EVIDENCE SUMMARY

A systematic review by the Agency for Healthcare Research and Quality of adult female outpatients with SUI examined the effectiveness of PFMT, electrical stimulation, magnetic stimulation, and vaginal cones compared with no active treatment or sham treatment to produce continence (90% to 100% symptom reduction) or improve symptoms (at least 50% patient-reported symptom reduction).¹ The TABLE summarizes the results.¹ Investigators also assessed improvement in patient-reported QOL.

Pelvic floor muscle training improves continence, quality of life

A meta-analysis of 10 RCTs demonstrated that PFMT produced continence more often than placebo, and a meta-analysis of 6 RCTs found that PFMT improved SUI symptoms.¹ PFMT regimens ranged in duration from 8 weeks to 6 months, including unsupervised treatment (8 to 12 repetitions, 3 to 10 times a day) and supervised treatment (as long as an hour, as often as 3 times a week).¹

Both unsupervised and supervised PFMT produced similar results. One RCT evaluating QOL measures found that PFMT improved activity and reduced psychological impact (number needed to treat [NNT]=1; 95% confidence interval [CI], 1-2).¹

A meta-analysis of 7 RCTs found that intravaginal electrical stimulation increased continence compared with sham treatment.1 A meta-analysis of 8 RCTs found that intravaginal electrical stimulation also improved SUI symptoms.¹ All of the trials used electrical stimulation at frequencies between 4 and 50 Hz for 15 to 20 minutes, 1 to 3 times daily for 4 to 15 weeks.

Pelvic floor muscle training increases urinary continence and improves symptoms of stress urinary incontinence and quality of life.

Percutaneous electrical stimulation improves symptoms

A meta-analysis of 3 RCTs found that percutaneous electrical stimulation improved SUI symptoms compared with no active treatment. Four RCTs found that electrical stimulation improved QOL, although a meta-analysis couldn’t be performed because of clinical heterogeneity.¹

A meta-analysis of 3 RCTs found that magnetic stimulation at frequencies of 10 to 18.5 Hz given over 1 to 8 weeks didn’t increase continence. A meta-analysis of an additional 3 RCTs concluded that magnetic stimulation improved continence, but the individual studies reported conflicting results and were heterogenous.¹

Two RCTs evaluating QOL scores found conflicting results. One study found a mean difference of 3.9 points on the 100-point Incontinence Quality of Life Questionnaire (95% CI, 2.08-5.72; minimal clinically important difference rated 2-5 points).¹

Vaginal cones are ineffective and not well-tolerated

Two RCTs found that vaginal cones didn’t improve continence or QOL compared with no treatment. Investigators reported high discontinuation rates and adverse effects with the cones, which weighed 20 to 70 g and were worn for 20 minutes a day for as long as 24 weeks.¹

RECOMMENDATIONS

The National Institute for Health and Care Excellence recommends PFMT comprising at least 8 contractions 3 times daily for at least 3 months as first-line therapy for women with SUI.² They don’t recommend electrical stimulation or intravaginal devices for women who can actively contract their pelvic floor muscles. The American College of Obstetricians and Gynecologists recommends PFMT as first-line therapy for women with SUI and states that PFMT is more effective than electrical stimulation or vaginal cones.³

EVIDENCE SUMMARY

A systematic review by the Agency for Healthcare Research and Quality of adult female outpatients with SUI examined the effectiveness of PFMT, electrical stimulation, magnetic stimulation, and vaginal cones compared with no active treatment or sham treatment to produce continence (90% to 100% symptom reduction) or improve symptoms (at least 50% patient-reported symptom reduction).¹ The TABLE summarizes the results.¹ Investigators also assessed improvement in patient-reported QOL.

Pelvic floor muscle training improves continence, quality of life

A meta-analysis of 10 RCTs demonstrated that PFMT produced continence more often than placebo, and a meta-analysis of 6 RCTs found that PFMT improved SUI symptoms.¹ PFMT regimens ranged in duration from 8 weeks to 6 months, including unsupervised treatment (8 to 12 repetitions, 3 to 10 times a day) and supervised treatment (as long as an hour, as often as 3 times a week).¹

Both unsupervised and supervised PFMT produced similar results. One RCT evaluating QOL measures found that PFMT improved activity and reduced psychological impact (number needed to treat [NNT]=1; 95% confidence interval [CI], 1-2).¹

A meta-analysis of 7 RCTs found that intravaginal electrical stimulation increased continence compared with sham treatment.1 A meta-analysis of 8 RCTs found that intravaginal electrical stimulation also improved SUI symptoms.¹ All of the trials used electrical stimulation at frequencies between 4 and 50 Hz for 15 to 20 minutes, 1 to 3 times daily for 4 to 15 weeks.

Pelvic floor muscle training increases urinary continence and improves symptoms of stress urinary incontinence and quality of life.

Percutaneous electrical stimulation improves symptoms

A meta-analysis of 3 RCTs found that percutaneous electrical stimulation improved SUI symptoms compared with no active treatment. Four RCTs found that electrical stimulation improved QOL, although a meta-analysis couldn’t be performed because of clinical heterogeneity.¹

A meta-analysis of 3 RCTs found that magnetic stimulation at frequencies of 10 to 18.5 Hz given over 1 to 8 weeks didn’t increase continence. A meta-analysis of an additional 3 RCTs concluded that magnetic stimulation improved continence, but the individual studies reported conflicting results and were heterogenous.¹

Two RCTs evaluating QOL scores found conflicting results. One study found a mean difference of 3.9 points on the 100-point Incontinence Quality of Life Questionnaire (95% CI, 2.08-5.72; minimal clinically important difference rated 2-5 points).¹

Vaginal cones are ineffective and not well-tolerated

Two RCTs found that vaginal cones didn’t improve continence or QOL compared with no treatment. Investigators reported high discontinuation rates and adverse effects with the cones, which weighed 20 to 70 g and were worn for 20 minutes a day for as long as 24 weeks.¹

RECOMMENDATIONS

The National Institute for Health and Care Excellence recommends PFMT comprising at least 8 contractions 3 times daily for at least 3 months as first-line therapy for women with SUI.² They don’t recommend electrical stimulation or intravaginal devices for women who can actively contract their pelvic floor muscles. The American College of Obstetricians and Gynecologists recommends PFMT as first-line therapy for women with SUI and states that PFMT is more effective than electrical stimulation or vaginal cones.³

EVIDENCE SUMMARY

A systematic review by the Agency for Healthcare Research and Quality of adult female outpatients with SUI examined the effectiveness of PFMT, electrical stimulation, magnetic stimulation, and vaginal cones compared with no active treatment or sham treatment to produce continence (90% to 100% symptom reduction) or improve symptoms (at least 50% patient-reported symptom reduction).¹ The TABLE summarizes the results.¹ Investigators also assessed improvement in patient-reported QOL.

Pelvic floor muscle training improves continence, quality of life

A meta-analysis of 10 RCTs demonstrated that PFMT produced continence more often than placebo, and a meta-analysis of 6 RCTs found that PFMT improved SUI symptoms.¹ PFMT regimens ranged in duration from 8 weeks to 6 months, including unsupervised treatment (8 to 12 repetitions, 3 to 10 times a day) and supervised treatment (as long as an hour, as often as 3 times a week).¹

Both unsupervised and supervised PFMT produced similar results. One RCT evaluating QOL measures found that PFMT improved activity and reduced psychological impact (number needed to treat [NNT]=1; 95% confidence interval [CI], 1-2).¹

A meta-analysis of 7 RCTs found that intravaginal electrical stimulation increased continence compared with sham treatment.1 A meta-analysis of 8 RCTs found that intravaginal electrical stimulation also improved SUI symptoms.¹ All of the trials used electrical stimulation at frequencies between 4 and 50 Hz for 15 to 20 minutes, 1 to 3 times daily for 4 to 15 weeks.

Pelvic floor muscle training increases urinary continence and improves symptoms of stress urinary incontinence and quality of life.

Percutaneous electrical stimulation improves symptoms

A meta-analysis of 3 RCTs found that percutaneous electrical stimulation improved SUI symptoms compared with no active treatment. Four RCTs found that electrical stimulation improved QOL, although a meta-analysis couldn’t be performed because of clinical heterogeneity.¹

A meta-analysis of 3 RCTs found that magnetic stimulation at frequencies of 10 to 18.5 Hz given over 1 to 8 weeks didn’t increase continence. A meta-analysis of an additional 3 RCTs concluded that magnetic stimulation improved continence, but the individual studies reported conflicting results and were heterogenous.¹

Two RCTs evaluating QOL scores found conflicting results. One study found a mean difference of 3.9 points on the 100-point Incontinence Quality of Life Questionnaire (95% CI, 2.08-5.72; minimal clinically important difference rated 2-5 points).¹

Vaginal cones are ineffective and not well-tolerated

Two RCTs found that vaginal cones didn’t improve continence or QOL compared with no treatment. Investigators reported high discontinuation rates and adverse effects with the cones, which weighed 20 to 70 g and were worn for 20 minutes a day for as long as 24 weeks.¹

RECOMMENDATIONS

The National Institute for Health and Care Excellence recommends PFMT comprising at least 8 contractions 3 times daily for at least 3 months as first-line therapy for women with SUI.² They don’t recommend electrical stimulation or intravaginal devices for women who can actively contract their pelvic floor muscles. The American College of Obstetricians and Gynecologists recommends PFMT as first-line therapy for women with SUI and states that PFMT is more effective than electrical stimulation or vaginal cones.³

Laboratory mistakes are not defined as diagnostic errors, but they contribute significantly to the thousands of medical errors that occur every year.¹ Part of the problem: While accurate interpretation of lab tests often depends on the use of statistical concepts we all learned in medical training, it is difficult to find the time to incorporate these principles into a busy practice.

Overuse of lab tests presents problems, as well. Because “normal ranges” for test results are based on statistical analysis, as many as 5% of patients in a standard distribution fall outside of the range.² It is important to order only the tests you really need, as extra testing automatically means more false positive results.

This article was written with such pitfalls in mind. In the pages that follow, we focus on 8 types of tests family physicians rely on regularly—all cases in which test results are reliable only if comorbidities, pre- and post-test probabilities, and clinical context are carefully considered. To help you put these lab tests into the proper context, we’ve addressed a key question—and highlighted both pitfalls and pearls—about each.

1. Hemoglobin A1c: How does anemia affect it?

Hemoglobin A1c (HbA1c) can be measured in many ways, including high-performance liquid chromatography, boronate affinity, capillary electrophoresis, and immunoassay, all of which can provide equivalent values without significant variability.^3,4 In interpreting these tests, however, it is important to understand the effect that anemia has on HbA1c.

Two primary variables influencing HbA1c are the average glucose level and the average lifespan of red blood cells (RBCs). Normally, there is a direct correlation between average serum glucose and HbA1c.⁴ In patients with anemia, however, this relationship is less clear, and may be affected by erythropoiesis and RBC destruction.⁵ In iron deficiency anemia (IDA),^6,7 hemoglobin production falls secondary to iron stores, resulting in microcytic cells with a longer lifespan and elevated HbA1c. In at least one study,^5,7 HbA1c approached levels associated with diabetes (with increases as high as 1.5%) in nondiabetic patients, but resolved with treatment of IDA.

Increased destruction as well as increased production of RBCs lowers their lifespan, and in turn decreases HbA1c levels (TABLE 1).⁴ This can be seen in conditions such as splenomegaly and hemoglobinopathies. In patients with hemoglobinopathies, the percentage of hemoglobin A is significantly decreased, often to undetectable levels—thereby making HbA1c tests inaccurate. Hemoglobin electrophoresis and determination of glycation by capillary electrophoresis or high-performance liquid chromatography can be used instead, but neither is practical because of cost and limited availability.^4,8,9

THE TAKEAWAY: When you evaluate HbA1c test results, it is crucial to assess the patient for anemia and other conditions or comorbidities that can significantly affect RBC lifespan and skew test results.^2,4-6

2. D-dimer: When should you use it?

D-dimer is a fibrin degradation product that is increased when active clotting is present,10 and its assay—which has high sensitivity and low specificity—is widely used to screen for pulmonary embolism (PE) and deep vein thrombosis (DVT). While the minimal number of false negatives makes the D-dimer a good screening test, the higher rate of false positives makes it difficult to arrive at a definitive diagnosis. Appropriate use of the D-dimer assay is crucial to minimize the potential for adverse consequences, such as bleeding in patients who are subjected to unnecessary anticoagulation because of false positive results.

Further testing typically follows. A positive D-dimer test is commonly followed by a computed tomography (CT) scan of the chest or a ventilation/perfusion scan to establish a PE or DVT diagnosis. But this subsequent testing increases both the cost of health care and the patient’s radiation exposure. Use of these subsequent scans can be reduced by first considering the patient’s pretest probability for PE or DVT. The Wells’ Criteria (available at www.mdcalc.com/wells-criteriafor-pulmonary-embolism-pe/) and Geneva Score (Revised) (www.mdcalc.com/genevascore-revised-for-pulmonary-embolism/) can both be used for this purpose.^10,11

Nonfasting lipid values can offer useful information—particularly in patients who are unwilling or unable to return for fasting labs.Patients with high pretest probability should undergo immediate scanning, foregoing the D-dimer—which should be reserved for patients who have a low or moderate pretest probability but sufficient reason to suspect PE or DVT.^10-12

The low specificity of the D-dimer assay poses another challenge to its effective use. There are many things that can increase D-dimer levels, such as age, cancer, prolonged immobility, autoimmune disease, inflammation, sickle cell disease, pregnancy, trauma, and surgery.^13-15 All these factors must be taken into consideration prior to ordering this test.

In fact, one recent study found that using an age-adjusted D-dimer cutoff (patient’s age in years x 10 mcg/L)—rather than a conventional cutoff of 500 mcg/L—for patients older than 50 years reduces false positives without substantially increasing false negatives.¹⁶

Also of note: An anticoagulant can decrease D-dimer levels in plasma, so the test should not be used to rule out PE or DVT in patients who are undergoing anticoagulation.^13,15

THE TAKEAWAY: In evaluating patients for PE or DVT, use the Wells’ Criteria or Geneva Score (Revised) to determine a patient’s pretest probability of disease. Use the D-dimer assay to safely rule out these conditions in patients with a low or intermediate pretest probability, but go directly to scans for those with a high pretest probability.

3. Lipid panels: How important is fasting?

Patients are often instructed to report for fasting lab studies, specifically for lipid profiles. Traditionally, this had been defined as an 8- to 12-hour period without food.¹⁷ In clinical practice, however, this is often misinterpreted by patients, who may be confused about the duration of the fast or unsure about whether to eat or drink immediately before the test.

Studies investigating the effect of meals on lab values have found that triglycerides are consistently elevated postprandially, to a maximum of 12 hours.^18-21 The effect of the fasting state on total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol is more controversial; while some postprandial differences have been detected, the clinical relevance is equivocal.^18-21

Nonfasting lipid values can offer useful information, particularly in patients who are unwilling or unable to return for fasting labs. The US Preventive Services Task Force (USPSTF) supports this practice.²² Because guidelines for evaluation and treatment are based on fasting lipids, however, fasting lab work should be used, whenever possible, for initiating treatment and monitoring patients with abnormal values. If nonfasting lipids are used, it is crucial to factor in the postprandial effects on triglycerides and the subsequent difficulty of assessing LDL cholesterol levels.

THE TAKEAWAY: The clinical relevance of postprandial vs fasting lipid levels is equivocal. Nonfasting lipid panels have reasonable clinical utility in screening and initial treatment, particularly in cases in which obtaining fasting lab values may be problematic.^18,19

4. Mononucleoosis spot test: When should you use it?

The monospot test is a latex assay that causes hemagglutination of horse RBCs in the presence of heterophile antibodies characteristic of infectious mononucleosis.²³ The antibodies develop within the first 7 days of onset of symptoms, but do not peak for 2 to 5 weeks.²⁴ As a result, monospot testing yields a high incidence of false negatives during the first 2 weeks of active infection.²⁵ False negatives are also common in patients younger than 14 years. Heterophile antibodies may be present for up to a year after active infection.²⁴

Patients at increased risk for splenic rupture, such as athletes, pose considerable diagnostic difficulty.²⁶ When there is strong clinical suspicion of mononucleosis despite a negative monospot test in such high-risk individuals, follow-up testing is recommended to differentiate it from other mononucleosis-like illnesses (TABLE 2).²⁷ The optimal combination of Epstein-Barr virus (EBV) serologic testing consists of the antibody titration of 4 markers: immunoglobulins M (IgM) and G (IgG) to the viral capsid antigen, IgM to the early antigen, and antibody to Epstein-Barr nuclear antigen (EBNA).²⁸ Acute phase reactants in the setting of an antibody to EBNA could indicate reactivation. A positive test does not exclude other medical causes, however, because up to 20% of patients have acute phase antibodies that persist for years.²⁹

Digoxin levels need to be drawn at least 6 to 8 hours after the last dose is taken to allow for appropriate drug distribution. Appropriate diagnosis is important because of the significant morbidity associated with EBV. Risk of splenic injury is greatest between 4 and 21 days after onset of symptoms but persists at 7 weeks,²⁶ so conservative therapy followed by monospot retesting one week later is a reasonable approach.

Mononucleosis or routine tonsillitis? It is important to note that there is no evidence that a positive monospot test will affect the management or outcome of routine tonsillitis, raising questions of the utility of the test in such cases. A better approach: Reserve testing for patients with additional findings—ie, splenomegaly—or whose symptoms have persisted ≥ 2 weeks.

THE TAKEAWAY: Wait at least 2 weeks to conduct monospot testing in patients with routine tonsillitis. If strong clinical suspicion exists, proceed with specific IgM and IgG serologic testing.^24,25,27,28

5. Evaluating prescription drug levels: Which factors interfere?

Correct interpretation of lab tests conducted to measure prescription drug levels has major implications with regard to patient safety, particularly for medications with a narrow therapeutic index.

Conduct a confirmatory test before making decisions based on the results of urine drug screens.Most drug level tests measure the total concentration, which includes both bound and unbound (free) forms. The unbound forms are the active components of the drug; thus, for an accurate evaluation, it is important to be aware of factors that increase free drug concentration. Chief among them is low protein levels, or hypoalbuminemia.³⁰

Risk factors for hypoalbuminemia include significant burns, advanced age, pregnancy, malnutrition, and human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS).³⁰ HIV/AIDS is a particularly high risk because certain protease inhibitors are highly protein bound.

Drug protein binding is classified as low, moderate, or high. The main proteins involved in the process are albumin, alpha-1-acid glycoprotein, and lipoprotein. Medications that are highly protein bound (>80%) are the most affected by low protein levels: Problems can arise when drugs completely bind to all the available proteins and excess drug availability increases free drug levels.

Medications that are most likely to be affected by a high degree of protein binding include carbamazepine, cyclosporine, mycophenolic acid, phenytoin, protease inhibitors (with the exception of indinavir), tacrolimus, and valproic acid. It is important to consider free levels when you order medication assays for these drugs to avoid misinterpreting the serum levels as being too low-a scenario that raises the risk of drug toxicity and adverse outcomes.^30,31

A study of 119 phenytoin samples from 70 patients found significantly higher free phenytoin levels in patients with lower albumin levels.³² Higher free phenytoin levels were also seen in older patients and in those with diminished renal function (creatinine clearance <25 mL/min).³² The degree of protein binding is affected by both the serum drug concentration and the albumin level, with saturable protein binding occurring at higher drug levels.³³

Calculate phenytoin levels with this equation. To calculate corrected phenytoin levels in patients with low albumin levels, use the following formula, known as the Sheiner-Tozer equation:³⁴

Concentration adjusted=concentration reported/([adjustment x serum albumin] + 0.1); adjustment=0.2 for creatinine clearance ≥20 or 0.1 for creatinine clearance <20.

