷ reported that oxygen saturation dropped precipitously—from 98% to 70%—15 minutes after a patient took just 7.5 mg of hydrocodone in the middle of the night. Mogri et al⁸ reported that a patient had 91 apnea events within 1 hour of taking 15 mg of oxycodone at 2 am.

Opioids, benzodiazepines, barbiturates, and ethanol individually and additively suppress medullary reflex ventilatory drive during sleep, especially during non–rapid-eye-movement (non-REM) sleep.⁶ During waking hours, in contrast, there is redundant backup of cerebral cortical drive, ensuring that we keep breathing. Therefore, people are most vulnerable to dying of opioid ingestion during sleep.

Moreover, oxygen desaturation during episodes of sleep apnea may precipitate seizures (which may be lethal) or coronary vasospasm with consequent malignant arrhythmias and myocardial ischemia.

Continuous positive airway pressure protects against obstructive sleep apnea, but not against central sleep apnea.⁹

Patients need to be aware of the danger, and physicians need to consider the pharmacokinetic profiles of the opioid preparations they prescribe. If patients are taking an opioid that has a short half-life, such as immediate-release oxycodone, they should not take it within 5 hours of sleep. Longer-lasting preparations need a longer interval, and some, such as extended-release tramadol, may need to be taken only on awakening.

Safe sleep can be facilitated by medications that are sedating but do not compromise ventilation. Optimal agents also enhance restorative REM and stage III and IV deep-sleep duration, and some may have the additional benefit of reducing the risk of cancer.^10,11 Such agents may include baclofen, cyproheptadine, gabapentin, mirtazepine, and melatonin. Nonpharmacologic measures include sleep hygiene, aerobic exercise, and cognitive behavioral therapy.

A retrospective study¹² found that 301 (60.4%) of 498 patients who died while on opioid therapy and whose death was judged to be related to the opioid were also taking benzodiazepines. Patients who take opioids should avoid taking benzodiazepines, barbiturates, or alcohol before going to sleep, and physicians should be extremely cautious about prescribing benzodiazepines and barbiturates to patients who are on opioids. 

In Reply: Dr. Geller makes some excellent points about sleep and opioid use.

Opioids pose risks,¹ just like any other type of medication. In particular, opioids have been linked to sleep-disordered breathing, which affects 70% to 85% of patients taking opioids.^2–4

Other options can be used in some older adults, but they are not always successful. Ideally, nonpharmacologic strategies and nonopioid medications such as acetaminophen, nonsteroidal anti-inflammatory agents, antidepressants, and anticonvulsants should be used, although these medications have their own side effects. Optimum pain control may offer the potential for significant improvement in function, and opioids are but one tool in the clinician’s kit.

Ongoing discussions of the risks and benefits are necessary, along with continuous re-evaluation of the need for and effect of opioids.

In Reply: Dr. Geller makes some excellent points about sleep and opioid use.

Opioids pose risks,¹ just like any other type of medication. In particular, opioids have been linked to sleep-disordered breathing, which affects 70% to 85% of patients taking opioids.^2–4

Other options can be used in some older adults, but they are not always successful. Ideally, nonpharmacologic strategies and nonopioid medications such as acetaminophen, nonsteroidal anti-inflammatory agents, antidepressants, and anticonvulsants should be used, although these medications have their own side effects. Optimum pain control may offer the potential for significant improvement in function, and opioids are but one tool in the clinician’s kit.

Ongoing discussions of the risks and benefits are necessary, along with continuous re-evaluation of the need for and effect of opioids.

In Reply: Dr. Geller makes some excellent points about sleep and opioid use.

Opioids pose risks,¹ just like any other type of medication. In particular, opioids have been linked to sleep-disordered breathing, which affects 70% to 85% of patients taking opioids.^2–4

Other options can be used in some older adults, but they are not always successful. Ideally, nonpharmacologic strategies and nonopioid medications such as acetaminophen, nonsteroidal anti-inflammatory agents, antidepressants, and anticonvulsants should be used, although these medications have their own side effects. Optimum pain control may offer the potential for significant improvement in function, and opioids are but one tool in the clinician’s kit.

Ongoing discussions of the risks and benefits are necessary, along with continuous re-evaluation of the need for and effect of opioids.

To the Editor: I read with interest the review on submassive pulmonary embolism by Ataya et al¹ in the December 2016 issue. I had 3 questions or observations for the authors

First, systemic thrombolytic therapy for massive or hemodynamically unstable pulmonary embolism is given a grade 2C recommendation, similar to the level for select patients with submassive pulmonary embolism with low bleeding risk but at high risk of developing hypotension. The reference for this is the 2012 American College of Chest Physicians guidelines.² I would like to point out that these guidelines were updated and published in February 2016,³ and systemic thrombolytic therapy for massive pulmonary embolism now carries a grade 2B recommendation. Thrombolytic therapy still has a grade 2C recommendation for select patients with submassive pulmonary embolism.