Additional causes of misinterpreted drug levels. While hypoalbuminemia plays a major role in the misinterpretation of drug levels, other factors affect serum drug concentration, as well. These include drug-drug interactions, which can significantly increase the concentration of the medications involved, and the timing of the test with regard to medication administration. Digoxin levels, in particular, need to be drawn at least 6 to 8 hours after the last dose is taken to allow for appropriate drug distribution.³⁵

THE TAKEAWAY: It is essential to consider free drug level monitoring in patients who either have hypoalbuminemia or have one or more risk factors for hypoalbuminemia to avoid falsely low estimation of drug levels.^36,37

6 Liver function tests: Necessary for patients on statin therapy?

Since statins gained US Food and Drug Administration (FDA) approval, the drugs have been associated with increased liver function tests (LFTs). Indeed, there had been a long-standing belief, based on clinical trials, that by monitoring alanine aminotransferase (ALT) and maintaining it at <3 times the upper limit normal (ULN), hepatotoxicity could be avoided.³⁸ In clinical practice, however, further ALT elevation is frequently allowed based on patient tolerability.

In February 2012, the FDA revised its safety data to reflect this practice.³⁹ The FDA update confirmed that routine LFT monitoring is unnecessary for patients on statins—and that it is not very effective in identifying or preventing liver damage.

Overall, serious hepatotoxicity is very rare, with an incidence ≤2 per 1 million patient-years.³⁹ The National Lipid Association Statin Safety Assessment Task Force recommends repeating LFTs that are 3 to 5 times the ULN within 6 months and continuing with the statin dose if the patient is asymptomatic.³⁸

THE TAKEAWAY: Routine liver function monitoring is not necessary for patients on statins. A better approach: Obtain baseline ALT levels, and repeat the testing only as clinically indicated thereafter.^38,39

7. Urine drug screens: Which factors affect their accuracy?

The gold standard for testing for drugs of abuse, urine drug screens (UDS) have good sensitivity and specificity, easy administration, and reasonable cost.⁴⁰ UDS can detect various narcotics, such as morphine, oxycodone, ,and methadone, and identify other illicit drugs, although which drugs and metabolites are tested for is laboratory- and test-specific.

Cross-reactivity. There are 6 currently available immunoassays, all of which use competitive binding between the sample drug and a drug chemically labeled with an enzyme, radioisotope, or fluorophore. The sample drug and labeled drug compete for substrate binding sites on drug-specific antibodies.^41,42 Similar to competitive binding for enzymatic reactions in the body, the substrate binding site can experience cross-reactivity—causing substances other than the drug in question to bind to the immunoglobulin, leading to a false positive result (TABLE 3).⁴³ Other factors that can alter the results include the cutoff value of the test and the absorption, distribution, metabolism, and excretion of the drug.⁴² Thus, a confirmatory test of gas chromatography-mass spectrometry is recommended before making decisions based on the results of UDS.^43-45

Routine screens for patients on chronic opioid therapy. Routine use of UDS in emergency departments is no longer recommended, based on evidence that the results are unlikely to have a significant effect on patient management.⁴⁶ For patients on chronic opioid therapy, however, routine screening has proven helpful in detecting prescription opioid abuse, illicit drug use, and diversion. Up to 34% of patients on prescription opioids have been found to be using illicit drugs, as well.⁴²

THE TAKEAWAY: Use UDS as a tool in managing patients on chronic opioid therapy, but before acting on results, assess for factors, such as the use of oral or topical medications and the cutoff value of the test, that may be associated with false positive or false negative results.^43-45

8. Thyroid function testing: When should you test?

Thyroid-stimulating hormone (TSH) is the first-line test when investigating presumed hyper- or hypothyroidism.^47,48 Third-generation chemiluminometric assays can reliably measure TSH concentrations <0.01 mU/L by using multiple antibodies to produce a sandwich-type effect on the molecule in question.⁴⁹

Retesting TSH to assess treatment response should be postponed until ≥2 months after any change in medication or dosing.TSH levels exhibit diurnal variation, however, and are affected by other medications, including steroids, opiates, and some antihistamines, among others, as well as comorbidities.^47,48 Chronic and acute conditions unrelated to thyroid disease can cause transient changes in TSH concentrations, and have the potential to modify the binding capacity of plasma thyroid hormone binding proteins.⁴⁸ Thus, TSH should be ordered for hospitalized patients only when clinical suspicion of a thyroid problem exists.⁴⁸ The USPSTF recommends against routine TSH screening for asymptomatic adults.⁴⁶

How to respond to abnormal results. For patients found to have abnormal TSH levels, free T4 (fT4) is the next test to order.^47,49 An fT4 assay is a superior indicator of thyroid status because it is not affected by changes in iodothyronine-binding proteins, which influence total hormone measurements.⁴⁹ The results will be elevated in hyperthyroidism and reduced in hypothyroidism.⁴⁷

Triiodothyronine (T3) measures can be useful in diagnosing Graves’ disease, in which T3 toxicosis may be the initial symptom—or an indication of a relapse. Because T3 is often a peripheral product, however, nonthyroid illnesses and medications can cause artifactually abnormal results.⁴⁹

Other thyroid-specific labs include thyroid ,antibodies such as antithyroid peroxidase, antithyroglobulin, and TSH receptor, both blocking and stimulating.⁴⁹ Thyroglobulin is a precursor form of thyroid hormone and should be measured when factitious hyperthyroidism is suspected. Management of hyper- and hypothyroidism often is independent of etiology. Retesting TSH to assess treatment response should be postponed until ≥2 months after any change in medication or dosing.⁵⁰

Thyroid studies can be very difficult to interpret. TSH should be the first test ordered. However, if TSH values do not match the clinical picture, fT4, T3, and other thyroid tests that are less affected by outside factors can be useful in identifying the cause.

THE TAKEAWAY: Routine TSH testing is not indicated for asymptomatic adults. When evaluating thyroid function is clinically indicated, TSH is the initial test of choice.^47,48,51

CORRESPONDENCE
Joshua Tessier, DO, Iowa Lutheran Family Medicine Residency, 840 East University Avenue, Des Moines, IA 50316; joshua.tessier@unitypoint.org

Laboratory mistakes are not defined as diagnostic errors, but they contribute significantly to the thousands of medical errors that occur every year.¹ Part of the problem: While accurate interpretation of lab tests often depends on the use of statistical concepts we all learned in medical training, it is difficult to find the time to incorporate these principles into a busy practice.

Overuse of lab tests presents problems, as well. Because “normal ranges” for test results are based on statistical analysis, as many as 5% of patients in a standard distribution fall outside of the range.² It is important to order only the tests you really need, as extra testing automatically means more false positive results.

This article was written with such pitfalls in mind. In the pages that follow, we focus on 8 types of tests family physicians rely on regularly—all cases in which test results are reliable only if comorbidities, pre- and post-test probabilities, and clinical context are carefully considered. To help you put these lab tests into the proper context, we’ve addressed a key question—and highlighted both pitfalls and pearls—about each.

1. Hemoglobin A1c: How does anemia affect it?

Hemoglobin A1c (HbA1c) can be measured in many ways, including high-performance liquid chromatography, boronate affinity, capillary electrophoresis, and immunoassay, all of which can provide equivalent values without significant variability.^3,4 In interpreting these tests, however, it is important to understand the effect that anemia has on HbA1c.

Two primary variables influencing HbA1c are the average glucose level and the average lifespan of red blood cells (RBCs). Normally, there is a direct correlation between average serum glucose and HbA1c.⁴ In patients with anemia, however, this relationship is less clear, and may be affected by erythropoiesis and RBC destruction.⁵ In iron deficiency anemia (IDA),^6,7 hemoglobin production falls secondary to iron stores, resulting in microcytic cells with a longer lifespan and elevated HbA1c. In at least one study,^5,7 HbA1c approached levels associated with diabetes (with increases as high as 1.5%) in nondiabetic patients, but resolved with treatment of IDA.

Increased destruction as well as increased production of RBCs lowers their lifespan, and in turn decreases HbA1c levels (TABLE 1).⁴ This can be seen in conditions such as splenomegaly and hemoglobinopathies. In patients with hemoglobinopathies, the percentage of hemoglobin A is significantly decreased, often to undetectable levels—thereby making HbA1c tests inaccurate. Hemoglobin electrophoresis and determination of glycation by capillary electrophoresis or high-performance liquid chromatography can be used instead, but neither is practical because of cost and limited availability.^4,8,9

THE TAKEAWAY: When you evaluate HbA1c test results, it is crucial to assess the patient for anemia and other conditions or comorbidities that can significantly affect RBC lifespan and skew test results.^2,4-6

2. D-dimer: When should you use it?

D-dimer is a fibrin degradation product that is increased when active clotting is present,10 and its assay—which has high sensitivity and low specificity—is widely used to screen for pulmonary embolism (PE) and deep vein thrombosis (DVT). While the minimal number of false negatives makes the D-dimer a good screening test, the higher rate of false positives makes it difficult to arrive at a definitive diagnosis. Appropriate use of the D-dimer assay is crucial to minimize the potential for adverse consequences, such as bleeding in patients who are subjected to unnecessary anticoagulation because of false positive results.

Further testing typically follows. A positive D-dimer test is commonly followed by a computed tomography (CT) scan of the chest or a ventilation/perfusion scan to establish a PE or DVT diagnosis. But this subsequent testing increases both the cost of health care and the patient’s radiation exposure. Use of these subsequent scans can be reduced by first considering the patient’s pretest probability for PE or DVT. The Wells’ Criteria (available at www.mdcalc.com/wells-criteriafor-pulmonary-embolism-pe/) and Geneva Score (Revised) (www.mdcalc.com/genevascore-revised-for-pulmonary-embolism/) can both be used for this purpose.^10,11

Nonfasting lipid values can offer useful information—particularly in patients who are unwilling or unable to return for fasting labs.Patients with high pretest probability should undergo immediate scanning, foregoing the D-dimer—which should be reserved for patients who have a low or moderate pretest probability but sufficient reason to suspect PE or DVT.^10-12

The low specificity of the D-dimer assay poses another challenge to its effective use. There are many things that can increase D-dimer levels, such as age, cancer, prolonged immobility, autoimmune disease, inflammation, sickle cell disease, pregnancy, trauma, and surgery.^13-15 All these factors must be taken into consideration prior to ordering this test.

In fact, one recent study found that using an age-adjusted D-dimer cutoff (patient’s age in years x 10 mcg/L)—rather than a conventional cutoff of 500 mcg/L—for patients older than 50 years reduces false positives without substantially increasing false negatives.¹⁶

Also of note: An anticoagulant can decrease D-dimer levels in plasma, so the test should not be used to rule out PE or DVT in patients who are undergoing anticoagulation.^13,15

THE TAKEAWAY: In evaluating patients for PE or DVT, use the Wells’ Criteria or Geneva Score (Revised) to determine a patient’s pretest probability of disease. Use the D-dimer assay to safely rule out these conditions in patients with a low or intermediate pretest probability, but go directly to scans for those with a high pretest probability.

3. Lipid panels: How important is fasting?

Patients are often instructed to report for fasting lab studies, specifically for lipid profiles. Traditionally, this had been defined as an 8- to 12-hour period without food.¹⁷ In clinical practice, however, this is often misinterpreted by patients, who may be confused about the duration of the fast or unsure about whether to eat or drink immediately before the test.

Studies investigating the effect of meals on lab values have found that triglycerides are consistently elevated postprandially, to a maximum of 12 hours.^18-21 The effect of the fasting state on total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol is more controversial; while some postprandial differences have been detected, the clinical relevance is equivocal.^18-21

Nonfasting lipid values can offer useful information, particularly in patients who are unwilling or unable to return for fasting labs. The US Preventive Services Task Force (USPSTF) supports this practice.²² Because guidelines for evaluation and treatment are based on fasting lipids, however, fasting lab work should be used, whenever possible, for initiating treatment and monitoring patients with abnormal values. If nonfasting lipids are used, it is crucial to factor in the postprandial effects on triglycerides and the subsequent difficulty of assessing LDL cholesterol levels.

THE TAKEAWAY: The clinical relevance of postprandial vs fasting lipid levels is equivocal. Nonfasting lipid panels have reasonable clinical utility in screening and initial treatment, particularly in cases in which obtaining fasting lab values may be problematic.^18,19

4. Mononucleoosis spot test: When should you use it?

The monospot test is a latex assay that causes hemagglutination of horse RBCs in the presence of heterophile antibodies characteristic of infectious mononucleosis.²³ The antibodies develop within the first 7 days of onset of symptoms, but do not peak for 2 to 5 weeks.²⁴ As a result, monospot testing yields a high incidence of false negatives during the first 2 weeks of active infection.²⁵ False negatives are also common in patients younger than 14 years. Heterophile antibodies may be present for up to a year after active infection.²⁴

Patients at increased risk for splenic rupture, such as athletes, pose considerable diagnostic difficulty.²⁶ When there is strong clinical suspicion of mononucleosis despite a negative monospot test in such high-risk individuals, follow-up testing is recommended to differentiate it from other mononucleosis-like illnesses (TABLE 2).²⁷ The optimal combination of Epstein-Barr virus (EBV) serologic testing consists of the antibody titration of 4 markers: immunoglobulins M (IgM) and G (IgG) to the viral capsid antigen, IgM to the early antigen, and antibody to Epstein-Barr nuclear antigen (EBNA).²⁸ Acute phase reactants in the setting of an antibody to EBNA could indicate reactivation. A positive test does not exclude other medical causes, however, because up to 20% of patients have acute phase antibodies that persist for years.²⁹

Digoxin levels need to be drawn at least 6 to 8 hours after the last dose is taken to allow for appropriate drug distribution. Appropriate diagnosis is important because of the significant morbidity associated with EBV. Risk of splenic injury is greatest between 4 and 21 days after onset of symptoms but persists at 7 weeks,²⁶ so conservative therapy followed by monospot retesting one week later is a reasonable approach.

Mononucleosis or routine tonsillitis? It is important to note that there is no evidence that a positive monospot test will affect the management or outcome of routine tonsillitis, raising questions of the utility of the test in such cases. A better approach: Reserve testing for patients with additional findings—ie, splenomegaly—or whose symptoms have persisted ≥ 2 weeks.

THE TAKEAWAY: Wait at least 2 weeks to conduct monospot testing in patients with routine tonsillitis. If strong clinical suspicion exists, proceed with specific IgM and IgG serologic testing.^24,25,27,28

5. Evaluating prescription drug levels: Which factors interfere?

Correct interpretation of lab tests conducted to measure prescription drug levels has major implications with regard to patient safety, particularly for medications with a narrow therapeutic index.

Conduct a confirmatory test before making decisions based on the results of urine drug screens.Most drug level tests measure the total concentration, which includes both bound and unbound (free) forms. The unbound forms are the active components of the drug; thus, for an accurate evaluation, it is important to be aware of factors that increase free drug concentration. Chief among them is low protein levels, or hypoalbuminemia.³⁰

Risk factors for hypoalbuminemia include significant burns, advanced age, pregnancy, malnutrition, and human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS).³⁰ HIV/AIDS is a particularly high risk because certain protease inhibitors are highly protein bound.

Drug protein binding is classified as low, moderate, or high. The main proteins involved in the process are albumin, alpha-1-acid glycoprotein, and lipoprotein. Medications that are highly protein bound (>80%) are the most affected by low protein levels: Problems can arise when drugs completely bind to all the available proteins and excess drug availability increases free drug levels.

Medications that are most likely to be affected by a high degree of protein binding include carbamazepine, cyclosporine, mycophenolic acid, phenytoin, protease inhibitors (with the exception of indinavir), tacrolimus, and valproic acid. It is important to consider free levels when you order medication assays for these drugs to avoid misinterpreting the serum levels as being too low-a scenario that raises the risk of drug toxicity and adverse outcomes.^30,31

A study of 119 phenytoin samples from 70 patients found significantly higher free phenytoin levels in patients with lower albumin levels.³² Higher free phenytoin levels were also seen in older patients and in those with diminished renal function (creatinine clearance <25 mL/min).³² The degree of protein binding is affected by both the serum drug concentration and the albumin level, with saturable protein binding occurring at higher drug levels.³³

Calculate phenytoin levels with this equation. To calculate corrected phenytoin levels in patients with low albumin levels, use the following formula, known as the Sheiner-Tozer equation:³⁴

Concentration adjusted=concentration reported/([adjustment x serum albumin] + 0.1); adjustment=0.2 for creatinine clearance ≥20 or 0.1 for creatinine clearance <20.

Additional causes of misinterpreted drug levels. While hypoalbuminemia plays a major role in the misinterpretation of drug levels, other factors affect serum drug concentration, as well. These include drug-drug interactions, which can significantly increase the concentration of the medications involved, and the timing of the test with regard to medication administration. Digoxin levels, in particular, need to be drawn at least 6 to 8 hours after the last dose is taken to allow for appropriate drug distribution.³⁵

THE TAKEAWAY: It is essential to consider free drug level monitoring in patients who either have hypoalbuminemia or have one or more risk factors for hypoalbuminemia to avoid falsely low estimation of drug levels.^36,37

6 Liver function tests: Necessary for patients on statin therapy?

Since statins gained US Food and Drug Administration (FDA) approval, the drugs have been associated with increased liver function tests (LFTs). Indeed, there had been a long-standing belief, based on clinical trials, that by monitoring alanine aminotransferase (ALT) and maintaining it at <3 times the upper limit normal (ULN), hepatotoxicity could be avoided.³⁸ In clinical practice, however, further ALT elevation is frequently allowed based on patient tolerability.

In February 2012, the FDA revised its safety data to reflect this practice.³⁹ The FDA update confirmed that routine LFT monitoring is unnecessary for patients on statins—and that it is not very effective in identifying or preventing liver damage.

Overall, serious hepatotoxicity is very rare, with an incidence ≤2 per 1 million patient-years.³⁹ The National Lipid Association Statin Safety Assessment Task Force recommends repeating LFTs that are 3 to 5 times the ULN within 6 months and continuing with the statin dose if the patient is asymptomatic.³⁸

THE TAKEAWAY: Routine liver function monitoring is not necessary for patients on statins. A better approach: Obtain baseline ALT levels, and repeat the testing only as clinically indicated thereafter.^38,39

7. Urine drug screens: Which factors affect their accuracy?

The gold standard for testing for drugs of abuse, urine drug screens (UDS) have good sensitivity and specificity, easy administration, and reasonable cost.⁴⁰ UDS can detect various narcotics, such as morphine, oxycodone, ,and methadone, and identify other illicit drugs, although which drugs and metabolites are tested for is laboratory- and test-specific.

Cross-reactivity. There are 6 currently available immunoassays, all of which use competitive binding between the sample drug and a drug chemically labeled with an enzyme, radioisotope, or fluorophore. The sample drug and labeled drug compete for substrate binding sites on drug-specific antibodies.^41,42 Similar to competitive binding for enzymatic reactions in the body, the substrate binding site can experience cross-reactivity—causing substances other than the drug in question to bind to the immunoglobulin, leading to a false positive result (TABLE 3).⁴³ Other factors that can alter the results include the cutoff value of the test and the absorption, distribution, metabolism, and excretion of the drug.⁴² Thus, a confirmatory test of gas chromatography-mass spectrometry is recommended before making decisions based on the results of UDS.^43-45

Routine screens for patients on chronic opioid therapy. Routine use of UDS in emergency departments is no longer recommended, based on evidence that the results are unlikely to have a significant effect on patient management.⁴⁶ For patients on chronic opioid therapy, however, routine screening has proven helpful in detecting prescription opioid abuse, illicit drug use, and diversion. Up to 34% of patients on prescription opioids have been found to be using illicit drugs, as well.⁴²

THE TAKEAWAY: Use UDS as a tool in managing patients on chronic opioid therapy, but before acting on results, assess for factors, such as the use of oral or topical medications and the cutoff value of the test, that may be associated with false positive or false negative results.^43-45

8. Thyroid function testing: When should you test?

Thyroid-stimulating hormone (TSH) is the first-line test when investigating presumed hyper- or hypothyroidism.^47,48 Third-generation chemiluminometric assays can reliably measure TSH concentrations <0.01 mU/L by using multiple antibodies to produce a sandwich-type effect on the molecule in question.⁴⁹

Retesting TSH to assess treatment response should be postponed until ≥2 months after any change in medication or dosing.TSH levels exhibit diurnal variation, however, and are affected by other medications, including steroids, opiates, and some antihistamines, among others, as well as comorbidities.^47,48 Chronic and acute conditions unrelated to thyroid disease can cause transient changes in TSH concentrations, and have the potential to modify the binding capacity of plasma thyroid hormone binding proteins.⁴⁸ Thus, TSH should be ordered for hospitalized patients only when clinical suspicion of a thyroid problem exists.⁴⁸ The USPSTF recommends against routine TSH screening for asymptomatic adults.⁴⁶

How to respond to abnormal results. For patients found to have abnormal TSH levels, free T4 (fT4) is the next test to order.^47,49 An fT4 assay is a superior indicator of thyroid status because it is not affected by changes in iodothyronine-binding proteins, which influence total hormone measurements.⁴⁹ The results will be elevated in hyperthyroidism and reduced in hypothyroidism.⁴⁷

Triiodothyronine (T3) measures can be useful in diagnosing Graves’ disease, in which T3 toxicosis may be the initial symptom—or an indication of a relapse. Because T3 is often a peripheral product, however, nonthyroid illnesses and medications can cause artifactually abnormal results.⁴⁹

Other thyroid-specific labs include thyroid ,antibodies such as antithyroid peroxidase, antithyroglobulin, and TSH receptor, both blocking and stimulating.⁴⁹ Thyroglobulin is a precursor form of thyroid hormone and should be measured when factitious hyperthyroidism is suspected. Management of hyper- and hypothyroidism often is independent of etiology. Retesting TSH to assess treatment response should be postponed until ≥2 months after any change in medication or dosing.⁵⁰

Thyroid studies can be very difficult to interpret. TSH should be the first test ordered. However, if TSH values do not match the clinical picture, fT4, T3, and other thyroid tests that are less affected by outside factors can be useful in identifying the cause.

THE TAKEAWAY: Routine TSH testing is not indicated for asymptomatic adults. When evaluating thyroid function is clinically indicated, TSH is the initial test of choice.^47,48,51

CORRESPONDENCE
Joshua Tessier, DO, Iowa Lutheran Family Medicine Residency, 840 East University Avenue, Des Moines, IA 50316; joshua.tessier@unitypoint.org

Laboratory mistakes are not defined as diagnostic errors, but they contribute significantly to the thousands of medical errors that occur every year.¹ Part of the problem: While accurate interpretation of lab tests often depends on the use of statistical concepts we all learned in medical training, it is difficult to find the time to incorporate these principles into a busy practice.

Overuse of lab tests presents problems, as well. Because “normal ranges” for test results are based on statistical analysis, as many as 5% of patients in a standard distribution fall outside of the range.² It is important to order only the tests you really need, as extra testing automatically means more false positive results.

This article was written with such pitfalls in mind. In the pages that follow, we focus on 8 types of tests family physicians rely on regularly—all cases in which test results are reliable only if comorbidities, pre- and post-test probabilities, and clinical context are carefully considered. To help you put these lab tests into the proper context, we’ve addressed a key question—and highlighted both pitfalls and pearls—about each.

1. Hemoglobin A1c: How does anemia affect it?

Hemoglobin A1c (HbA1c) can be measured in many ways, including high-performance liquid chromatography, boronate affinity, capillary electrophoresis, and immunoassay, all of which can provide equivalent values without significant variability.^3,4 In interpreting these tests, however, it is important to understand the effect that anemia has on HbA1c.

Two primary variables influencing HbA1c are the average glucose level and the average lifespan of red blood cells (RBCs). Normally, there is a direct correlation between average serum glucose and HbA1c.⁴ In patients with anemia, however, this relationship is less clear, and may be affected by erythropoiesis and RBC destruction.⁵ In iron deficiency anemia (IDA),^6,7 hemoglobin production falls secondary to iron stores, resulting in microcytic cells with a longer lifespan and elevated HbA1c. In at least one study,^5,7 HbA1c approached levels associated with diabetes (with increases as high as 1.5%) in nondiabetic patients, but resolved with treatment of IDA.

Increased destruction as well as increased production of RBCs lowers their lifespan, and in turn decreases HbA1c levels (TABLE 1).⁴ This can be seen in conditions such as splenomegaly and hemoglobinopathies. In patients with hemoglobinopathies, the percentage of hemoglobin A is significantly decreased, often to undetectable levels—thereby making HbA1c tests inaccurate. Hemoglobin electrophoresis and determination of glycation by capillary electrophoresis or high-performance liquid chromatography can be used instead, but neither is practical because of cost and limited availability.^4,8,9

THE TAKEAWAY: When you evaluate HbA1c test results, it is crucial to assess the patient for anemia and other conditions or comorbidities that can significantly affect RBC lifespan and skew test results.^2,4-6

2. D-dimer: When should you use it?

D-dimer is a fibrin degradation product that is increased when active clotting is present,10 and its assay—which has high sensitivity and low specificity—is widely used to screen for pulmonary embolism (PE) and deep vein thrombosis (DVT). While the minimal number of false negatives makes the D-dimer a good screening test, the higher rate of false positives makes it difficult to arrive at a definitive diagnosis. Appropriate use of the D-dimer assay is crucial to minimize the potential for adverse consequences, such as bleeding in patients who are subjected to unnecessary anticoagulation because of false positive results.

Further testing typically follows. A positive D-dimer test is commonly followed by a computed tomography (CT) scan of the chest or a ventilation/perfusion scan to establish a PE or DVT diagnosis. But this subsequent testing increases both the cost of health care and the patient’s radiation exposure. Use of these subsequent scans can be reduced by first considering the patient’s pretest probability for PE or DVT. The Wells’ Criteria (available at www.mdcalc.com/wells-criteriafor-pulmonary-embolism-pe/) and Geneva Score (Revised) (www.mdcalc.com/genevascore-revised-for-pulmonary-embolism/) can both be used for this purpose.^10,11

Nonfasting lipid values can offer useful information—particularly in patients who are unwilling or unable to return for fasting labs.Patients with high pretest probability should undergo immediate scanning, foregoing the D-dimer—which should be reserved for patients who have a low or moderate pretest probability but sufficient reason to suspect PE or DVT.^10-12

The low specificity of the D-dimer assay poses another challenge to its effective use. There are many things that can increase D-dimer levels, such as age, cancer, prolonged immobility, autoimmune disease, inflammation, sickle cell disease, pregnancy, trauma, and surgery.^13-15 All these factors must be taken into consideration prior to ordering this test.

In fact, one recent study found that using an age-adjusted D-dimer cutoff (patient’s age in years x 10 mcg/L)—rather than a conventional cutoff of 500 mcg/L—for patients older than 50 years reduces false positives without substantially increasing false negatives.¹⁶

Also of note: An anticoagulant can decrease D-dimer levels in plasma, so the test should not be used to rule out PE or DVT in patients who are undergoing anticoagulation.^13,15

THE TAKEAWAY: In evaluating patients for PE or DVT, use the Wells’ Criteria or Geneva Score (Revised) to determine a patient’s pretest probability of disease. Use the D-dimer assay to safely rule out these conditions in patients with a low or intermediate pretest probability, but go directly to scans for those with a high pretest probability.

3. Lipid panels: How important is fasting?

Patients are often instructed to report for fasting lab studies, specifically for lipid profiles. Traditionally, this had been defined as an 8- to 12-hour period without food.¹⁷ In clinical practice, however, this is often misinterpreted by patients, who may be confused about the duration of the fast or unsure about whether to eat or drink immediately before the test.

Studies investigating the effect of meals on lab values have found that triglycerides are consistently elevated postprandially, to a maximum of 12 hours.^18-21 The effect of the fasting state on total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol is more controversial; while some postprandial differences have been detected, the clinical relevance is equivocal.^18-21

Nonfasting lipid values can offer useful information, particularly in patients who are unwilling or unable to return for fasting labs. The US Preventive Services Task Force (USPSTF) supports this practice.²² Because guidelines for evaluation and treatment are based on fasting lipids, however, fasting lab work should be used, whenever possible, for initiating treatment and monitoring patients with abnormal values. If nonfasting lipids are used, it is crucial to factor in the postprandial effects on triglycerides and the subsequent difficulty of assessing LDL cholesterol levels.

THE TAKEAWAY: The clinical relevance of postprandial vs fasting lipid levels is equivocal. Nonfasting lipid panels have reasonable clinical utility in screening and initial treatment, particularly in cases in which obtaining fasting lab values may be problematic.^18,19

4. Mononucleoosis spot test: When should you use it?

The monospot test is a latex assay that causes hemagglutination of horse RBCs in the presence of heterophile antibodies characteristic of infectious mononucleosis.²³ The antibodies develop within the first 7 days of onset of symptoms, but do not peak for 2 to 5 weeks.²⁴ As a result, monospot testing yields a high incidence of false negatives during the first 2 weeks of active infection.²⁵ False negatives are also common in patients younger than 14 years. Heterophile antibodies may be present for up to a year after active infection.²⁴

Patients at increased risk for splenic rupture, such as athletes, pose considerable diagnostic difficulty.²⁶ When there is strong clinical suspicion of mononucleosis despite a negative monospot test in such high-risk individuals, follow-up testing is recommended to differentiate it from other mononucleosis-like illnesses (TABLE 2).²⁷ The optimal combination of Epstein-Barr virus (EBV) serologic testing consists of the antibody titration of 4 markers: immunoglobulins M (IgM) and G (IgG) to the viral capsid antigen, IgM to the early antigen, and antibody to Epstein-Barr nuclear antigen (EBNA).²⁸ Acute phase reactants in the setting of an antibody to EBNA could indicate reactivation. A positive test does not exclude other medical causes, however, because up to 20% of patients have acute phase antibodies that persist for years.²⁹

Digoxin levels need to be drawn at least 6 to 8 hours after the last dose is taken to allow for appropriate drug distribution. Appropriate diagnosis is important because of the significant morbidity associated with EBV. Risk of splenic injury is greatest between 4 and 21 days after onset of symptoms but persists at 7 weeks,²⁶ so conservative therapy followed by monospot retesting one week later is a reasonable approach.

Mononucleosis or routine tonsillitis? It is important to note that there is no evidence that a positive monospot test will affect the management or outcome of routine tonsillitis, raising questions of the utility of the test in such cases. A better approach: Reserve testing for patients with additional findings—ie, splenomegaly—or whose symptoms have persisted ≥ 2 weeks.

THE TAKEAWAY: Wait at least 2 weeks to conduct monospot testing in patients with routine tonsillitis. If strong clinical suspicion exists, proceed with specific IgM and IgG serologic testing.^24,25,27,28

5. Evaluating prescription drug levels: Which factors interfere?

Correct interpretation of lab tests conducted to measure prescription drug levels has major implications with regard to patient safety, particularly for medications with a narrow therapeutic index.

Conduct a confirmatory test before making decisions based on the results of urine drug screens.Most drug level tests measure the total concentration, which includes both bound and unbound (free) forms. The unbound forms are the active components of the drug; thus, for an accurate evaluation, it is important to be aware of factors that increase free drug concentration. Chief among them is low protein levels, or hypoalbuminemia.³⁰

Risk factors for hypoalbuminemia include significant burns, advanced age, pregnancy, malnutrition, and human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS).³⁰ HIV/AIDS is a particularly high risk because certain protease inhibitors are highly protein bound.

Drug protein binding is classified as low, moderate, or high. The main proteins involved in the process are albumin, alpha-1-acid glycoprotein, and lipoprotein. Medications that are highly protein bound (>80%) are the most affected by low protein levels: Problems can arise when drugs completely bind to all the available proteins and excess drug availability increases free drug levels.

Medications that are most likely to be affected by a high degree of protein binding include carbamazepine, cyclosporine, mycophenolic acid, phenytoin, protease inhibitors (with the exception of indinavir), tacrolimus, and valproic acid. It is important to consider free levels when you order medication assays for these drugs to avoid misinterpreting the serum levels as being too low-a scenario that raises the risk of drug toxicity and adverse outcomes.^30,31

A study of 119 phenytoin samples from 70 patients found significantly higher free phenytoin levels in patients with lower albumin levels.³² Higher free phenytoin levels were also seen in older patients and in those with diminished renal function (creatinine clearance <25 mL/min).³² The degree of protein binding is affected by both the serum drug concentration and the albumin level, with saturable protein binding occurring at higher drug levels.³³

Calculate phenytoin levels with this equation. To calculate corrected phenytoin levels in patients with low albumin levels, use the following formula, known as the Sheiner-Tozer equation:³⁴

Concentration adjusted=concentration reported/([adjustment x serum albumin] + 0.1); adjustment=0.2 for creatinine clearance ≥20 or 0.1 for creatinine clearance <20.

Additional causes of misinterpreted drug levels. While hypoalbuminemia plays a major role in the misinterpretation of drug levels, other factors affect serum drug concentration, as well. These include drug-drug interactions, which can significantly increase the concentration of the medications involved, and the timing of the test with regard to medication administration. Digoxin levels, in particular, need to be drawn at least 6 to 8 hours after the last dose is taken to allow for appropriate drug distribution.³⁵

THE TAKEAWAY: It is essential to consider free drug level monitoring in patients who either have hypoalbuminemia or have one or more risk factors for hypoalbuminemia to avoid falsely low estimation of drug levels.^36,37

6 Liver function tests: Necessary for patients on statin therapy?

Since statins gained US Food and Drug Administration (FDA) approval, the drugs have been associated with increased liver function tests (LFTs). Indeed, there had been a long-standing belief, based on clinical trials, that by monitoring alanine aminotransferase (ALT) and maintaining it at <3 times the upper limit normal (ULN), hepatotoxicity could be avoided.³⁸ In clinical practice, however, further ALT elevation is frequently allowed based on patient tolerability.

In February 2012, the FDA revised its safety data to reflect this practice.³⁹ The FDA update confirmed that routine LFT monitoring is unnecessary for patients on statins—and that it is not very effective in identifying or preventing liver damage.

Overall, serious hepatotoxicity is very rare, with an incidence ≤2 per 1 million patient-years.³⁹ The National Lipid Association Statin Safety Assessment Task Force recommends repeating LFTs that are 3 to 5 times the ULN within 6 months and continuing with the statin dose if the patient is asymptomatic.³⁸

THE TAKEAWAY: Routine liver function monitoring is not necessary for patients on statins. A better approach: Obtain baseline ALT levels, and repeat the testing only as clinically indicated thereafter.^38,39

7. Urine drug screens: Which factors affect their accuracy?

The gold standard for testing for drugs of abuse, urine drug screens (UDS) have good sensitivity and specificity, easy administration, and reasonable cost.⁴⁰ UDS can detect various narcotics, such as morphine, oxycodone, ,and methadone, and identify other illicit drugs, although which drugs and metabolites are tested for is laboratory- and test-specific.

Cross-reactivity. There are 6 currently available immunoassays, all of which use competitive binding between the sample drug and a drug chemically labeled with an enzyme, radioisotope, or fluorophore. The sample drug and labeled drug compete for substrate binding sites on drug-specific antibodies.^41,42 Similar to competitive binding for enzymatic reactions in the body, the substrate binding site can experience cross-reactivity—causing substances other than the drug in question to bind to the immunoglobulin, leading to a false positive result (TABLE 3).⁴³ Other factors that can alter the results include the cutoff value of the test and the absorption, distribution, metabolism, and excretion of the drug.⁴² Thus, a confirmatory test of gas chromatography-mass spectrometry is recommended before making decisions based on the results of UDS.^43-45

Routine screens for patients on chronic opioid therapy. Routine use of UDS in emergency departments is no longer recommended, based on evidence that the results are unlikely to have a significant effect on patient management.⁴⁶ For patients on chronic opioid therapy, however, routine screening has proven helpful in detecting prescription opioid abuse, illicit drug use, and diversion. Up to 34% of patients on prescription opioids have been found to be using illicit drugs, as well.⁴²

THE TAKEAWAY: Use UDS as a tool in managing patients on chronic opioid therapy, but before acting on results, assess for factors, such as the use of oral or topical medications and the cutoff value of the test, that may be associated with false positive or false negative results.^43-45

8. Thyroid function testing: When should you test?

Thyroid-stimulating hormone (TSH) is the first-line test when investigating presumed hyper- or hypothyroidism.^47,48 Third-generation chemiluminometric assays can reliably measure TSH concentrations <0.01 mU/L by using multiple antibodies to produce a sandwich-type effect on the molecule in question.⁴⁹

Retesting TSH to assess treatment response should be postponed until ≥2 months after any change in medication or dosing.TSH levels exhibit diurnal variation, however, and are affected by other medications, including steroids, opiates, and some antihistamines, among others, as well as comorbidities.^47,48 Chronic and acute conditions unrelated to thyroid disease can cause transient changes in TSH concentrations, and have the potential to modify the binding capacity of plasma thyroid hormone binding proteins.⁴⁸ Thus, TSH should be ordered for hospitalized patients only when clinical suspicion of a thyroid problem exists.⁴⁸ The USPSTF recommends against routine TSH screening for asymptomatic adults.⁴⁶

How to respond to abnormal results. For patients found to have abnormal TSH levels, free T4 (fT4) is the next test to order.^47,49 An fT4 assay is a superior indicator of thyroid status because it is not affected by changes in iodothyronine-binding proteins, which influence total hormone measurements.⁴⁹ The results will be elevated in hyperthyroidism and reduced in hypothyroidism.⁴⁷

Triiodothyronine (T3) measures can be useful in diagnosing Graves’ disease, in which T3 toxicosis may be the initial symptom—or an indication of a relapse. Because T3 is often a peripheral product, however, nonthyroid illnesses and medications can cause artifactually abnormal results.⁴⁹

Other thyroid-specific labs include thyroid ,antibodies such as antithyroid peroxidase, antithyroglobulin, and TSH receptor, both blocking and stimulating.⁴⁹ Thyroglobulin is a precursor form of thyroid hormone and should be measured when factitious hyperthyroidism is suspected. Management of hyper- and hypothyroidism often is independent of etiology. Retesting TSH to assess treatment response should be postponed until ≥2 months after any change in medication or dosing.⁵⁰

Thyroid studies can be very difficult to interpret. TSH should be the first test ordered. However, if TSH values do not match the clinical picture, fT4, T3, and other thyroid tests that are less affected by outside factors can be useful in identifying the cause.

THE TAKEAWAY: Routine TSH testing is not indicated for asymptomatic adults. When evaluating thyroid function is clinically indicated, TSH is the initial test of choice.^47,48,51

CORRESPONDENCE
Joshua Tessier, DO, Iowa Lutheran Family Medicine Residency, 840 East University Avenue, Des Moines, IA 50316; joshua.tessier@unitypoint.org

Burkitt lymphoma

Credit: Ed Uthman

Researchers say they’ve discovered how the protein STAT3 interferes with an antitumor mechanism in cells, thereby promoting the growth of lymphoma and other cancers.

The group made their discovery using the Epstein-Barr virus (EBV) as a tool to investigate cancer development.

“Our findings add to the short list of known mechanisms by which a key cellular antitumor barrier is breached by STAT3 prior to cancer development,” said Sumita Bhaduri-McIntosh, MD, PhD, of Stony Brook University School of Medicine in New York.

“Because STAT3 interferes with this innate antitumor mechanism in cells, the opposite occurs when blood cells are infected in the lab with the cancer-causing virus EBV, and the cells continue to divide—a necessary step in cancer development.”

Dr Bhaduri-McIntosh and her colleagues described their research in PNAS.

The team explained that STAT3 inhibits a cancer-suppressing cellular activity called the DNA damage response (DDR). Normally, this response pauses cell division, allowing for the repair of damaged DNA.

But this study showed that EBV not only causes DNA damage when it infects and replicates in cells; it also activates and increases STAT3 expression. This starts a chain reaction that leads to an “un-pause” in cell division, thereby promoting cell proliferation. This, in combination with other pro-proliferative effects of the virus, can lead to cancers.

The researchers found that DDR does detect replication stress-associated DNA damage resulting from EBV infection. But signaling downstream of ATR proteins is impaired by STAT3. And this leads to relaxation of the intra-S phase checkpoint of the cell cycle.

STAT3 interrupts signaling from ATR to the protein Chk1 by promoting the loss of Claspin, a protein that assists ATR to phosphorylate Chk1. The loss of Claspin, which facilitates cell proliferation, is mediated by caspase 7.

Previous research suggested that STAT3 and Chk1 are potential targets for cancer therapies. Dr Bhaduri-McIntosh’s team said their results provide new insight into anticancer drug development because they reveal a mechanistic link between these 2 proteins.

Dr Bhaduri-McIntosh emphasized that, because STAT3 is involved in most cancers, her group’s findings could potentially impact the prevention or treatment of several types of cancer—something her lab is investigating.