Second, the Moderate Pulmonary Embolism Treated With Thrombolysis (MOPETT) trial is described as a randomized trial in patients with moderate pulmonary hypertension and right ventricular dysfunction. I would like to point out that right ventricular dysfunction was not a criterion for enrollment in the trial.⁴

Finally, catheter-directed thrombolytic therapy is mentioned as an option for select patients with submassive and massive pulmonary embolism. The advantage is believed to be due to local action of the drug with fewer systemic effects. Since the protocol involves alteplase for 12 or 24 hours with a maximum dose of 24 mg, and since in most cases pulmonary embolism originates in the lower extremity, are we not exposing these patients to further clot propagation for 12 or 24 hours without the benefit of concomitant systemic anticoagulation or an inferior vena cava filter?

To the Editor: I read with interest the review on submassive pulmonary embolism by Ataya et al¹ in the December 2016 issue. I had 3 questions or observations for the authors

First, systemic thrombolytic therapy for massive or hemodynamically unstable pulmonary embolism is given a grade 2C recommendation, similar to the level for select patients with submassive pulmonary embolism with low bleeding risk but at high risk of developing hypotension. The reference for this is the 2012 American College of Chest Physicians guidelines.² I would like to point out that these guidelines were updated and published in February 2016,³ and systemic thrombolytic therapy for massive pulmonary embolism now carries a grade 2B recommendation. Thrombolytic therapy still has a grade 2C recommendation for select patients with submassive pulmonary embolism.

Second, the Moderate Pulmonary Embolism Treated With Thrombolysis (MOPETT) trial is described as a randomized trial in patients with moderate pulmonary hypertension and right ventricular dysfunction. I would like to point out that right ventricular dysfunction was not a criterion for enrollment in the trial.⁴

Finally, catheter-directed thrombolytic therapy is mentioned as an option for select patients with submassive and massive pulmonary embolism. The advantage is believed to be due to local action of the drug with fewer systemic effects. Since the protocol involves alteplase for 12 or 24 hours with a maximum dose of 24 mg, and since in most cases pulmonary embolism originates in the lower extremity, are we not exposing these patients to further clot propagation for 12 or 24 hours without the benefit of concomitant systemic anticoagulation or an inferior vena cava filter?

To the Editor: I read with interest the review on submassive pulmonary embolism by Ataya et al¹ in the December 2016 issue. I had 3 questions or observations for the authors

First, systemic thrombolytic therapy for massive or hemodynamically unstable pulmonary embolism is given a grade 2C recommendation, similar to the level for select patients with submassive pulmonary embolism with low bleeding risk but at high risk of developing hypotension. The reference for this is the 2012 American College of Chest Physicians guidelines.² I would like to point out that these guidelines were updated and published in February 2016,³ and systemic thrombolytic therapy for massive pulmonary embolism now carries a grade 2B recommendation. Thrombolytic therapy still has a grade 2C recommendation for select patients with submassive pulmonary embolism.

Second, the Moderate Pulmonary Embolism Treated With Thrombolysis (MOPETT) trial is described as a randomized trial in patients with moderate pulmonary hypertension and right ventricular dysfunction. I would like to point out that right ventricular dysfunction was not a criterion for enrollment in the trial.⁴

Finally, catheter-directed thrombolytic therapy is mentioned as an option for select patients with submassive and massive pulmonary embolism. The advantage is believed to be due to local action of the drug with fewer systemic effects. Since the protocol involves alteplase for 12 or 24 hours with a maximum dose of 24 mg, and since in most cases pulmonary embolism originates in the lower extremity, are we not exposing these patients to further clot propagation for 12 or 24 hours without the benefit of concomitant systemic anticoagulation or an inferior vena cava filter?

In Reply: We thank Dr. Katyal for his thoughtful comments.

Dr. Katyal points out that the grade of recommendation for thrombolysis in patients with massive pulmonary embolism was upgraded from 2C to 2B in the 2016 American College of Chest Physicians (ACCP) guidelines¹ compared with the 2012 guidelines² that we cited. The upgrade in this recommendation was owing to 2 small trials and 1 large randomized controlled trial that included patients with submassive pulmonary embolism.^3–5 Interestingly, these 3 studies led to an upgrade in the level of recommendation for thrombolysis in the treatment of massive pulmonary embolism, perhaps more from a safety aspect (in view of the incidence of major bleeding vs mortality). Regardless, Dr. Katyal is correct in highlighting that the new 2016 ACCP guidelines now give a grade of 2B for thrombolytic therapy in the treatment of massive pulmonary embolism. These guidelines had not been published at the time of submission of our manuscript.