Burkitt lymphoma

Credit: Ed Uthman

Researchers say they’ve discovered how the protein STAT3 interferes with an antitumor mechanism in cells, thereby promoting the growth of lymphoma and other cancers.

The group made their discovery using the Epstein-Barr virus (EBV) as a tool to investigate cancer development.

“Our findings add to the short list of known mechanisms by which a key cellular antitumor barrier is breached by STAT3 prior to cancer development,” said Sumita Bhaduri-McIntosh, MD, PhD, of Stony Brook University School of Medicine in New York.

“Because STAT3 interferes with this innate antitumor mechanism in cells, the opposite occurs when blood cells are infected in the lab with the cancer-causing virus EBV, and the cells continue to divide—a necessary step in cancer development.”

Dr Bhaduri-McIntosh and her colleagues described their research in PNAS.

The team explained that STAT3 inhibits a cancer-suppressing cellular activity called the DNA damage response (DDR). Normally, this response pauses cell division, allowing for the repair of damaged DNA.

But this study showed that EBV not only causes DNA damage when it infects and replicates in cells; it also activates and increases STAT3 expression. This starts a chain reaction that leads to an “un-pause” in cell division, thereby promoting cell proliferation. This, in combination with other pro-proliferative effects of the virus, can lead to cancers.

The researchers found that DDR does detect replication stress-associated DNA damage resulting from EBV infection. But signaling downstream of ATR proteins is impaired by STAT3. And this leads to relaxation of the intra-S phase checkpoint of the cell cycle.

STAT3 interrupts signaling from ATR to the protein Chk1 by promoting the loss of Claspin, a protein that assists ATR to phosphorylate Chk1. The loss of Claspin, which facilitates cell proliferation, is mediated by caspase 7.

Previous research suggested that STAT3 and Chk1 are potential targets for cancer therapies. Dr Bhaduri-McIntosh’s team said their results provide new insight into anticancer drug development because they reveal a mechanistic link between these 2 proteins.

Dr Bhaduri-McIntosh emphasized that, because STAT3 is involved in most cancers, her group’s findings could potentially impact the prevention or treatment of several types of cancer—something her lab is investigating.

Burkitt lymphoma

Credit: Ed Uthman

Researchers say they’ve discovered how the protein STAT3 interferes with an antitumor mechanism in cells, thereby promoting the growth of lymphoma and other cancers.

The group made their discovery using the Epstein-Barr virus (EBV) as a tool to investigate cancer development.

“Our findings add to the short list of known mechanisms by which a key cellular antitumor barrier is breached by STAT3 prior to cancer development,” said Sumita Bhaduri-McIntosh, MD, PhD, of Stony Brook University School of Medicine in New York.

“Because STAT3 interferes with this innate antitumor mechanism in cells, the opposite occurs when blood cells are infected in the lab with the cancer-causing virus EBV, and the cells continue to divide—a necessary step in cancer development.”

Dr Bhaduri-McIntosh and her colleagues described their research in PNAS.

The team explained that STAT3 inhibits a cancer-suppressing cellular activity called the DNA damage response (DDR). Normally, this response pauses cell division, allowing for the repair of damaged DNA.

But this study showed that EBV not only causes DNA damage when it infects and replicates in cells; it also activates and increases STAT3 expression. This starts a chain reaction that leads to an “un-pause” in cell division, thereby promoting cell proliferation. This, in combination with other pro-proliferative effects of the virus, can lead to cancers.

The researchers found that DDR does detect replication stress-associated DNA damage resulting from EBV infection. But signaling downstream of ATR proteins is impaired by STAT3. And this leads to relaxation of the intra-S phase checkpoint of the cell cycle.

STAT3 interrupts signaling from ATR to the protein Chk1 by promoting the loss of Claspin, a protein that assists ATR to phosphorylate Chk1. The loss of Claspin, which facilitates cell proliferation, is mediated by caspase 7.

Previous research suggested that STAT3 and Chk1 are potential targets for cancer therapies. Dr Bhaduri-McIntosh’s team said their results provide new insight into anticancer drug development because they reveal a mechanistic link between these 2 proteins.

Dr Bhaduri-McIntosh emphasized that, because STAT3 is involved in most cancers, her group’s findings could potentially impact the prevention or treatment of several types of cancer—something her lab is investigating.

Foods commonly consumed as

part of a Mediterranean diet

In a large study, individuals who strictly followed a Mediterranean diet had lower levels of platelets and white blood cells (WBCs) than those who deviated from the diet.

And the lower cell counts were associated with lower levels of inflammation.

The research also suggested the diet as a whole, and not just certain components, was responsible for these markers of improved health.

Marialaura Bonaccio, PhD, of the IRCCS Istituto Neurologico Mediterraneo NEUROMED in Italy, and her colleagues reported these findings in Blood.

The team noted that the Mediterranean diet—which is characterized by a wide consumption of plant foods, cereals, legumes, fish, and olive oil, as well as moderate wine consumption—has long been hailed as a heart-healthy eating plan. And previous research suggested the diet can reduce inflammation.

But the connection between the diet and levels of platelets and WBCs, 2 specific inflammatory markers in the body, has remained unclear.

“We undertook this study to understand the correlation between consuming a Mediterranean diet and specific health markers, including platelet levels and white blood cell counts, which can more specifically explain the diet’s benefits in reducing the long-term risk of cerebral and heart disease or other chronic conditions,” Dr Bonaccio said.

To do this, she and her colleagues analyzed the eating habits of 14,586 healthy Italian men and women aged 35 and older. At baseline, all subjects were healthy.

The researchers measured total platelet and WBC counts and grouped participants according to their levels (low, normal, or high), based on age- and gender-specific cut-offs.

Participants with high platelet levels were younger and had a greater incidence of high cholesterol and increased levels of common inflammation marker C-reactive protein when compared to subjects in the normal or low-platelet categories.

Individuals in the high-WBC category were mainly younger, male, and smokers. They had a higher body-mass index and higher levels of C-reactive protein and blood glucose than subjects in the other groups. They also showed higher prevalence of high blood pressure and high cholesterol.

The researchers determined participants’ adherence to a Mediterranean using 2 dietary scoring systems, the Mediterranean diet score or the Italian Mediterranean Index, which helped to accurately determine intake levels and portion sizes.

Results of these analyses revealed that adherence to the Mediterranean diet was directly related to lower levels of platelets and WBCs (P<0.0001 and P=0.008, respectively), which was correlated with lower levels of inflammation.

When compared with participants who did not follow the eating plan as closely, subjects who strictly followed the diet were less likely to belong to the group with the highest platelet counts (odds ratio=0.50) and more likely to belong to the group with the lowest WBC counts (odds ratio=1.41).

“Because the study included healthy participants, the lower levels of platelets and white blood cells in those who were more strictly consuming a Mediterranean diet indicate that this eating plan could account for substantial changes within normal ranges of variability,” Dr Bonaccio said.

“This is an important finding that has implications for how these anti-inflammatory markers are tracked among the general population.”

The researchers also evaluated the role of specific components of the diet to help clarify the observed correlation, including food antioxidant content and fiber intake, both of which have previously been connected to cardiovascular benefits.

These components only partially accounted for the link between the diet and WBC count. And they did not fully explain the correlation to platelet levels.

“An important finding of this study is that it indicates that the Mediterranean diet as a whole, and not just a few specific ingredients, is likely responsible for the beneficial health outcomes among the healthy population and should be encouraged as part of healthy eating habits,” Dr Bonaccio said.

“Building on these important findings, we continue to study this population to determine if the dietary habits may have an influence on cardiovascular disease-related mortality.”

Foods commonly consumed as

part of a Mediterranean diet

In a large study, individuals who strictly followed a Mediterranean diet had lower levels of platelets and white blood cells (WBCs) than those who deviated from the diet.

And the lower cell counts were associated with lower levels of inflammation.

The research also suggested the diet as a whole, and not just certain components, was responsible for these markers of improved health.

Marialaura Bonaccio, PhD, of the IRCCS Istituto Neurologico Mediterraneo NEUROMED in Italy, and her colleagues reported these findings in Blood.

The team noted that the Mediterranean diet—which is characterized by a wide consumption of plant foods, cereals, legumes, fish, and olive oil, as well as moderate wine consumption—has long been hailed as a heart-healthy eating plan. And previous research suggested the diet can reduce inflammation.

But the connection between the diet and levels of platelets and WBCs, 2 specific inflammatory markers in the body, has remained unclear.

“We undertook this study to understand the correlation between consuming a Mediterranean diet and specific health markers, including platelet levels and white blood cell counts, which can more specifically explain the diet’s benefits in reducing the long-term risk of cerebral and heart disease or other chronic conditions,” Dr Bonaccio said.

To do this, she and her colleagues analyzed the eating habits of 14,586 healthy Italian men and women aged 35 and older. At baseline, all subjects were healthy.

The researchers measured total platelet and WBC counts and grouped participants according to their levels (low, normal, or high), based on age- and gender-specific cut-offs.

Participants with high platelet levels were younger and had a greater incidence of high cholesterol and increased levels of common inflammation marker C-reactive protein when compared to subjects in the normal or low-platelet categories.

Individuals in the high-WBC category were mainly younger, male, and smokers. They had a higher body-mass index and higher levels of C-reactive protein and blood glucose than subjects in the other groups. They also showed higher prevalence of high blood pressure and high cholesterol.

The researchers determined participants’ adherence to a Mediterranean using 2 dietary scoring systems, the Mediterranean diet score or the Italian Mediterranean Index, which helped to accurately determine intake levels and portion sizes.

Results of these analyses revealed that adherence to the Mediterranean diet was directly related to lower levels of platelets and WBCs (P<0.0001 and P=0.008, respectively), which was correlated with lower levels of inflammation.

When compared with participants who did not follow the eating plan as closely, subjects who strictly followed the diet were less likely to belong to the group with the highest platelet counts (odds ratio=0.50) and more likely to belong to the group with the lowest WBC counts (odds ratio=1.41).

“Because the study included healthy participants, the lower levels of platelets and white blood cells in those who were more strictly consuming a Mediterranean diet indicate that this eating plan could account for substantial changes within normal ranges of variability,” Dr Bonaccio said.

“This is an important finding that has implications for how these anti-inflammatory markers are tracked among the general population.”

The researchers also evaluated the role of specific components of the diet to help clarify the observed correlation, including food antioxidant content and fiber intake, both of which have previously been connected to cardiovascular benefits.

These components only partially accounted for the link between the diet and WBC count. And they did not fully explain the correlation to platelet levels.

“An important finding of this study is that it indicates that the Mediterranean diet as a whole, and not just a few specific ingredients, is likely responsible for the beneficial health outcomes among the healthy population and should be encouraged as part of healthy eating habits,” Dr Bonaccio said.

“Building on these important findings, we continue to study this population to determine if the dietary habits may have an influence on cardiovascular disease-related mortality.”

Foods commonly consumed as

part of a Mediterranean diet

In a large study, individuals who strictly followed a Mediterranean diet had lower levels of platelets and white blood cells (WBCs) than those who deviated from the diet.

And the lower cell counts were associated with lower levels of inflammation.

The research also suggested the diet as a whole, and not just certain components, was responsible for these markers of improved health.

Marialaura Bonaccio, PhD, of the IRCCS Istituto Neurologico Mediterraneo NEUROMED in Italy, and her colleagues reported these findings in Blood.

The team noted that the Mediterranean diet—which is characterized by a wide consumption of plant foods, cereals, legumes, fish, and olive oil, as well as moderate wine consumption—has long been hailed as a heart-healthy eating plan. And previous research suggested the diet can reduce inflammation.

But the connection between the diet and levels of platelets and WBCs, 2 specific inflammatory markers in the body, has remained unclear.

“We undertook this study to understand the correlation between consuming a Mediterranean diet and specific health markers, including platelet levels and white blood cell counts, which can more specifically explain the diet’s benefits in reducing the long-term risk of cerebral and heart disease or other chronic conditions,” Dr Bonaccio said.

To do this, she and her colleagues analyzed the eating habits of 14,586 healthy Italian men and women aged 35 and older. At baseline, all subjects were healthy.

The researchers measured total platelet and WBC counts and grouped participants according to their levels (low, normal, or high), based on age- and gender-specific cut-offs.

Participants with high platelet levels were younger and had a greater incidence of high cholesterol and increased levels of common inflammation marker C-reactive protein when compared to subjects in the normal or low-platelet categories.

Individuals in the high-WBC category were mainly younger, male, and smokers. They had a higher body-mass index and higher levels of C-reactive protein and blood glucose than subjects in the other groups. They also showed higher prevalence of high blood pressure and high cholesterol.

The researchers determined participants’ adherence to a Mediterranean using 2 dietary scoring systems, the Mediterranean diet score or the Italian Mediterranean Index, which helped to accurately determine intake levels and portion sizes.

Results of these analyses revealed that adherence to the Mediterranean diet was directly related to lower levels of platelets and WBCs (P<0.0001 and P=0.008, respectively), which was correlated with lower levels of inflammation.

When compared with participants who did not follow the eating plan as closely, subjects who strictly followed the diet were less likely to belong to the group with the highest platelet counts (odds ratio=0.50) and more likely to belong to the group with the lowest WBC counts (odds ratio=1.41).

“Because the study included healthy participants, the lower levels of platelets and white blood cells in those who were more strictly consuming a Mediterranean diet indicate that this eating plan could account for substantial changes within normal ranges of variability,” Dr Bonaccio said.

“This is an important finding that has implications for how these anti-inflammatory markers are tracked among the general population.”

The researchers also evaluated the role of specific components of the diet to help clarify the observed correlation, including food antioxidant content and fiber intake, both of which have previously been connected to cardiovascular benefits.

These components only partially accounted for the link between the diet and WBC count. And they did not fully explain the correlation to platelet levels.

“An important finding of this study is that it indicates that the Mediterranean diet as a whole, and not just a few specific ingredients, is likely responsible for the beneficial health outcomes among the healthy population and should be encouraged as part of healthy eating habits,” Dr Bonaccio said.

“Building on these important findings, we continue to study this population to determine if the dietary habits may have an influence on cardiovascular disease-related mortality.”

Saline solution

In an attempt to alleviate the shortage of saline (0.9% sodium chloride injection) in the US, the Food and Drug Administration (FDA) is allowing saline products to be imported from Norway.

The company importing the products is Fresenius Kabi USA. The FDA inspected the company’s Norway manufacturing facility and found the site meets FDA standards.

So Fresenius Kabi has begun importing Sodium Chloride 0.9% Freeflex Injection Solution for Intravenous Infusion.

The European product contains the same active ingredient in the same concentration as the 0.9% sodium chloride injection products approved in the US.

For a complete list of all the Fresenius Kabi saline products, as well as a list of differences between the European and US prescribing information, see the “Dear Healthcare Professional” letter posted on the FDA website.

The FDA is asking that healthcare professionals contact Fresenius Kabi USA directly to obtain saline products. The company’s customer service number is 1-888-386-1300.

The FDA concedes that, while the shipments from Norway will help, they will not resolve the saline shortage. However, the agency says it is working closely with manufacturers to meet the needs for saline across the US.

Saline solution

In an attempt to alleviate the shortage of saline (0.9% sodium chloride injection) in the US, the Food and Drug Administration (FDA) is allowing saline products to be imported from Norway.

The company importing the products is Fresenius Kabi USA. The FDA inspected the company’s Norway manufacturing facility and found the site meets FDA standards.

So Fresenius Kabi has begun importing Sodium Chloride 0.9% Freeflex Injection Solution for Intravenous Infusion.

The European product contains the same active ingredient in the same concentration as the 0.9% sodium chloride injection products approved in the US.

For a complete list of all the Fresenius Kabi saline products, as well as a list of differences between the European and US prescribing information, see the “Dear Healthcare Professional” letter posted on the FDA website.

The FDA is asking that healthcare professionals contact Fresenius Kabi USA directly to obtain saline products. The company’s customer service number is 1-888-386-1300.

The FDA concedes that, while the shipments from Norway will help, they will not resolve the saline shortage. However, the agency says it is working closely with manufacturers to meet the needs for saline across the US.

Saline solution

In an attempt to alleviate the shortage of saline (0.9% sodium chloride injection) in the US, the Food and Drug Administration (FDA) is allowing saline products to be imported from Norway.

The company importing the products is Fresenius Kabi USA. The FDA inspected the company’s Norway manufacturing facility and found the site meets FDA standards.

So Fresenius Kabi has begun importing Sodium Chloride 0.9% Freeflex Injection Solution for Intravenous Infusion.

The European product contains the same active ingredient in the same concentration as the 0.9% sodium chloride injection products approved in the US.

For a complete list of all the Fresenius Kabi saline products, as well as a list of differences between the European and US prescribing information, see the “Dear Healthcare Professional” letter posted on the FDA website.

The FDA is asking that healthcare professionals contact Fresenius Kabi USA directly to obtain saline products. The company’s customer service number is 1-888-386-1300.

The FDA concedes that, while the shipments from Norway will help, they will not resolve the saline shortage. However, the agency says it is working closely with manufacturers to meet the needs for saline across the US.

Thrombus

Credit: Andre E.X. Brown

WASHINGTON, DC—A new analysis suggests cangrelor can reduce the risk of stent thrombosis in patients undergoing percutaneous coronary intervention (PCI), when compared to clopidogrel.

In fact, cangrelor was an independent predictor of freedom from stent thrombosis at 30 days after PCI.

These results, obtained by analyzing patients from the CHAMPION PHOENIX trial, were presented at the American College of Cardiology’s 63rd Annual Scientific Session & Expo (presentation 2105-290).

CHAMPION PHOENIX was a prospective, double-blind trial that included 11,145 patients. They were randomized to receive intravenous cangrelor or oral clopidogrel at the time of PCI.

In a previous analysis of the trial data, researchers found that cangrelor reduced the overall odds of complications from stenting procedures—including death, myocardial infarction, ischemia-driven revascularization, and stent thrombosis—compared to clopidogrel. However, cangrelor also increased the risk of major and minor bleeding.

In the new analysis, an independent core laboratory blinded to the treatment performed angiographic analysis in 10,939 of the patients. The researchers defined stent thrombosis as the occurrence of intraprocedural stent thrombosis (IPST) or ARC-defined stent thrombosis (definite or probable).

Stent thrombosis occurred in 120 patients (1.1%) at 48 hours after PCI and in 175 patients (1.6%) at 30 days. The occurrence of stent thrombosis at 48 hours and 30 days was associated with a marked increase in 30-day mortality, with odds ratios (ORs) of 15.3 (P<0.001) and 55.2 (P<0.001), respectively.

IPST, ARC acute stent thrombosis (≤ 24 hrs), and ARC subacute stent thrombosis (1-30 days) occurred in 89 (0.8%), 32 (0.3%), and 60 (0.5%) patients, respectively.

Each type of stent thrombosis was associated with an increase in 30-day mortality. The ORs were 17.4 for IPST (P<0.001), 43.3 for ARC acute stent thrombosis (P<0.001), and 189.1 for ARC subacute stent thrombosis (P<0.001).

“Regardless of the exact type of stent thrombosis, it remains associated with a high rate of death,” said investigator Deepak L. Bhatt, MD, MPH, a professor at Harvard Medical School and co-chair of the CHAMPION program.

However, patients who received cangrelor were less likely than those treated with clopidogrel to develop stent thrombosis, both at 48 hours and at 30 days.

At 48 hours, stent thrombosis had occurred in 0.8% and 1.4% of patients, respectively (P=0.01). And at 30 days, stent thrombosis had occurred in 1.3% and 1.9%, respectively (P=0.01).

Cangrelor appeared to be more effective than clopidogrel at preventing all types of stent thrombosis, although the difference was only statistically significant for IPST.

IPST occurred in 0.6% and 1.0% of patients, respectively (P=0.04). Acute ARC stent thrombosis occurred in 0.2% and 0.4%, respectively (P=0.8). And subacute ARC stent thrombosis occurred in 0.5% and 0.6%, respectively (P=0.60).

Multivariable analysis suggested the use of cangrelor was as an independent predictor of freedom from stent thrombosis at 30 days.

The CHAMPION PHOENIX trial was funded by The Medicines Company, makers of cangrelor.

Thrombus

Credit: Andre E.X. Brown

WASHINGTON, DC—A new analysis suggests cangrelor can reduce the risk of stent thrombosis in patients undergoing percutaneous coronary intervention (PCI), when compared to clopidogrel.

In fact, cangrelor was an independent predictor of freedom from stent thrombosis at 30 days after PCI.

These results, obtained by analyzing patients from the CHAMPION PHOENIX trial, were presented at the American College of Cardiology’s 63rd Annual Scientific Session & Expo (presentation 2105-290).

CHAMPION PHOENIX was a prospective, double-blind trial that included 11,145 patients. They were randomized to receive intravenous cangrelor or oral clopidogrel at the time of PCI.

In a previous analysis of the trial data, researchers found that cangrelor reduced the overall odds of complications from stenting procedures—including death, myocardial infarction, ischemia-driven revascularization, and stent thrombosis—compared to clopidogrel. However, cangrelor also increased the risk of major and minor bleeding.

In the new analysis, an independent core laboratory blinded to the treatment performed angiographic analysis in 10,939 of the patients. The researchers defined stent thrombosis as the occurrence of intraprocedural stent thrombosis (IPST) or ARC-defined stent thrombosis (definite or probable).

Stent thrombosis occurred in 120 patients (1.1%) at 48 hours after PCI and in 175 patients (1.6%) at 30 days. The occurrence of stent thrombosis at 48 hours and 30 days was associated with a marked increase in 30-day mortality, with odds ratios (ORs) of 15.3 (P<0.001) and 55.2 (P<0.001), respectively.

IPST, ARC acute stent thrombosis (≤ 24 hrs), and ARC subacute stent thrombosis (1-30 days) occurred in 89 (0.8%), 32 (0.3%), and 60 (0.5%) patients, respectively.

Each type of stent thrombosis was associated with an increase in 30-day mortality. The ORs were 17.4 for IPST (P<0.001), 43.3 for ARC acute stent thrombosis (P<0.001), and 189.1 for ARC subacute stent thrombosis (P<0.001).

“Regardless of the exact type of stent thrombosis, it remains associated with a high rate of death,” said investigator Deepak L. Bhatt, MD, MPH, a professor at Harvard Medical School and co-chair of the CHAMPION program.

However, patients who received cangrelor were less likely than those treated with clopidogrel to develop stent thrombosis, both at 48 hours and at 30 days.

At 48 hours, stent thrombosis had occurred in 0.8% and 1.4% of patients, respectively (P=0.01). And at 30 days, stent thrombosis had occurred in 1.3% and 1.9%, respectively (P=0.01).

Cangrelor appeared to be more effective than clopidogrel at preventing all types of stent thrombosis, although the difference was only statistically significant for IPST.

IPST occurred in 0.6% and 1.0% of patients, respectively (P=0.04). Acute ARC stent thrombosis occurred in 0.2% and 0.4%, respectively (P=0.8). And subacute ARC stent thrombosis occurred in 0.5% and 0.6%, respectively (P=0.60).

Multivariable analysis suggested the use of cangrelor was as an independent predictor of freedom from stent thrombosis at 30 days.

The CHAMPION PHOENIX trial was funded by The Medicines Company, makers of cangrelor.

Thrombus

Credit: Andre E.X. Brown

WASHINGTON, DC—A new analysis suggests cangrelor can reduce the risk of stent thrombosis in patients undergoing percutaneous coronary intervention (PCI), when compared to clopidogrel.

In fact, cangrelor was an independent predictor of freedom from stent thrombosis at 30 days after PCI.

These results, obtained by analyzing patients from the CHAMPION PHOENIX trial, were presented at the American College of Cardiology’s 63rd Annual Scientific Session & Expo (presentation 2105-290).

CHAMPION PHOENIX was a prospective, double-blind trial that included 11,145 patients. They were randomized to receive intravenous cangrelor or oral clopidogrel at the time of PCI.

In a previous analysis of the trial data, researchers found that cangrelor reduced the overall odds of complications from stenting procedures—including death, myocardial infarction, ischemia-driven revascularization, and stent thrombosis—compared to clopidogrel. However, cangrelor also increased the risk of major and minor bleeding.

In the new analysis, an independent core laboratory blinded to the treatment performed angiographic analysis in 10,939 of the patients. The researchers defined stent thrombosis as the occurrence of intraprocedural stent thrombosis (IPST) or ARC-defined stent thrombosis (definite or probable).

Stent thrombosis occurred in 120 patients (1.1%) at 48 hours after PCI and in 175 patients (1.6%) at 30 days. The occurrence of stent thrombosis at 48 hours and 30 days was associated with a marked increase in 30-day mortality, with odds ratios (ORs) of 15.3 (P<0.001) and 55.2 (P<0.001), respectively.

IPST, ARC acute stent thrombosis (≤ 24 hrs), and ARC subacute stent thrombosis (1-30 days) occurred in 89 (0.8%), 32 (0.3%), and 60 (0.5%) patients, respectively.

Each type of stent thrombosis was associated with an increase in 30-day mortality. The ORs were 17.4 for IPST (P<0.001), 43.3 for ARC acute stent thrombosis (P<0.001), and 189.1 for ARC subacute stent thrombosis (P<0.001).

“Regardless of the exact type of stent thrombosis, it remains associated with a high rate of death,” said investigator Deepak L. Bhatt, MD, MPH, a professor at Harvard Medical School and co-chair of the CHAMPION program.

However, patients who received cangrelor were less likely than those treated with clopidogrel to develop stent thrombosis, both at 48 hours and at 30 days.

At 48 hours, stent thrombosis had occurred in 0.8% and 1.4% of patients, respectively (P=0.01). And at 30 days, stent thrombosis had occurred in 1.3% and 1.9%, respectively (P=0.01).

Cangrelor appeared to be more effective than clopidogrel at preventing all types of stent thrombosis, although the difference was only statistically significant for IPST.

IPST occurred in 0.6% and 1.0% of patients, respectively (P=0.04). Acute ARC stent thrombosis occurred in 0.2% and 0.4%, respectively (P=0.8). And subacute ARC stent thrombosis occurred in 0.5% and 0.6%, respectively (P=0.60).

Multivariable analysis suggested the use of cangrelor was as an independent predictor of freedom from stent thrombosis at 30 days.

The CHAMPION PHOENIX trial was funded by The Medicines Company, makers of cangrelor.

Dementia is not always due to Alzheimer disease. An accurate diagnosis is important, as the various causative conditions can differ in their course and treatment.

Dementia refers to cognitive impairment severe enough to interfere with the ability to independently perform activities of daily living. It can occur at any age but is most common after age 60. Some studies estimate that 13.9% of people age 71 and older have some form of dementia.¹ The prevalence increases with age, ranging from 5% at age 70 to 79 to 37% at age 90 and older.¹

Alzheimer disease accounts for about 60% to 80% of cases,² or an estimated 4.7 million people age 65 and older in the United States, a number anticipated to climb to 13.8 million by 2050.³

Other types of dementia are less often considered and are challenging to recognize, although many have distinct characteristics. This article summarizes the features and management of the more common non-Alzheimer dementias:

• Vascular dementia
• Dementia with Lewy bodies
• Progressive supranuclear palsy
• Corticobasal degeneration
• Multiple system atrophy
• Parkinson disease dementia
• Frontotemporal dementia
• Primary progressive aphasia
• Normal-pressure hydrocephalus
• Rapidly progressive dementia (ie, Creutzfeld-Jakob disease, autoimmune disease).

VASCULAR DEMENTIA

After Alzheimer disease, vascular dementia is the most common dementia, accounting for about 20% to 30% of cases. Clinical criteria have not been widely accepted, although several have been published, including those in the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) and the National Institute of Neurological and Communicative Diseases and Stroke-Association Internationale pour la Recherche et l’Enseignement en Neurosciences.

Risk factors for vascular dementia include cerebrovascular disease (hypertension, diabetes, hyperlipidemia) and coexisting conditions related to atherosclerosis (coronary artery disease, peripheral artery disease).

The Hachinski Ischemic Score is a good bedside tool to help differentiate Alzheimer dementia from vascular dementia.⁵

Sudden onset and stepwise decline

Vascular dementia often presents as a sudden and stepwise progression of cognitive deficits that stabilize and that are caused by vascular insults (Table 1).^6–10 Some patients have continuous decline after a vascular event, indicating that Alzheimer dementia may also be present. Dementia is then defined as a mixed type.

Behavioral problems such as physical aggression, hallucinations, paranoia, and mood fluctuations are common.¹¹

Deficits depend on vascular areas affected

Cognitive deficits are heterogeneous and are often related to the location of the vascular insult. Involvement of subcortical areas may result in executive dysfunction, slowed processing speed, and behavioral changes.¹²

Executive dysfunction may be identified using the Trail Making Test (Part B) or the Executive Interview (EXIT25). Office-based tools such as the Folstein Mini-Mental State Examination, the Montreal Cognitive Assessment, or the St. Louis University Mental Status Examination may also uncover these deficits.

Focal neurologic deficits may be found on clinical examination.

Structural neuroimaging may identify small strokes in areas of the brain affecting cognitive function or occlusion of a larger vessel associated with more profound neurologic deficits. Neuroimaging findings may not correlate with any significant decline noted by the patient, suggesting “silent” strokes.

Treat symptoms and manage risk factors

Although the US Food and Drug Administration (FDA) has not approved any pharmacotherapy for vascular dementia, commonly prescribed cognitive enhancers have demonstrated some benefit.¹³

Behavioral problems such as aggression can be disturbing to the patient and the caregiver. Nonpharmacologic methods (eg, redirection, rescheduling care activities to avoid conflict, avoiding issues that lead to agitation) should be tried first to address these problems.

Drug therapy may be used off-label for neuropsychiatric symptoms such as hallucinations, delusions, and combativeness, but clinical trials of these agents for this purpose have shown mixed results,¹⁴ and their use is often associated with significant risk.¹⁵ Antipsychotic drugs are associated with a risk of death and pneumonia when prescribed for dementia. Many also carry a risk of QT prolongation, which is particularly concerning for patients with coronary artery disease or rhythm disturbances.

The key to reducing further decline is to optimize management of vascular risk factors to reduce stroke risk.

DEMENTIA WITH LEWY BODIES

Dementia with Lewy bodies, the next most common neurodegenerative dementia in the elderly, is characterized by progressive loss of cognitive function, prominent visual hallucinations, and parkinsonism (Table 1).⁶ Disease progression usually occurs over years but can be more rapid than in Alzheimer disease.

Alpha-synucleinopathy results in dysfunction of synaptic vesicles in presynaptic terminals. Lewy bodies may be diffusely spread in cortical and subcortical areas (appearing as spherical masses).

Visual hallucinations are typical

The McKeith criteria¹⁶ are the gold standard for diagnosing probable Lewy body dementia, based on clinical and imaging features (Table 2).

Visual hallucinations are usually well formed and detailed. They may initially be pleasant (eg, seeing children and little people) but may evolve to be accompanied by persecutory delusions.

Parkinsonism develops with or after dementia with Lewy bodies

Dementia with Lewy bodies and Parkinson disease dementia share many clinical and pathologic features; Parkinson dementia also is associated with cortical Lewy bodies.

Parkinsonian features include bradykinesia, masked facies, and rigidity. Resting tremor is less common.

The third report of the Dementia With Lewy Bodies Consortium recommends that the condition be diagnosed if dementia occurs before or concurrently with parkinsonism, and dementia with Parkinson disease should be diagnosed if dementia occurs in the context of well-established Parkinson disease.¹⁶ The development of dementia within 12 months of extrapyramidal signs suggests dementia with Lewy bodies.

Cognitive deficits fluctuate

Cognitive impairment in Lewy body dementia is characterized by progressive dementia with fluctuations in cognitive performance. Family members or caregivers may report that the patient can carry on a conversation one day and the next day be confused and inattentive. Compared with those with Alzheimer dementia, patients with Lewy body dementia have better delayed recall but more problems with executive functioning (planning) and visuospatial skills (following an unfamiliar route, copying a figure).

Specialized imaging provides clues

Dementia with Lewy bodies is associated with diffuse brain atrophy, with no established characteristic pattern on structural neuroimaging with computed tomography (CT) or magnetic resonance imaging (MRI).¹⁷ The contrast agent ioflupane iodine-123 injection (DaTscan) used with single-photon emission CT (SPECT) detects dopamine transporters, which are reduced in parkinsonian syndromes. The scan can also help differentiate between Alzheimer dementia and Lewy body dementia by detecting the loss of functional dopaminergic terminals in the striatum in Lewy body dementia. Alpha-synuclein imaging may become another useful diagnostic tool in the future.

Alzheimer medications may help in dementia with Lewy bodies

Medications with anticholinergic effects and dopamine agonists should be discontinued because of possible effects on cognitive function and parkinsonism. In one clinical trial,¹⁸ rivastigmine (Exelon) was found to help cognitive functioning as well as reduce psychotic symptoms in dementia with Lewy bodies, although a recent Cochrane review could not support the evidence for use of all cholinesterase inhibitors in Lewy body dementia.¹⁹ In another trial,²⁰ memantine (Namenda) was found to improve global clinical status and behavioral symptoms of Lewy body dementia.

Treating hallucinations of dementia with Lewy bodies

Patients with dementia with Lewy bodies are extremely sensitive to the extrapyramidal side effects of neuroleptic drugs. Some evidence indicates that the atypical antipsychotic drug quetiapine (Seroquel) helps with prominent and disturbing psychotic features and is less likely to worsen parkinsonism than other antipsychotics.²¹ The best evidence is for clozapine (Clozaril) as a treatment for hallucinations in Parkinson dementia, but the possible side effect of agranulocytosis limits its clinical use. Other atypical antipsychotics such as risperidone (Risperdal) and olanzapine (Zyprexa) are not recommended.²²

PROGRESSIVE SUPRANUCLEAR PALSY

Progressive supranuclear palsy is a sporadic atypical parkinsonian disorder with onset between age 50 and 70. Familial cases are infrequent.

Progressive supranuclear palsy presents as early postural instability, vertical supranuclear gaze palsy, and axial muscle rigidity in the first few years. Disease progression is gradual: one study of 50 patients found that the median time from onset to the first key motor impairment (unintelligible speech, no independent walking, inability to stand unassisted, wheelchair-bound, or recommendation for feeding tube placement) was 4 years.²³

Histologically, progressive supranuclear palsy is characterized by accumulation of tau protein aggregates in the basal ganglia, brainstem, and cerebral cortex. The degenerative process involves dopaminergic, cholinergic, and gamma-aminobutyric acid (GABA)-ergic neurons.²⁴

Gait and balance problems predominate early in progressive supranuclear palsy

The most commonly used diagnostic criteria are from the National Institute of Neurological Disorders and Stroke. The diagnosis of probable progressive supranuclear palsy requires vertical gaze palsy and falls or the tendency to fall within the first year of disease onset and exclusion of other causes.

The earliest symptom is usually gait and balance impairment.²⁵ Falls (usually backward) and postural instability occur during the first year in 58% of patients.²⁶ Instead of turning en bloc as in Parkinson disease, patients with progressive supranuclear palsy tend to pivot quickly. Patients may also have a coarse groaning voice and moaning. Insomnia has been reported, but rapid-eye-movement sleep behavior disorders are infrequent (unlike in Parkinson disease, multiple system atrophy, and Lewy body dementia).²⁷

Apathy and extreme mood swings

Cognitive impairment is seen in 50% of patients in the early stage of progressive supranuclear palsy. It mostly involves the frontal lobe, including frontal behavioral disturbances (eg, apathy in 91% of patients²⁶ or pseudobulbar affect and extreme emotional lability) and deficits in abstract thoughts or verbal fluency (to test this, patients are asked to say as many words as possible from a category in a given time). Ideomotor apraxia (inability to correctly imitate hand gestures and voluntarily pantomime tool use, such as pretending to brush hair) is rare, despite corticobasal degeneration.²⁸

Vertical gaze palsy

The hallmark of progressive supranuclear palsy is vertical gaze palsy. Initially, this involves slowing of vertical saccades, followed by diminished vertical gaze and more characteristic downward gaze palsy. These findings may develop over 3 to 4 years. Vertical gaze palsy leads to spilling food and tripping while walking.

The gaze abnormality combined with rare blinking and facial dystonia form the classic facial expression of astonishment called “leonine facies.” The face is stiff and deeply furrowed, with a look of surprise.

Axial (especially neck) rigidity is more prominent than limb rigidity. Retrocollis (the head is drawn back) occurs in less than 25% of patients. Parkinsonian features such as bradykinesia affect nearly half of patients by the time of diagnosis.

Instead of the classic symptoms of progressive supranuclear palsy, about one-third of patients present with progressive supranuclear palsy-parkinsonism, which involves asymmetric parkinsonism that initially responds to levodopa.²⁹

MRI shows ‘hummingbird sign’

Brain MRI shows atrophy of the brainstem, particularly the midbrain. Thinning of the superior part of the midbrain and dilation of the third ventricle (“hummingbird sign” on sagittal sections or “morning glory flower” on axial sections) support a diagnosis of progressive supranuclear palsy and differentiate it from Parkinson disease and other atypical parkinsonian disorders.^30,31

Levodopa ineffective for supranuclear palsy

There is no treatment to slow progressive supranuclear palsy. Even in high doses, levodopa rarely alleviates parkinsonian features in a clinically meaningful way.²⁶ Successful experimental biologic therapies have been studied in animal models.³² Davunetide is thought to help with neuronal integrity and cell survival through the stabilization of microtubules in preclinical studies, but it has not been used in clinical practice.³³

CORTICOBASAL DEGENERATION

Corticobasal degeneration is a progressive, asymmetric movement disorder often manifesting initially with cognitive or behavioral impairment. It is associated with abnormality of the cytoskeleton protein tau. Onset is usually after age 60.

Asymmetric movement disorder with cognitive dysfunction

This diagnosis is clinical. Diagnostic criteria proposed in 2003 include the following core features³⁴:

• Insidious onset and progressive course
• No identifiable cause
• Cortical dysfunction with at least one of the following: apraxia, alien limb phenomenon (one limb moves involuntarily with complex movements, eg, grabbing the other hand), cortical sensory loss, visual hemineglect, nonfluent aphasia
• Extrapyramidal dysfunction: focal rigidity unresponsive to levodopa, asymmetric dystonia.

An international consortium has developed more specific clinical research criteria for probable and possible corticobasal degeneration.³⁵ In a series of 147 patients, the following clinical features were found: parkinsonism (100%), higher cortical dysfunction (93%), dyspraxia (82%), gait disorder (80%), unilateral limb dystonia (71%), tremor (55%), and dementia (25%).³⁶

Behavioral problems commonly include depression; apathy, irritability, and agitation are also reported.³⁷

Cognitive testing may reveal deficits in frontal-parietal cognitive domains including attention and concentration, executive function, verbal fluency, and visuospatial skills.³⁸ Learning disabilities may be improved with verbal cueing (in contrast to Alzheimer disease). Patients may also have impaired graphesthesia (the ability to recognize writing on the skin only by the sensation of touch).^39,40

Motor examination may reveal marked asymmetry. Hand, limb, speech, and gait apraxias are common. Gait is typically slow, with short steps and shuffling, and a wide-based or freezing gait. Arm swing may be absent on one side.

Asymmetric cortical atrophy

Early on, MRI may be normal. As the disease progresses, asymmetric cortical atrophy may be seen, especially in the posterior frontal and parietal lobes.

Levodopa ineffective in corticobasal degeneration

Corticobasal degeneration responds poorly to levodopa. Botulinum toxin has been used to help with dystonia and limb pain.

MULTIPLE SYSTEM ATROPHY

Multiple system atrophy is another atypical parkinsonian disorder, most often diagnosed in men over age 60. It is characterized by sporadic parkinsonism, cerebellar signs (involving balance and coordination), pyramidal tract dysfunction, and autonomic insufficiency in varying combinations. Two major subtypes are recognized, depending on whether the predominating presenting features are cerebellar signs or parkinsonism. In contrast to dementia with Lewy bodies, psychiatric symptoms are not a major feature, except possibly depression.⁴¹

Diagnosis requires a sporadic progressive disorder that has features of autonomic failure and poor response of parkinsonism or cerebellar ataxia to levodopa.⁴²

Multiple system atrophy is usually not associated with dementia in the early stages, but patients develop deficits in learning, recognition, memory, and verbal fluency as the disease progresses.⁴³ Rapid-eye-movement sleep behavior disorder has been reported in more than half of patients.⁴⁴

A neurologic examination provides clues

Parkinsonian features are usually symmetric, in contrast to idiopathic Parkinson disease. These signs may include akinesia with rigidity, postural instability, hypokinetic speech, and tremor.