Dr. Katyal is also correct that patients were not required to have right ventricular dysfunction to be enrolled in the MOPETT trial.³ As we pointed out, “Only 20% of the participants were enrolled on the basis of right ventricular dysfunction on echocardiography, whereas almost 60% had elevated cardiac biomarkers.”⁶

Regarding catheter-directed therapy, patients who received low-dose catheter-directed alteplase were also concurrently anticoagulated with systemic unfractionated heparin in the Ultrasound-Assisted, Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism (ULTIMA) trial.⁷ The ULTIMA trial authors commented that unfractionated heparin was started with an 80-U/kg bolus followed by an 18-U/kg/hour infusion to target an anti-factor Xa level of 0.3 to 0.7 μg/mL, which is considered therapeutic anticoagulation. The investigators in the SEATTLE II trial⁸ continued systemic unfractionated heparin but targeted a lower “intermediate” anticoagulation target (an augmented partial thromboplastin time of 40–60 seconds), so these patients weren’t completely without systemic anticoagulation either. At our institution, the current practice is to target an anti-Xa level of 0.3 to 0.7 μg/mL in patients receiving catheter-directed therapy for large-volume pulmonary embolism.

In Reply: We thank Dr. Katyal for his thoughtful comments.

Dr. Katyal points out that the grade of recommendation for thrombolysis in patients with massive pulmonary embolism was upgraded from 2C to 2B in the 2016 American College of Chest Physicians (ACCP) guidelines¹ compared with the 2012 guidelines² that we cited. The upgrade in this recommendation was owing to 2 small trials and 1 large randomized controlled trial that included patients with submassive pulmonary embolism.^3–5 Interestingly, these 3 studies led to an upgrade in the level of recommendation for thrombolysis in the treatment of massive pulmonary embolism, perhaps more from a safety aspect (in view of the incidence of major bleeding vs mortality). Regardless, Dr. Katyal is correct in highlighting that the new 2016 ACCP guidelines now give a grade of 2B for thrombolytic therapy in the treatment of massive pulmonary embolism. These guidelines had not been published at the time of submission of our manuscript.

Dr. Katyal is also correct that patients were not required to have right ventricular dysfunction to be enrolled in the MOPETT trial.³ As we pointed out, “Only 20% of the participants were enrolled on the basis of right ventricular dysfunction on echocardiography, whereas almost 60% had elevated cardiac biomarkers.”⁶

Regarding catheter-directed therapy, patients who received low-dose catheter-directed alteplase were also concurrently anticoagulated with systemic unfractionated heparin in the Ultrasound-Assisted, Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism (ULTIMA) trial.⁷ The ULTIMA trial authors commented that unfractionated heparin was started with an 80-U/kg bolus followed by an 18-U/kg/hour infusion to target an anti-factor Xa level of 0.3 to 0.7 μg/mL, which is considered therapeutic anticoagulation. The investigators in the SEATTLE II trial⁸ continued systemic unfractionated heparin but targeted a lower “intermediate” anticoagulation target (an augmented partial thromboplastin time of 40–60 seconds), so these patients weren’t completely without systemic anticoagulation either. At our institution, the current practice is to target an anti-Xa level of 0.3 to 0.7 μg/mL in patients receiving catheter-directed therapy for large-volume pulmonary embolism.

In Reply: We thank Dr. Katyal for his thoughtful comments.

Dr. Katyal points out that the grade of recommendation for thrombolysis in patients with massive pulmonary embolism was upgraded from 2C to 2B in the 2016 American College of Chest Physicians (ACCP) guidelines¹ compared with the 2012 guidelines² that we cited. The upgrade in this recommendation was owing to 2 small trials and 1 large randomized controlled trial that included patients with submassive pulmonary embolism.^3–5 Interestingly, these 3 studies led to an upgrade in the level of recommendation for thrombolysis in the treatment of massive pulmonary embolism, perhaps more from a safety aspect (in view of the incidence of major bleeding vs mortality). Regardless, Dr. Katyal is correct in highlighting that the new 2016 ACCP guidelines now give a grade of 2B for thrombolytic therapy in the treatment of massive pulmonary embolism. These guidelines had not been published at the time of submission of our manuscript.

Dr. Katyal is also correct that patients were not required to have right ventricular dysfunction to be enrolled in the MOPETT trial.³ As we pointed out, “Only 20% of the participants were enrolled on the basis of right ventricular dysfunction on echocardiography, whereas almost 60% had elevated cardiac biomarkers.”⁶

Regarding catheter-directed therapy, patients who received low-dose catheter-directed alteplase were also concurrently anticoagulated with systemic unfractionated heparin in the Ultrasound-Assisted, Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism (ULTIMA) trial.⁷ The ULTIMA trial authors commented that unfractionated heparin was started with an 80-U/kg bolus followed by an 18-U/kg/hour infusion to target an anti-factor Xa level of 0.3 to 0.7 μg/mL, which is considered therapeutic anticoagulation. The investigators in the SEATTLE II trial⁸ continued systemic unfractionated heparin but targeted a lower “intermediate” anticoagulation target (an augmented partial thromboplastin time of 40–60 seconds), so these patients weren’t completely without systemic anticoagulation either. At our institution, the current practice is to target an anti-Xa level of 0.3 to 0.7 μg/mL in patients receiving catheter-directed therapy for large-volume pulmonary embolism.