Cerebellar signs include nystagmus and dysarthria (speech disturbance), and gait and limb ataxia.

Pyramidal features include extensor plantar responses and hyperreflexia.

Autonomic dysfunction includes orthostatic hypotension, bladder and rectal atony, loss of sweating, urinary or fecal incontinence, and erectile dysfunction.

Electromyography may demonstrate decreased anal sphincter tone.

MRI shows atrophy of putamen and pons

Brain MRI may show atrophy of the putamen (hypointensity of the putamen with a hyperintense rim). Pons atrophy may also be present, revealing a “hot cross bun” sign in axial images. These combined findings have specificity above 90% but limited sensitivity. These signs are useful to distinguish multiple system atrophy from Parkinson dementia, but their absence does not exclude the diagnosis of multiple system atrophy.^45,46

Multiple system atrophy typically responds poorly to levodopa

Levodopa may improve movement and rigidity, but many respond poorly to treatment or lose response after a few years. Fludrocortisone (Florinef) or vasoconstrictors such as midodrine (Orvaten, Proamatine) may help with orthostatic hypotension.^47,48

PARKINSON DISEASE DEMENTIA

Dementia eventually develops in most patients with Parkinson disease. Older age and the akinetic rigid form of the disease are associated with higher risk. Diagnosis of idiopathic Parkinson disease before the development of dementia is essential for the diagnosis.

The Movement Disorder Society Task Force has developed new diagnostic criteria.⁴⁹ Deficits must be present in at least two of the four core cognitive domains (attention, memory, executive, and visuospatial functions) and must be severe enough to affect daily functioning.

Behavioral symptoms such as affective changes, hallucinations, and apathy are common.

MRI shows characteristic brain atrophy in Parkinson disease dementia

MRI shows reduced gray matter volume in the frontal lobe in patients with Parkinson disease without dementia compared with controls. In Parkinson disease dementia, reduced volume extends to temporal, occipital, and subcortical areas. No significant volumetric differences have been observed in Parkinson dementia compared with dementia with Lewy bodies.⁵⁰ A greater decrease of glucose metabolism has been found in the inferior parietal and occipital lobes in Parkinson disease dementia than in Parkinson disease without dementia.⁵¹

Rivastigmine effective for dementia

A Cochrane review supports the use of acetylcholinesterase inhibitors in patients with Parkinson disease dementia, with a positive impact on global assessment, cognitive function, behavioral disturbance, and activities of daily living rating scales.¹⁹ At this time, rivastigmine is the only FDA-approved cholinesterase inhibitor for treating Parkinson disease dementia. In clinical trials, memantine did not improve global clinical status or behavioral symptoms of dementia of Parkinson disease.⁵¹

FRONTOTEMPORAL DEMENTIA

Frontotemporal dementia frequently starts before age 65 and accounts for 20% to 50% of dementias in this age group.⁵² Recognition of the condition in older patients is also growing.⁵³ Frontotemporal dementia encompasses a spectrum of dementias, including behavioral variant frontotemporal dementia, semantic dementia, and progressive nonfluent aphasia.⁵⁴

Gradual onset of uncharacteristic behaviors

Accepted diagnostic criteria include core features of gradual onset, early decline in social and interpersonal conduct, early impairment of self-regulation, emotional blunting, and loss of insight. Many patients are diagnosed with psychiatric conditions. Changes reported by family and caregivers typically deviate substantially from the person’s usual behavior, such as impulsive and inappropriate behaviors or complete withdrawal and apathy.

Language sometimes affected in frontotemporal dementia

Language impairment may be present in some variants. Behavioral and language changes often accompany other forms of dementia (Alzheimer disease, vascular dementia, primary progressive aphasia), making diagnosis more challenging. Office-based testing often does not reveal any deficits, although the Frontal Behavioral Inventory may help.⁵⁵ A referral to a clinical neuropsychologist may help identify and quantify cognitive impairments.

MRI shows frontotemporal lobes affected

Structural neuroimaging may not reveal abnormalities initially, but with progression, atrophy may be seen in the frontal and temporal lobes. Functional neuroimaging (positron emission tomography, brain SPECT, functional MRI) show hypometabolism in the same areas.

Treat symptoms

There are no specific FDA-approved therapies for frontotemporal dementia. Acetylcholinesterase inhibitors can help progressive nonfluent aphasia in some cases. Selective serotonin reuptake inhibitors may alleviate depressive symptoms, and low doses of atypical antipsychotic medications may help with impulsivity, disinhibition, and aggressive or disruptive behaviors.⁵⁶

PRIMARY PROGRESSIVE APHASIA

Language impairment predominates

Primary progressive aphasia is a rare form of dementia in which symptoms typically develop around age 60. Pathology is varied. In a study of 60 patients with initial clinical symptoms of primary progressive aphasia, postmortem histology of brain tissue revealed various findings, including those consistent with Alzheimer pathology and motor neuron diseasetype inclusions.⁵⁷

Patients typically present with expressive language problems as the primary deficit for the first 2 years of the disease, with preservation in other cognitive areas such as memory, visuospatial skills, and executive function.⁵⁸ Office-based testing may overstate the severity of the dementia, given the dependence of performance on intact language.

It is important to distinguish primary progressive aphasia from other dementias that also affect language. In the frontal variant of frontotemporal dementia, the primary language problem is anomia (inability to name objects) or diminished speech output, which may be accompanied by behavioral problems. Semantic dementia affects word recognition as well as comprehension. In Alzheimer disease, language may be affected along with memory and other areas of cognitive function.

Imaging shows focal degeneration in the left hemisphere

Structural neuroimaging does not initially reveal any deficits, but later it may reveal atrophy in the frontal, perisylvian complex, and temporal areas of the left hemisphere, reflecting the focal nature of the degeneration.⁵⁹ Functional neuroimaging (positron emission tomography, SPECT) may reveal hypometabolism or diminished blood flow in these areas prior to changes in structural neuroimaging.⁶⁰

Other communication methods may help

There are no FDA-approved therapies for primary progressive aphasia. Off-label use of some agents (eg, selective serotonin reuptake inhibitors and small doses of antipsychotic medications) has been found useful in small trials.⁵⁶ Patients may benefit from learning other forms of communication, such as using sign language, laminated cards with printed words or pictures, or artificial voice synthesizers, to express their needs.

NORMAL-PRESSURE HYDROCEPHALUS

Classic triad: Gait, cognition, incontinence

With the onset of symptoms in the sixth or seventh decade, normal-pressure hydrocephalus affects less than 1% of people age 65 and older. It represents up to 5% of dementias, although estimates are influenced by the varied criteria for diagnosis.⁶¹ It is characterized by the classic triad of gait impairment, cognitive impairment, and urinary frequency or incontinence.⁶²

Symptoms progress over a period of years, with gait impairment often predominating. As this triad is common in the geriatric population, identifying other explanations is important. Gait impairment caused by spinal stenosis, peripheral neuropathy, or parkinsonism should be explored. Cognitive impairment could be due to depression, Alzheimer disease, or other forms of dementia. Urinary symptoms may be related to detrusor instability or an enlarged prostate.

Gait impairment initially manifests as slowing of gait, but progresses to difficulty with gait initiation. Gait tends to be wide-based (stance more than 1 foot wide).

Cognitive impairment is typically subcortical, manifested as slowed processing speed and impaired executive function. Recall and working memory may be impaired.

Enlarged ventricles seen on imaging in normal-pressure hydrocephalus

Structural neuroimaging reveals enlarged ventricles (Evan’s ratio > 0.358). This can be difficult to distinguish from ventriculomegaly due to cerebral atrophy; assessing the callosal angle on MRI may distinguish the two.^63,64 Diagnosis of normal-pressure hydrocephalus can be confirmed using a cerebrospinal fluid infusion test to assess resistance of fluid to resorption.⁶⁵

Treat with cerebrospinal fluid drainage

Specific tests should be performed to determine candidacy for surgery. These include a high-volume lumbar puncture (40 to 50 mL) or a trial of external lumbar drainage (10 mL per hour for 48 to 72 hours).⁶⁵ Definitive treatment is surgical placement of a shunt to allow cerebrospinal fluid to drain into the atria or peritoneal cavity.

Surgery may improve gait, but cognitive symptoms often remain,⁶⁶ and clinical decline may occur after the shunt is placed. Once gait dysfunction is resolved, other explanations for cognitive impairment or residual gait impairment should be considered. An underlying reason for progression of normal-pressure hydrocephalus symptoms after surgical intervention should be identified.⁶⁷

RAPIDLY PROGRESSIVE DEMENTIAS

Rapidly progressive dementias are among the most challenging of dementing illnesses. They are characterized by a subacute course and an accelerated rate of decline, developing in less than 2 years. Evaluation should typically be more comprehensive than for other types of dementia. The main goal is to diagnose potentially treatable conditions, such as Hashimoto encephalopathy or paraneoplastic limbic encephalitis, and to distinguish these conditions from diseases with a very poor prognosis, such as Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease

Creutzfeldt-Jakob disease is a fatal prion-related neurodegenerative illness. Sporadic disease is most common, but variant, familial, and iatrogenic types have been reported. The most common initial symptoms in sporadic disease are cognitive (39%), cerebellar (21%), behavioral (20%), constitutional (20%), sensory (11%), motor (9%), and visual (7%).⁶⁸

Chronic neurodegenerative diseases can be misdiagnosed as Creutzfeldt-Jakob disease because of an atypical time course and multi-system neurologic findings.

The US Centers for Disease Control and Prevention has adopted criteria for diagnosing probable Creutzfeldt-Jakob disease (Table 3). Routine investigations should also not suggest an alternative diagnosis.⁶⁹

Autoimmune diseases

Autoimmune conditions may present as a rapidly progressive dementia, including Hashimoto encephalopathy and antibody-mediated limbic encephalitis, either associated with cancer (paraneoplastic) or without cancer (nonparaneoplastic).

Paraneoplastic limbic encephalitis is a group of inflammatory conditions involving antibodies produced within the cerebrospinal fluid and serum resulting in neurologic symptoms. These antibodies react against proteins expressed mostly by a tumor somewhere else in the body.⁷⁰

Hashimoto encephalitis is a subacute to chronic encephalopathy that may present as dementia with abnormally high levels of thyroid antibodies. The symptoms can vary from confusion to psychosis. There are two main presentations: one involves a relapsing-remitting course with stroke-like episodes (27% of patients) and the second consists of insidious onset of seizures (66% of patients).

Diagnosis involves testing for elevated anti-thyroid peroxidase and thyroglobulin antibodies. MRI findings are nonspecific. Hashimoto encephalitis responds to treatment with corticosteroids, plasmapheresis, or immunosuppressive therapy.⁷¹

Dementia is not always due to Alzheimer disease. An accurate diagnosis is important, as the various causative conditions can differ in their course and treatment.

Dementia refers to cognitive impairment severe enough to interfere with the ability to independently perform activities of daily living. It can occur at any age but is most common after age 60. Some studies estimate that 13.9% of people age 71 and older have some form of dementia.¹ The prevalence increases with age, ranging from 5% at age 70 to 79 to 37% at age 90 and older.¹

Alzheimer disease accounts for about 60% to 80% of cases,² or an estimated 4.7 million people age 65 and older in the United States, a number anticipated to climb to 13.8 million by 2050.³

Other types of dementia are less often considered and are challenging to recognize, although many have distinct characteristics. This article summarizes the features and management of the more common non-Alzheimer dementias:

• Vascular dementia
• Dementia with Lewy bodies
• Progressive supranuclear palsy
• Corticobasal degeneration
• Multiple system atrophy
• Parkinson disease dementia
• Frontotemporal dementia
• Primary progressive aphasia
• Normal-pressure hydrocephalus
• Rapidly progressive dementia (ie, Creutzfeld-Jakob disease, autoimmune disease).

VASCULAR DEMENTIA

After Alzheimer disease, vascular dementia is the most common dementia, accounting for about 20% to 30% of cases. Clinical criteria have not been widely accepted, although several have been published, including those in the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) and the National Institute of Neurological and Communicative Diseases and Stroke-Association Internationale pour la Recherche et l’Enseignement en Neurosciences.

Risk factors for vascular dementia include cerebrovascular disease (hypertension, diabetes, hyperlipidemia) and coexisting conditions related to atherosclerosis (coronary artery disease, peripheral artery disease).

The Hachinski Ischemic Score is a good bedside tool to help differentiate Alzheimer dementia from vascular dementia.⁵

Sudden onset and stepwise decline

Vascular dementia often presents as a sudden and stepwise progression of cognitive deficits that stabilize and that are caused by vascular insults (Table 1).^6–10 Some patients have continuous decline after a vascular event, indicating that Alzheimer dementia may also be present. Dementia is then defined as a mixed type.

Behavioral problems such as physical aggression, hallucinations, paranoia, and mood fluctuations are common.¹¹

Deficits depend on vascular areas affected

Cognitive deficits are heterogeneous and are often related to the location of the vascular insult. Involvement of subcortical areas may result in executive dysfunction, slowed processing speed, and behavioral changes.¹²

Executive dysfunction may be identified using the Trail Making Test (Part B) or the Executive Interview (EXIT25). Office-based tools such as the Folstein Mini-Mental State Examination, the Montreal Cognitive Assessment, or the St. Louis University Mental Status Examination may also uncover these deficits.

Focal neurologic deficits may be found on clinical examination.

Structural neuroimaging may identify small strokes in areas of the brain affecting cognitive function or occlusion of a larger vessel associated with more profound neurologic deficits. Neuroimaging findings may not correlate with any significant decline noted by the patient, suggesting “silent” strokes.

Treat symptoms and manage risk factors

Although the US Food and Drug Administration (FDA) has not approved any pharmacotherapy for vascular dementia, commonly prescribed cognitive enhancers have demonstrated some benefit.¹³

Behavioral problems such as aggression can be disturbing to the patient and the caregiver. Nonpharmacologic methods (eg, redirection, rescheduling care activities to avoid conflict, avoiding issues that lead to agitation) should be tried first to address these problems.

Drug therapy may be used off-label for neuropsychiatric symptoms such as hallucinations, delusions, and combativeness, but clinical trials of these agents for this purpose have shown mixed results,¹⁴ and their use is often associated with significant risk.¹⁵ Antipsychotic drugs are associated with a risk of death and pneumonia when prescribed for dementia. Many also carry a risk of QT prolongation, which is particularly concerning for patients with coronary artery disease or rhythm disturbances.

The key to reducing further decline is to optimize management of vascular risk factors to reduce stroke risk.

DEMENTIA WITH LEWY BODIES

Dementia with Lewy bodies, the next most common neurodegenerative dementia in the elderly, is characterized by progressive loss of cognitive function, prominent visual hallucinations, and parkinsonism (Table 1).⁶ Disease progression usually occurs over years but can be more rapid than in Alzheimer disease.

Alpha-synucleinopathy results in dysfunction of synaptic vesicles in presynaptic terminals. Lewy bodies may be diffusely spread in cortical and subcortical areas (appearing as spherical masses).

Visual hallucinations are typical

The McKeith criteria¹⁶ are the gold standard for diagnosing probable Lewy body dementia, based on clinical and imaging features (Table 2).

Visual hallucinations are usually well formed and detailed. They may initially be pleasant (eg, seeing children and little people) but may evolve to be accompanied by persecutory delusions.

Parkinsonism develops with or after dementia with Lewy bodies

Dementia with Lewy bodies and Parkinson disease dementia share many clinical and pathologic features; Parkinson dementia also is associated with cortical Lewy bodies.

Parkinsonian features include bradykinesia, masked facies, and rigidity. Resting tremor is less common.

The third report of the Dementia With Lewy Bodies Consortium recommends that the condition be diagnosed if dementia occurs before or concurrently with parkinsonism, and dementia with Parkinson disease should be diagnosed if dementia occurs in the context of well-established Parkinson disease.¹⁶ The development of dementia within 12 months of extrapyramidal signs suggests dementia with Lewy bodies.

Cognitive deficits fluctuate

Cognitive impairment in Lewy body dementia is characterized by progressive dementia with fluctuations in cognitive performance. Family members or caregivers may report that the patient can carry on a conversation one day and the next day be confused and inattentive. Compared with those with Alzheimer dementia, patients with Lewy body dementia have better delayed recall but more problems with executive functioning (planning) and visuospatial skills (following an unfamiliar route, copying a figure).

Specialized imaging provides clues

Dementia with Lewy bodies is associated with diffuse brain atrophy, with no established characteristic pattern on structural neuroimaging with computed tomography (CT) or magnetic resonance imaging (MRI).¹⁷ The contrast agent ioflupane iodine-123 injection (DaTscan) used with single-photon emission CT (SPECT) detects dopamine transporters, which are reduced in parkinsonian syndromes. The scan can also help differentiate between Alzheimer dementia and Lewy body dementia by detecting the loss of functional dopaminergic terminals in the striatum in Lewy body dementia. Alpha-synuclein imaging may become another useful diagnostic tool in the future.

Alzheimer medications may help in dementia with Lewy bodies

Medications with anticholinergic effects and dopamine agonists should be discontinued because of possible effects on cognitive function and parkinsonism. In one clinical trial,¹⁸ rivastigmine (Exelon) was found to help cognitive functioning as well as reduce psychotic symptoms in dementia with Lewy bodies, although a recent Cochrane review could not support the evidence for use of all cholinesterase inhibitors in Lewy body dementia.¹⁹ In another trial,²⁰ memantine (Namenda) was found to improve global clinical status and behavioral symptoms of Lewy body dementia.

Treating hallucinations of dementia with Lewy bodies

Patients with dementia with Lewy bodies are extremely sensitive to the extrapyramidal side effects of neuroleptic drugs. Some evidence indicates that the atypical antipsychotic drug quetiapine (Seroquel) helps with prominent and disturbing psychotic features and is less likely to worsen parkinsonism than other antipsychotics.²¹ The best evidence is for clozapine (Clozaril) as a treatment for hallucinations in Parkinson dementia, but the possible side effect of agranulocytosis limits its clinical use. Other atypical antipsychotics such as risperidone (Risperdal) and olanzapine (Zyprexa) are not recommended.²²

PROGRESSIVE SUPRANUCLEAR PALSY

Progressive supranuclear palsy is a sporadic atypical parkinsonian disorder with onset between age 50 and 70. Familial cases are infrequent.

Progressive supranuclear palsy presents as early postural instability, vertical supranuclear gaze palsy, and axial muscle rigidity in the first few years. Disease progression is gradual: one study of 50 patients found that the median time from onset to the first key motor impairment (unintelligible speech, no independent walking, inability to stand unassisted, wheelchair-bound, or recommendation for feeding tube placement) was 4 years.²³

Histologically, progressive supranuclear palsy is characterized by accumulation of tau protein aggregates in the basal ganglia, brainstem, and cerebral cortex. The degenerative process involves dopaminergic, cholinergic, and gamma-aminobutyric acid (GABA)-ergic neurons.²⁴

Gait and balance problems predominate early in progressive supranuclear palsy

The most commonly used diagnostic criteria are from the National Institute of Neurological Disorders and Stroke. The diagnosis of probable progressive supranuclear palsy requires vertical gaze palsy and falls or the tendency to fall within the first year of disease onset and exclusion of other causes.

The earliest symptom is usually gait and balance impairment.²⁵ Falls (usually backward) and postural instability occur during the first year in 58% of patients.²⁶ Instead of turning en bloc as in Parkinson disease, patients with progressive supranuclear palsy tend to pivot quickly. Patients may also have a coarse groaning voice and moaning. Insomnia has been reported, but rapid-eye-movement sleep behavior disorders are infrequent (unlike in Parkinson disease, multiple system atrophy, and Lewy body dementia).²⁷

Apathy and extreme mood swings

Cognitive impairment is seen in 50% of patients in the early stage of progressive supranuclear palsy. It mostly involves the frontal lobe, including frontal behavioral disturbances (eg, apathy in 91% of patients²⁶ or pseudobulbar affect and extreme emotional lability) and deficits in abstract thoughts or verbal fluency (to test this, patients are asked to say as many words as possible from a category in a given time). Ideomotor apraxia (inability to correctly imitate hand gestures and voluntarily pantomime tool use, such as pretending to brush hair) is rare, despite corticobasal degeneration.²⁸

Vertical gaze palsy

The hallmark of progressive supranuclear palsy is vertical gaze palsy. Initially, this involves slowing of vertical saccades, followed by diminished vertical gaze and more characteristic downward gaze palsy. These findings may develop over 3 to 4 years. Vertical gaze palsy leads to spilling food and tripping while walking.

The gaze abnormality combined with rare blinking and facial dystonia form the classic facial expression of astonishment called “leonine facies.” The face is stiff and deeply furrowed, with a look of surprise.

Axial (especially neck) rigidity is more prominent than limb rigidity. Retrocollis (the head is drawn back) occurs in less than 25% of patients. Parkinsonian features such as bradykinesia affect nearly half of patients by the time of diagnosis.

Instead of the classic symptoms of progressive supranuclear palsy, about one-third of patients present with progressive supranuclear palsy-parkinsonism, which involves asymmetric parkinsonism that initially responds to levodopa.²⁹

MRI shows ‘hummingbird sign’

Brain MRI shows atrophy of the brainstem, particularly the midbrain. Thinning of the superior part of the midbrain and dilation of the third ventricle (“hummingbird sign” on sagittal sections or “morning glory flower” on axial sections) support a diagnosis of progressive supranuclear palsy and differentiate it from Parkinson disease and other atypical parkinsonian disorders.^30,31

Levodopa ineffective for supranuclear palsy

There is no treatment to slow progressive supranuclear palsy. Even in high doses, levodopa rarely alleviates parkinsonian features in a clinically meaningful way.²⁶ Successful experimental biologic therapies have been studied in animal models.³² Davunetide is thought to help with neuronal integrity and cell survival through the stabilization of microtubules in preclinical studies, but it has not been used in clinical practice.³³

CORTICOBASAL DEGENERATION

Corticobasal degeneration is a progressive, asymmetric movement disorder often manifesting initially with cognitive or behavioral impairment. It is associated with abnormality of the cytoskeleton protein tau. Onset is usually after age 60.

Asymmetric movement disorder with cognitive dysfunction

This diagnosis is clinical. Diagnostic criteria proposed in 2003 include the following core features³⁴:

• Insidious onset and progressive course
• No identifiable cause
• Cortical dysfunction with at least one of the following: apraxia, alien limb phenomenon (one limb moves involuntarily with complex movements, eg, grabbing the other hand), cortical sensory loss, visual hemineglect, nonfluent aphasia
• Extrapyramidal dysfunction: focal rigidity unresponsive to levodopa, asymmetric dystonia.

An international consortium has developed more specific clinical research criteria for probable and possible corticobasal degeneration.³⁵ In a series of 147 patients, the following clinical features were found: parkinsonism (100%), higher cortical dysfunction (93%), dyspraxia (82%), gait disorder (80%), unilateral limb dystonia (71%), tremor (55%), and dementia (25%).³⁶

Behavioral problems commonly include depression; apathy, irritability, and agitation are also reported.³⁷

Cognitive testing may reveal deficits in frontal-parietal cognitive domains including attention and concentration, executive function, verbal fluency, and visuospatial skills.³⁸ Learning disabilities may be improved with verbal cueing (in contrast to Alzheimer disease). Patients may also have impaired graphesthesia (the ability to recognize writing on the skin only by the sensation of touch).^39,40

Motor examination may reveal marked asymmetry. Hand, limb, speech, and gait apraxias are common. Gait is typically slow, with short steps and shuffling, and a wide-based or freezing gait. Arm swing may be absent on one side.

Asymmetric cortical atrophy

Early on, MRI may be normal. As the disease progresses, asymmetric cortical atrophy may be seen, especially in the posterior frontal and parietal lobes.

Levodopa ineffective in corticobasal degeneration

Corticobasal degeneration responds poorly to levodopa. Botulinum toxin has been used to help with dystonia and limb pain.

MULTIPLE SYSTEM ATROPHY

Multiple system atrophy is another atypical parkinsonian disorder, most often diagnosed in men over age 60. It is characterized by sporadic parkinsonism, cerebellar signs (involving balance and coordination), pyramidal tract dysfunction, and autonomic insufficiency in varying combinations. Two major subtypes are recognized, depending on whether the predominating presenting features are cerebellar signs or parkinsonism. In contrast to dementia with Lewy bodies, psychiatric symptoms are not a major feature, except possibly depression.⁴¹

Diagnosis requires a sporadic progressive disorder that has features of autonomic failure and poor response of parkinsonism or cerebellar ataxia to levodopa.⁴²

Multiple system atrophy is usually not associated with dementia in the early stages, but patients develop deficits in learning, recognition, memory, and verbal fluency as the disease progresses.⁴³ Rapid-eye-movement sleep behavior disorder has been reported in more than half of patients.⁴⁴

A neurologic examination provides clues

Parkinsonian features are usually symmetric, in contrast to idiopathic Parkinson disease. These signs may include akinesia with rigidity, postural instability, hypokinetic speech, and tremor.

Cerebellar signs include nystagmus and dysarthria (speech disturbance), and gait and limb ataxia.

Pyramidal features include extensor plantar responses and hyperreflexia.

Autonomic dysfunction includes orthostatic hypotension, bladder and rectal atony, loss of sweating, urinary or fecal incontinence, and erectile dysfunction.

Electromyography may demonstrate decreased anal sphincter tone.

MRI shows atrophy of putamen and pons

Brain MRI may show atrophy of the putamen (hypointensity of the putamen with a hyperintense rim). Pons atrophy may also be present, revealing a “hot cross bun” sign in axial images. These combined findings have specificity above 90% but limited sensitivity. These signs are useful to distinguish multiple system atrophy from Parkinson dementia, but their absence does not exclude the diagnosis of multiple system atrophy.^45,46

Multiple system atrophy typically responds poorly to levodopa

Levodopa may improve movement and rigidity, but many respond poorly to treatment or lose response after a few years. Fludrocortisone (Florinef) or vasoconstrictors such as midodrine (Orvaten, Proamatine) may help with orthostatic hypotension.^47,48

PARKINSON DISEASE DEMENTIA

Dementia eventually develops in most patients with Parkinson disease. Older age and the akinetic rigid form of the disease are associated with higher risk. Diagnosis of idiopathic Parkinson disease before the development of dementia is essential for the diagnosis.

The Movement Disorder Society Task Force has developed new diagnostic criteria.⁴⁹ Deficits must be present in at least two of the four core cognitive domains (attention, memory, executive, and visuospatial functions) and must be severe enough to affect daily functioning.

Behavioral symptoms such as affective changes, hallucinations, and apathy are common.

MRI shows characteristic brain atrophy in Parkinson disease dementia

MRI shows reduced gray matter volume in the frontal lobe in patients with Parkinson disease without dementia compared with controls. In Parkinson disease dementia, reduced volume extends to temporal, occipital, and subcortical areas. No significant volumetric differences have been observed in Parkinson dementia compared with dementia with Lewy bodies.⁵⁰ A greater decrease of glucose metabolism has been found in the inferior parietal and occipital lobes in Parkinson disease dementia than in Parkinson disease without dementia.⁵¹

Rivastigmine effective for dementia

A Cochrane review supports the use of acetylcholinesterase inhibitors in patients with Parkinson disease dementia, with a positive impact on global assessment, cognitive function, behavioral disturbance, and activities of daily living rating scales.¹⁹ At this time, rivastigmine is the only FDA-approved cholinesterase inhibitor for treating Parkinson disease dementia. In clinical trials, memantine did not improve global clinical status or behavioral symptoms of dementia of Parkinson disease.⁵¹

FRONTOTEMPORAL DEMENTIA

Frontotemporal dementia frequently starts before age 65 and accounts for 20% to 50% of dementias in this age group.⁵² Recognition of the condition in older patients is also growing.⁵³ Frontotemporal dementia encompasses a spectrum of dementias, including behavioral variant frontotemporal dementia, semantic dementia, and progressive nonfluent aphasia.⁵⁴

Gradual onset of uncharacteristic behaviors

Accepted diagnostic criteria include core features of gradual onset, early decline in social and interpersonal conduct, early impairment of self-regulation, emotional blunting, and loss of insight. Many patients are diagnosed with psychiatric conditions. Changes reported by family and caregivers typically deviate substantially from the person’s usual behavior, such as impulsive and inappropriate behaviors or complete withdrawal and apathy.

Language sometimes affected in frontotemporal dementia

Language impairment may be present in some variants. Behavioral and language changes often accompany other forms of dementia (Alzheimer disease, vascular dementia, primary progressive aphasia), making diagnosis more challenging. Office-based testing often does not reveal any deficits, although the Frontal Behavioral Inventory may help.⁵⁵ A referral to a clinical neuropsychologist may help identify and quantify cognitive impairments.

MRI shows frontotemporal lobes affected

Structural neuroimaging may not reveal abnormalities initially, but with progression, atrophy may be seen in the frontal and temporal lobes. Functional neuroimaging (positron emission tomography, brain SPECT, functional MRI) show hypometabolism in the same areas.

Treat symptoms

There are no specific FDA-approved therapies for frontotemporal dementia. Acetylcholinesterase inhibitors can help progressive nonfluent aphasia in some cases. Selective serotonin reuptake inhibitors may alleviate depressive symptoms, and low doses of atypical antipsychotic medications may help with impulsivity, disinhibition, and aggressive or disruptive behaviors.⁵⁶

PRIMARY PROGRESSIVE APHASIA

Language impairment predominates

Primary progressive aphasia is a rare form of dementia in which symptoms typically develop around age 60. Pathology is varied. In a study of 60 patients with initial clinical symptoms of primary progressive aphasia, postmortem histology of brain tissue revealed various findings, including those consistent with Alzheimer pathology and motor neuron diseasetype inclusions.⁵⁷

Patients typically present with expressive language problems as the primary deficit for the first 2 years of the disease, with preservation in other cognitive areas such as memory, visuospatial skills, and executive function.⁵⁸ Office-based testing may overstate the severity of the dementia, given the dependence of performance on intact language.

It is important to distinguish primary progressive aphasia from other dementias that also affect language. In the frontal variant of frontotemporal dementia, the primary language problem is anomia (inability to name objects) or diminished speech output, which may be accompanied by behavioral problems. Semantic dementia affects word recognition as well as comprehension. In Alzheimer disease, language may be affected along with memory and other areas of cognitive function.

Imaging shows focal degeneration in the left hemisphere

Structural neuroimaging does not initially reveal any deficits, but later it may reveal atrophy in the frontal, perisylvian complex, and temporal areas of the left hemisphere, reflecting the focal nature of the degeneration.⁵⁹ Functional neuroimaging (positron emission tomography, SPECT) may reveal hypometabolism or diminished blood flow in these areas prior to changes in structural neuroimaging.⁶⁰

Other communication methods may help

There are no FDA-approved therapies for primary progressive aphasia. Off-label use of some agents (eg, selective serotonin reuptake inhibitors and small doses of antipsychotic medications) has been found useful in small trials.⁵⁶ Patients may benefit from learning other forms of communication, such as using sign language, laminated cards with printed words or pictures, or artificial voice synthesizers, to express their needs.

NORMAL-PRESSURE HYDROCEPHALUS

Classic triad: Gait, cognition, incontinence

With the onset of symptoms in the sixth or seventh decade, normal-pressure hydrocephalus affects less than 1% of people age 65 and older. It represents up to 5% of dementias, although estimates are influenced by the varied criteria for diagnosis.⁶¹ It is characterized by the classic triad of gait impairment, cognitive impairment, and urinary frequency or incontinence.⁶²

Symptoms progress over a period of years, with gait impairment often predominating. As this triad is common in the geriatric population, identifying other explanations is important. Gait impairment caused by spinal stenosis, peripheral neuropathy, or parkinsonism should be explored. Cognitive impairment could be due to depression, Alzheimer disease, or other forms of dementia. Urinary symptoms may be related to detrusor instability or an enlarged prostate.

Gait impairment initially manifests as slowing of gait, but progresses to difficulty with gait initiation. Gait tends to be wide-based (stance more than 1 foot wide).

Cognitive impairment is typically subcortical, manifested as slowed processing speed and impaired executive function. Recall and working memory may be impaired.

Enlarged ventricles seen on imaging in normal-pressure hydrocephalus

Structural neuroimaging reveals enlarged ventricles (Evan’s ratio > 0.358). This can be difficult to distinguish from ventriculomegaly due to cerebral atrophy; assessing the callosal angle on MRI may distinguish the two.^63,64 Diagnosis of normal-pressure hydrocephalus can be confirmed using a cerebrospinal fluid infusion test to assess resistance of fluid to resorption.⁶⁵

Treat with cerebrospinal fluid drainage

Specific tests should be performed to determine candidacy for surgery. These include a high-volume lumbar puncture (40 to 50 mL) or a trial of external lumbar drainage (10 mL per hour for 48 to 72 hours).⁶⁵ Definitive treatment is surgical placement of a shunt to allow cerebrospinal fluid to drain into the atria or peritoneal cavity.

Surgery may improve gait, but cognitive symptoms often remain,⁶⁶ and clinical decline may occur after the shunt is placed. Once gait dysfunction is resolved, other explanations for cognitive impairment or residual gait impairment should be considered. An underlying reason for progression of normal-pressure hydrocephalus symptoms after surgical intervention should be identified.⁶⁷

RAPIDLY PROGRESSIVE DEMENTIAS

Rapidly progressive dementias are among the most challenging of dementing illnesses. They are characterized by a subacute course and an accelerated rate of decline, developing in less than 2 years. Evaluation should typically be more comprehensive than for other types of dementia. The main goal is to diagnose potentially treatable conditions, such as Hashimoto encephalopathy or paraneoplastic limbic encephalitis, and to distinguish these conditions from diseases with a very poor prognosis, such as Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease

Creutzfeldt-Jakob disease is a fatal prion-related neurodegenerative illness. Sporadic disease is most common, but variant, familial, and iatrogenic types have been reported. The most common initial symptoms in sporadic disease are cognitive (39%), cerebellar (21%), behavioral (20%), constitutional (20%), sensory (11%), motor (9%), and visual (7%).⁶⁸

Chronic neurodegenerative diseases can be misdiagnosed as Creutzfeldt-Jakob disease because of an atypical time course and multi-system neurologic findings.

The US Centers for Disease Control and Prevention has adopted criteria for diagnosing probable Creutzfeldt-Jakob disease (Table 3). Routine investigations should also not suggest an alternative diagnosis.⁶⁹

Autoimmune diseases

Autoimmune conditions may present as a rapidly progressive dementia, including Hashimoto encephalopathy and antibody-mediated limbic encephalitis, either associated with cancer (paraneoplastic) or without cancer (nonparaneoplastic).

Paraneoplastic limbic encephalitis is a group of inflammatory conditions involving antibodies produced within the cerebrospinal fluid and serum resulting in neurologic symptoms. These antibodies react against proteins expressed mostly by a tumor somewhere else in the body.⁷⁰

Hashimoto encephalitis is a subacute to chronic encephalopathy that may present as dementia with abnormally high levels of thyroid antibodies. The symptoms can vary from confusion to psychosis. There are two main presentations: one involves a relapsing-remitting course with stroke-like episodes (27% of patients) and the second consists of insidious onset of seizures (66% of patients).

Diagnosis involves testing for elevated anti-thyroid peroxidase and thyroglobulin antibodies. MRI findings are nonspecific. Hashimoto encephalitis responds to treatment with corticosteroids, plasmapheresis, or immunosuppressive therapy.⁷¹

Dementia is not always due to Alzheimer disease. An accurate diagnosis is important, as the various causative conditions can differ in their course and treatment.

Dementia refers to cognitive impairment severe enough to interfere with the ability to independently perform activities of daily living. It can occur at any age but is most common after age 60. Some studies estimate that 13.9% of people age 71 and older have some form of dementia.¹ The prevalence increases with age, ranging from 5% at age 70 to 79 to 37% at age 90 and older.¹

Alzheimer disease accounts for about 60% to 80% of cases,² or an estimated 4.7 million people age 65 and older in the United States, a number anticipated to climb to 13.8 million by 2050.³

Other types of dementia are less often considered and are challenging to recognize, although many have distinct characteristics. This article summarizes the features and management of the more common non-Alzheimer dementias:

• Vascular dementia
• Dementia with Lewy bodies
• Progressive supranuclear palsy
• Corticobasal degeneration
• Multiple system atrophy
• Parkinson disease dementia
• Frontotemporal dementia
• Primary progressive aphasia
• Normal-pressure hydrocephalus
• Rapidly progressive dementia (ie, Creutzfeld-Jakob disease, autoimmune disease).

VASCULAR DEMENTIA

After Alzheimer disease, vascular dementia is the most common dementia, accounting for about 20% to 30% of cases. Clinical criteria have not been widely accepted, although several have been published, including those in the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) and the National Institute of Neurological and Communicative Diseases and Stroke-Association Internationale pour la Recherche et l’Enseignement en Neurosciences.

Risk factors for vascular dementia include cerebrovascular disease (hypertension, diabetes, hyperlipidemia) and coexisting conditions related to atherosclerosis (coronary artery disease, peripheral artery disease).

The Hachinski Ischemic Score is a good bedside tool to help differentiate Alzheimer dementia from vascular dementia.⁵

Sudden onset and stepwise decline

Vascular dementia often presents as a sudden and stepwise progression of cognitive deficits that stabilize and that are caused by vascular insults (Table 1).^6–10 Some patients have continuous decline after a vascular event, indicating that Alzheimer dementia may also be present. Dementia is then defined as a mixed type.

Behavioral problems such as physical aggression, hallucinations, paranoia, and mood fluctuations are common.¹¹

Deficits depend on vascular areas affected

Cognitive deficits are heterogeneous and are often related to the location of the vascular insult. Involvement of subcortical areas may result in executive dysfunction, slowed processing speed, and behavioral changes.¹²

Executive dysfunction may be identified using the Trail Making Test (Part B) or the Executive Interview (EXIT25). Office-based tools such as the Folstein Mini-Mental State Examination, the Montreal Cognitive Assessment, or the St. Louis University Mental Status Examination may also uncover these deficits.

Focal neurologic deficits may be found on clinical examination.

Structural neuroimaging may identify small strokes in areas of the brain affecting cognitive function or occlusion of a larger vessel associated with more profound neurologic deficits. Neuroimaging findings may not correlate with any significant decline noted by the patient, suggesting “silent” strokes.

Treat symptoms and manage risk factors

Although the US Food and Drug Administration (FDA) has not approved any pharmacotherapy for vascular dementia, commonly prescribed cognitive enhancers have demonstrated some benefit.¹³

Behavioral problems such as aggression can be disturbing to the patient and the caregiver. Nonpharmacologic methods (eg, redirection, rescheduling care activities to avoid conflict, avoiding issues that lead to agitation) should be tried first to address these problems.

Drug therapy may be used off-label for neuropsychiatric symptoms such as hallucinations, delusions, and combativeness, but clinical trials of these agents for this purpose have shown mixed results,¹⁴ and their use is often associated with significant risk.¹⁵ Antipsychotic drugs are associated with a risk of death and pneumonia when prescribed for dementia. Many also carry a risk of QT prolongation, which is particularly concerning for patients with coronary artery disease or rhythm disturbances.

The key to reducing further decline is to optimize management of vascular risk factors to reduce stroke risk.

DEMENTIA WITH LEWY BODIES

Dementia with Lewy bodies, the next most common neurodegenerative dementia in the elderly, is characterized by progressive loss of cognitive function, prominent visual hallucinations, and parkinsonism (Table 1).⁶ Disease progression usually occurs over years but can be more rapid than in Alzheimer disease.

Alpha-synucleinopathy results in dysfunction of synaptic vesicles in presynaptic terminals. Lewy bodies may be diffusely spread in cortical and subcortical areas (appearing as spherical masses).

Visual hallucinations are typical

The McKeith criteria¹⁶ are the gold standard for diagnosing probable Lewy body dementia, based on clinical and imaging features (Table 2).

Visual hallucinations are usually well formed and detailed. They may initially be pleasant (eg, seeing children and little people) but may evolve to be accompanied by persecutory delusions.

Parkinsonism develops with or after dementia with Lewy bodies

Dementia with Lewy bodies and Parkinson disease dementia share many clinical and pathologic features; Parkinson dementia also is associated with cortical Lewy bodies.

Parkinsonian features include bradykinesia, masked facies, and rigidity. Resting tremor is less common.

The third report of the Dementia With Lewy Bodies Consortium recommends that the condition be diagnosed if dementia occurs before or concurrently with parkinsonism, and dementia with Parkinson disease should be diagnosed if dementia occurs in the context of well-established Parkinson disease.¹⁶ The development of dementia within 12 months of extrapyramidal signs suggests dementia with Lewy bodies.

Cognitive deficits fluctuate

Cognitive impairment in Lewy body dementia is characterized by progressive dementia with fluctuations in cognitive performance. Family members or caregivers may report that the patient can carry on a conversation one day and the next day be confused and inattentive. Compared with those with Alzheimer dementia, patients with Lewy body dementia have better delayed recall but more problems with executive functioning (planning) and visuospatial skills (following an unfamiliar route, copying a figure).

Specialized imaging provides clues

Dementia with Lewy bodies is associated with diffuse brain atrophy, with no established characteristic pattern on structural neuroimaging with computed tomography (CT) or magnetic resonance imaging (MRI).¹⁷ The contrast agent ioflupane iodine-123 injection (DaTscan) used with single-photon emission CT (SPECT) detects dopamine transporters, which are reduced in parkinsonian syndromes. The scan can also help differentiate between Alzheimer dementia and Lewy body dementia by detecting the loss of functional dopaminergic terminals in the striatum in Lewy body dementia. Alpha-synuclein imaging may become another useful diagnostic tool in the future.

Alzheimer medications may help in dementia with Lewy bodies

Medications with anticholinergic effects and dopamine agonists should be discontinued because of possible effects on cognitive function and parkinsonism. In one clinical trial,¹⁸ rivastigmine (Exelon) was found to help cognitive functioning as well as reduce psychotic symptoms in dementia with Lewy bodies, although a recent Cochrane review could not support the evidence for use of all cholinesterase inhibitors in Lewy body dementia.¹⁹ In another trial,²⁰ memantine (Namenda) was found to improve global clinical status and behavioral symptoms of Lewy body dementia.

Treating hallucinations of dementia with Lewy bodies

Patients with dementia with Lewy bodies are extremely sensitive to the extrapyramidal side effects of neuroleptic drugs. Some evidence indicates that the atypical antipsychotic drug quetiapine (Seroquel) helps with prominent and disturbing psychotic features and is less likely to worsen parkinsonism than other antipsychotics.²¹ The best evidence is for clozapine (Clozaril) as a treatment for hallucinations in Parkinson dementia, but the possible side effect of agranulocytosis limits its clinical use. Other atypical antipsychotics such as risperidone (Risperdal) and olanzapine (Zyprexa) are not recommended.²²

PROGRESSIVE SUPRANUCLEAR PALSY

Progressive supranuclear palsy is a sporadic atypical parkinsonian disorder with onset between age 50 and 70. Familial cases are infrequent.

Progressive supranuclear palsy presents as early postural instability, vertical supranuclear gaze palsy, and axial muscle rigidity in the first few years. Disease progression is gradual: one study of 50 patients found that the median time from onset to the first key motor impairment (unintelligible speech, no independent walking, inability to stand unassisted, wheelchair-bound, or recommendation for feeding tube placement) was 4 years.²³

Histologically, progressive supranuclear palsy is characterized by accumulation of tau protein aggregates in the basal ganglia, brainstem, and cerebral cortex. The degenerative process involves dopaminergic, cholinergic, and gamma-aminobutyric acid (GABA)-ergic neurons.²⁴

Gait and balance problems predominate early in progressive supranuclear palsy

The most commonly used diagnostic criteria are from the National Institute of Neurological Disorders and Stroke. The diagnosis of probable progressive supranuclear palsy requires vertical gaze palsy and falls or the tendency to fall within the first year of disease onset and exclusion of other causes.

The earliest symptom is usually gait and balance impairment.²⁵ Falls (usually backward) and postural instability occur during the first year in 58% of patients.²⁶ Instead of turning en bloc as in Parkinson disease, patients with progressive supranuclear palsy tend to pivot quickly. Patients may also have a coarse groaning voice and moaning. Insomnia has been reported, but rapid-eye-movement sleep behavior disorders are infrequent (unlike in Parkinson disease, multiple system atrophy, and Lewy body dementia).²⁷

Apathy and extreme mood swings

Cognitive impairment is seen in 50% of patients in the early stage of progressive supranuclear palsy. It mostly involves the frontal lobe, including frontal behavioral disturbances (eg, apathy in 91% of patients²⁶ or pseudobulbar affect and extreme emotional lability) and deficits in abstract thoughts or verbal fluency (to test this, patients are asked to say as many words as possible from a category in a given time). Ideomotor apraxia (inability to correctly imitate hand gestures and voluntarily pantomime tool use, such as pretending to brush hair) is rare, despite corticobasal degeneration.²⁸

Vertical gaze palsy

The hallmark of progressive supranuclear palsy is vertical gaze palsy. Initially, this involves slowing of vertical saccades, followed by diminished vertical gaze and more characteristic downward gaze palsy. These findings may develop over 3 to 4 years. Vertical gaze palsy leads to spilling food and tripping while walking.

The gaze abnormality combined with rare blinking and facial dystonia form the classic facial expression of astonishment called “leonine facies.” The face is stiff and deeply furrowed, with a look of surprise.

Axial (especially neck) rigidity is more prominent than limb rigidity. Retrocollis (the head is drawn back) occurs in less than 25% of patients. Parkinsonian features such as bradykinesia affect nearly half of patients by the time of diagnosis.

Instead of the classic symptoms of progressive supranuclear palsy, about one-third of patients present with progressive supranuclear palsy-parkinsonism, which involves asymmetric parkinsonism that initially responds to levodopa.²⁹

MRI shows ‘hummingbird sign’

Brain MRI shows atrophy of the brainstem, particularly the midbrain. Thinning of the superior part of the midbrain and dilation of the third ventricle (“hummingbird sign” on sagittal sections or “morning glory flower” on axial sections) support a diagnosis of progressive supranuclear palsy and differentiate it from Parkinson disease and other atypical parkinsonian disorders.^30,31

Levodopa ineffective for supranuclear palsy

There is no treatment to slow progressive supranuclear palsy. Even in high doses, levodopa rarely alleviates parkinsonian features in a clinically meaningful way.²⁶ Successful experimental biologic therapies have been studied in animal models.³² Davunetide is thought to help with neuronal integrity and cell survival through the stabilization of microtubules in preclinical studies, but it has not been used in clinical practice.³³

CORTICOBASAL DEGENERATION

Corticobasal degeneration is a progressive, asymmetric movement disorder often manifesting initially with cognitive or behavioral impairment. It is associated with abnormality of the cytoskeleton protein tau. Onset is usually after age 60.

Asymmetric movement disorder with cognitive dysfunction

This diagnosis is clinical. Diagnostic criteria proposed in 2003 include the following core features³⁴:

• Insidious onset and progressive course
• No identifiable cause
• Cortical dysfunction with at least one of the following: apraxia, alien limb phenomenon (one limb moves involuntarily with complex movements, eg, grabbing the other hand), cortical sensory loss, visual hemineglect, nonfluent aphasia
• Extrapyramidal dysfunction: focal rigidity unresponsive to levodopa, asymmetric dystonia.

An international consortium has developed more specific clinical research criteria for probable and possible corticobasal degeneration.³⁵ In a series of 147 patients, the following clinical features were found: parkinsonism (100%), higher cortical dysfunction (93%), dyspraxia (82%), gait disorder (80%), unilateral limb dystonia (71%), tremor (55%), and dementia (25%).³⁶

Behavioral problems commonly include depression; apathy, irritability, and agitation are also reported.³⁷

Cognitive testing may reveal deficits in frontal-parietal cognitive domains including attention and concentration, executive function, verbal fluency, and visuospatial skills.³⁸ Learning disabilities may be improved with verbal cueing (in contrast to Alzheimer disease). Patients may also have impaired graphesthesia (the ability to recognize writing on the skin only by the sensation of touch).^39,40

Motor examination may reveal marked asymmetry. Hand, limb, speech, and gait apraxias are common. Gait is typically slow, with short steps and shuffling, and a wide-based or freezing gait. Arm swing may be absent on one side.

Asymmetric cortical atrophy

Early on, MRI may be normal. As the disease progresses, asymmetric cortical atrophy may be seen, especially in the posterior frontal and parietal lobes.

Levodopa ineffective in corticobasal degeneration

Corticobasal degeneration responds poorly to levodopa. Botulinum toxin has been used to help with dystonia and limb pain.

MULTIPLE SYSTEM ATROPHY

Multiple system atrophy is another atypical parkinsonian disorder, most often diagnosed in men over age 60. It is characterized by sporadic parkinsonism, cerebellar signs (involving balance and coordination), pyramidal tract dysfunction, and autonomic insufficiency in varying combinations. Two major subtypes are recognized, depending on whether the predominating presenting features are cerebellar signs or parkinsonism. In contrast to dementia with Lewy bodies, psychiatric symptoms are not a major feature, except possibly depression.⁴¹

Diagnosis requires a sporadic progressive disorder that has features of autonomic failure and poor response of parkinsonism or cerebellar ataxia to levodopa.⁴²

Multiple system atrophy is usually not associated with dementia in the early stages, but patients develop deficits in learning, recognition, memory, and verbal fluency as the disease progresses.⁴³ Rapid-eye-movement sleep behavior disorder has been reported in more than half of patients.⁴⁴

A neurologic examination provides clues

Parkinsonian features are usually symmetric, in contrast to idiopathic Parkinson disease. These signs may include akinesia with rigidity, postural instability, hypokinetic speech, and tremor.

Cerebellar signs include nystagmus and dysarthria (speech disturbance), and gait and limb ataxia.

Pyramidal features include extensor plantar responses and hyperreflexia.

Autonomic dysfunction includes orthostatic hypotension, bladder and rectal atony, loss of sweating, urinary or fecal incontinence, and erectile dysfunction.

Electromyography may demonstrate decreased anal sphincter tone.

MRI shows atrophy of putamen and pons

Brain MRI may show atrophy of the putamen (hypointensity of the putamen with a hyperintense rim). Pons atrophy may also be present, revealing a “hot cross bun” sign in axial images. These combined findings have specificity above 90% but limited sensitivity. These signs are useful to distinguish multiple system atrophy from Parkinson dementia, but their absence does not exclude the diagnosis of multiple system atrophy.^45,46

Multiple system atrophy typically responds poorly to levodopa

Levodopa may improve movement and rigidity, but many respond poorly to treatment or lose response after a few years. Fludrocortisone (Florinef) or vasoconstrictors such as midodrine (Orvaten, Proamatine) may help with orthostatic hypotension.^47,48

PARKINSON DISEASE DEMENTIA

Dementia eventually develops in most patients with Parkinson disease. Older age and the akinetic rigid form of the disease are associated with higher risk. Diagnosis of idiopathic Parkinson disease before the development of dementia is essential for the diagnosis.

The Movement Disorder Society Task Force has developed new diagnostic criteria.⁴⁹ Deficits must be present in at least two of the four core cognitive domains (attention, memory, executive, and visuospatial functions) and must be severe enough to affect daily functioning.

Behavioral symptoms such as affective changes, hallucinations, and apathy are common.

MRI shows characteristic brain atrophy in Parkinson disease dementia

MRI shows reduced gray matter volume in the frontal lobe in patients with Parkinson disease without dementia compared with controls. In Parkinson disease dementia, reduced volume extends to temporal, occipital, and subcortical areas. No significant volumetric differences have been observed in Parkinson dementia compared with dementia with Lewy bodies.⁵⁰ A greater decrease of glucose metabolism has been found in the inferior parietal and occipital lobes in Parkinson disease dementia than in Parkinson disease without dementia.⁵¹

Rivastigmine effective for dementia

A Cochrane review supports the use of acetylcholinesterase inhibitors in patients with Parkinson disease dementia, with a positive impact on global assessment, cognitive function, behavioral disturbance, and activities of daily living rating scales.¹⁹ At this time, rivastigmine is the only FDA-approved cholinesterase inhibitor for treating Parkinson disease dementia. In clinical trials, memantine did not improve global clinical status or behavioral symptoms of dementia of Parkinson disease.⁵¹

FRONTOTEMPORAL DEMENTIA

Frontotemporal dementia frequently starts before age 65 and accounts for 20% to 50% of dementias in this age group.⁵² Recognition of the condition in older patients is also growing.⁵³ Frontotemporal dementia encompasses a spectrum of dementias, including behavioral variant frontotemporal dementia, semantic dementia, and progressive nonfluent aphasia.⁵⁴

Gradual onset of uncharacteristic behaviors

Accepted diagnostic criteria include core features of gradual onset, early decline in social and interpersonal conduct, early impairment of self-regulation, emotional blunting, and loss of insight. Many patients are diagnosed with psychiatric conditions. Changes reported by family and caregivers typically deviate substantially from the person’s usual behavior, such as impulsive and inappropriate behaviors or complete withdrawal and apathy.

Language sometimes affected in frontotemporal dementia

Language impairment may be present in some variants. Behavioral and language changes often accompany other forms of dementia (Alzheimer disease, vascular dementia, primary progressive aphasia), making diagnosis more challenging. Office-based testing often does not reveal any deficits, although the Frontal Behavioral Inventory may help.⁵⁵ A referral to a clinical neuropsychologist may help identify and quantify cognitive impairments.

MRI shows frontotemporal lobes affected

Structural neuroimaging may not reveal abnormalities initially, but with progression, atrophy may be seen in the frontal and temporal lobes. Functional neuroimaging (positron emission tomography, brain SPECT, functional MRI) show hypometabolism in the same areas.

Treat symptoms

There are no specific FDA-approved therapies for frontotemporal dementia. Acetylcholinesterase inhibitors can help progressive nonfluent aphasia in some cases. Selective serotonin reuptake inhibitors may alleviate depressive symptoms, and low doses of atypical antipsychotic medications may help with impulsivity, disinhibition, and aggressive or disruptive behaviors.⁵⁶

PRIMARY PROGRESSIVE APHASIA

Language impairment predominates

Primary progressive aphasia is a rare form of dementia in which symptoms typically develop around age 60. Pathology is varied. In a study of 60 patients with initial clinical symptoms of primary progressive aphasia, postmortem histology of brain tissue revealed various findings, including those consistent with Alzheimer pathology and motor neuron diseasetype inclusions.⁵⁷

Patients typically present with expressive language problems as the primary deficit for the first 2 years of the disease, with preservation in other cognitive areas such as memory, visuospatial skills, and executive function.⁵⁸ Office-based testing may overstate the severity of the dementia, given the dependence of performance on intact language.

It is important to distinguish primary progressive aphasia from other dementias that also affect language. In the frontal variant of frontotemporal dementia, the primary language problem is anomia (inability to name objects) or diminished speech output, which may be accompanied by behavioral problems. Semantic dementia affects word recognition as well as comprehension. In Alzheimer disease, language may be affected along with memory and other areas of cognitive function.

Imaging shows focal degeneration in the left hemisphere

Structural neuroimaging does not initially reveal any deficits, but later it may reveal atrophy in the frontal, perisylvian complex, and temporal areas of the left hemisphere, reflecting the focal nature of the degeneration.⁵⁹ Functional neuroimaging (positron emission tomography, SPECT) may reveal hypometabolism or diminished blood flow in these areas prior to changes in structural neuroimaging.⁶⁰

Other communication methods may help

There are no FDA-approved therapies for primary progressive aphasia. Off-label use of some agents (eg, selective serotonin reuptake inhibitors and small doses of antipsychotic medications) has been found useful in small trials.⁵⁶ Patients may benefit from learning other forms of communication, such as using sign language, laminated cards with printed words or pictures, or artificial voice synthesizers, to express their needs.

NORMAL-PRESSURE HYDROCEPHALUS

Classic triad: Gait, cognition, incontinence

With the onset of symptoms in the sixth or seventh decade, normal-pressure hydrocephalus affects less than 1% of people age 65 and older. It represents up to 5% of dementias, although estimates are influenced by the varied criteria for diagnosis.⁶¹ It is characterized by the classic triad of gait impairment, cognitive impairment, and urinary frequency or incontinence.⁶²

Symptoms progress over a period of years, with gait impairment often predominating. As this triad is common in the geriatric population, identifying other explanations is important. Gait impairment caused by spinal stenosis, peripheral neuropathy, or parkinsonism should be explored. Cognitive impairment could be due to depression, Alzheimer disease, or other forms of dementia. Urinary symptoms may be related to detrusor instability or an enlarged prostate.

Gait impairment initially manifests as slowing of gait, but progresses to difficulty with gait initiation. Gait tends to be wide-based (stance more than 1 foot wide).

Cognitive impairment is typically subcortical, manifested as slowed processing speed and impaired executive function. Recall and working memory may be impaired.

Enlarged ventricles seen on imaging in normal-pressure hydrocephalus

Structural neuroimaging reveals enlarged ventricles (Evan’s ratio > 0.358). This can be difficult to distinguish from ventriculomegaly due to cerebral atrophy; assessing the callosal angle on MRI may distinguish the two.^63,64 Diagnosis of normal-pressure hydrocephalus can be confirmed using a cerebrospinal fluid infusion test to assess resistance of fluid to resorption.⁶⁵

Treat with cerebrospinal fluid drainage

Specific tests should be performed to determine candidacy for surgery. These include a high-volume lumbar puncture (40 to 50 mL) or a trial of external lumbar drainage (10 mL per hour for 48 to 72 hours).⁶⁵ Definitive treatment is surgical placement of a shunt to allow cerebrospinal fluid to drain into the atria or peritoneal cavity.

Surgery may improve gait, but cognitive symptoms often remain,⁶⁶ and clinical decline may occur after the shunt is placed. Once gait dysfunction is resolved, other explanations for cognitive impairment or residual gait impairment should be considered. An underlying reason for progression of normal-pressure hydrocephalus symptoms after surgical intervention should be identified.⁶⁷

RAPIDLY PROGRESSIVE DEMENTIAS

Rapidly progressive dementias are among the most challenging of dementing illnesses. They are characterized by a subacute course and an accelerated rate of decline, developing in less than 2 years. Evaluation should typically be more comprehensive than for other types of dementia. The main goal is to diagnose potentially treatable conditions, such as Hashimoto encephalopathy or paraneoplastic limbic encephalitis, and to distinguish these conditions from diseases with a very poor prognosis, such as Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease

Creutzfeldt-Jakob disease is a fatal prion-related neurodegenerative illness. Sporadic disease is most common, but variant, familial, and iatrogenic types have been reported. The most common initial symptoms in sporadic disease are cognitive (39%), cerebellar (21%), behavioral (20%), constitutional (20%), sensory (11%), motor (9%), and visual (7%).⁶⁸

Chronic neurodegenerative diseases can be misdiagnosed as Creutzfeldt-Jakob disease because of an atypical time course and multi-system neurologic findings.

The US Centers for Disease Control and Prevention has adopted criteria for diagnosing probable Creutzfeldt-Jakob disease (Table 3). Routine investigations should also not suggest an alternative diagnosis.⁶⁹

Autoimmune diseases

Autoimmune conditions may present as a rapidly progressive dementia, including Hashimoto encephalopathy and antibody-mediated limbic encephalitis, either associated with cancer (paraneoplastic) or without cancer (nonparaneoplastic).

Paraneoplastic limbic encephalitis is a group of inflammatory conditions involving antibodies produced within the cerebrospinal fluid and serum resulting in neurologic symptoms. These antibodies react against proteins expressed mostly by a tumor somewhere else in the body.⁷⁰

Hashimoto encephalitis is a subacute to chronic encephalopathy that may present as dementia with abnormally high levels of thyroid antibodies. The symptoms can vary from confusion to psychosis. There are two main presentations: one involves a relapsing-remitting course with stroke-like episodes (27% of patients) and the second consists of insidious onset of seizures (66% of patients).

Diagnosis involves testing for elevated anti-thyroid peroxidase and thyroglobulin antibodies. MRI findings are nonspecific. Hashimoto encephalitis responds to treatment with corticosteroids, plasmapheresis, or immunosuppressive therapy.⁷¹