In patients with “borderline” hypertension or those in whom the duration of blood pressure elevation is hard to ascertain, the finding of end-organ damage has traditionally been used as an argument to institute aggressive antihypertensive therapy. In this setting, retinal hypertensive disease, an S4 gallop, and left ventricular hypertrophy (LVH) are often specifically sought.

LVH and otherwise unexplained chronic kidney disease in patients with hypertension have generally been believed to be products of the elevated arterial pressure, and primary treatment has targeted pressure control. Bauml and Underwood, in this issue of the Journal, emphasize some published clinical trial data indicating that LVH may be an independent risk factor for poorer cardiovascular outcome. Even more provocative is the suggestion that LVH can be reversed, as can the associated increased risk of cardiovascular morbidity, independently of the hypertension.

Given our current understanding that LVH, under some conditions, can be induced by products of the renin-angiotensin system, this would suggest that pharmacologic blockade of this enzyme system should have extra benefit, above that seen from other antihypertensive agents. Conceivably, this may be true only in patients with LVH, and the time course of benefit may not directly parallel that seen with the control of hypertension. That theoretically may explain the lack of uniform advantage of angiotensin blockade over other effective antihypertensive approaches.

Since electrocardiography is a specific but not very sensitive test for LVH, the authors suggest that patients with hypertension be routinely screened for LVH using echocardiography. I am not sure the weight of the evidence supports this approach at present, particularly in the current frenzy of cost containment. Nonetheless, this concept warrants consideration, and at the least, large patient databases might be screened retrospectively to further validate or refute the concept that hypertension-associated LVH is an independent, reversible risk factor for cardiovascular morbidity.

In patients with “borderline” hypertension or those in whom the duration of blood pressure elevation is hard to ascertain, the finding of end-organ damage has traditionally been used as an argument to institute aggressive antihypertensive therapy. In this setting, retinal hypertensive disease, an S4 gallop, and left ventricular hypertrophy (LVH) are often specifically sought.

LVH and otherwise unexplained chronic kidney disease in patients with hypertension have generally been believed to be products of the elevated arterial pressure, and primary treatment has targeted pressure control. Bauml and Underwood, in this issue of the Journal, emphasize some published clinical trial data indicating that LVH may be an independent risk factor for poorer cardiovascular outcome. Even more provocative is the suggestion that LVH can be reversed, as can the associated increased risk of cardiovascular morbidity, independently of the hypertension.

Given our current understanding that LVH, under some conditions, can be induced by products of the renin-angiotensin system, this would suggest that pharmacologic blockade of this enzyme system should have extra benefit, above that seen from other antihypertensive agents. Conceivably, this may be true only in patients with LVH, and the time course of benefit may not directly parallel that seen with the control of hypertension. That theoretically may explain the lack of uniform advantage of angiotensin blockade over other effective antihypertensive approaches.

Since electrocardiography is a specific but not very sensitive test for LVH, the authors suggest that patients with hypertension be routinely screened for LVH using echocardiography. I am not sure the weight of the evidence supports this approach at present, particularly in the current frenzy of cost containment. Nonetheless, this concept warrants consideration, and at the least, large patient databases might be screened retrospectively to further validate or refute the concept that hypertension-associated LVH is an independent, reversible risk factor for cardiovascular morbidity.

In patients with “borderline” hypertension or those in whom the duration of blood pressure elevation is hard to ascertain, the finding of end-organ damage has traditionally been used as an argument to institute aggressive antihypertensive therapy. In this setting, retinal hypertensive disease, an S4 gallop, and left ventricular hypertrophy (LVH) are often specifically sought.

LVH and otherwise unexplained chronic kidney disease in patients with hypertension have generally been believed to be products of the elevated arterial pressure, and primary treatment has targeted pressure control. Bauml and Underwood, in this issue of the Journal, emphasize some published clinical trial data indicating that LVH may be an independent risk factor for poorer cardiovascular outcome. Even more provocative is the suggestion that LVH can be reversed, as can the associated increased risk of cardiovascular morbidity, independently of the hypertension.

Given our current understanding that LVH, under some conditions, can be induced by products of the renin-angiotensin system, this would suggest that pharmacologic blockade of this enzyme system should have extra benefit, above that seen from other antihypertensive agents. Conceivably, this may be true only in patients with LVH, and the time course of benefit may not directly parallel that seen with the control of hypertension. That theoretically may explain the lack of uniform advantage of angiotensin blockade over other effective antihypertensive approaches.

Since electrocardiography is a specific but not very sensitive test for LVH, the authors suggest that patients with hypertension be routinely screened for LVH using echocardiography. I am not sure the weight of the evidence supports this approach at present, particularly in the current frenzy of cost containment. Nonetheless, this concept warrants consideration, and at the least, large patient databases might be screened retrospectively to further validate or refute the concept that hypertension-associated LVH is an independent, reversible risk factor for cardiovascular morbidity.

Left ventricular hypertrophy (LVH) strongly predicts cardiovascular morbidity and overall mortality in hypertensive patients. ^1–7 Antihypertensive treatment that causes LVH to regress decreases the rates of adverse cardiovascular events and improves survival, independent of how much the blood pressure is lowered.^8–11 It is clinically important to recognize that LVH is a modifiable risk factor and that management is more complex than just blood pressure control.

This paper reviews the definition of LVH, compares the diagnostic tests for it, and discusses the current evidence-based approach to managing this dangerous risk factor.

A CHRONICALLY ELEVATED CARDIAC WORKLOAD CAUSES LVH

LVH is an abnormal increase in the mass of the left ventricular myocardium caused by a chronically increased workload on the heart.¹² This most commonly results from the heart pumping against an elevated afterload, as in hypertension and aortic stenosis. Another notable cause is increased filling of the left ventricle (ie, diastolic overload), which is the underlying mechanism for LVH in patients with aortic or mitral regurgitation and dilated cardiomyopathy. Coronary artery disease can also play a role in the pathogenesis of LVH, as the normal myocardium attempts to compensate for the ischemic or infarcted tissue.¹³

The development of myocardial fibrosis appears to be pathophysiologically linked to the renin-angiotensin-aldosterone system. Specifically, there is evidence that angiotensin II has a profibrotic effect on the myocardium of hypertensive patients.¹⁵ This may explain why angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are among the most potent agents for treating LVH, as we will discuss later in this review.

DIAGNOSIS BY ELECTROCARDIOGRAPHY, ECHOCARDIOGRAPHY, OR MRI

Many different criteria for electrocardiographic LVH have been proposed over the years. Most use the voltage in one or more leads, with or without additional factors such as QRS duration, secondary ST-T wave abnormalities, or left atrial abnormalities. The most well known electrocardiographic criteria are the Cornell voltage,²¹ the Cornell product,²² the Sokolow-Lyon index,²³ and the Romhilt-Estes point score system (Table 1).²⁴

• Cornell voltage—median sensitivity 15%, median specificity 96%
• Cornell product—median sensitivity 19.5%, median specificity 91%
• Sokolow-Lyon voltage—median sensitivity 21%, median specificity 89%
• Romhilt-Estes point score—median sensitivity 17%, median specificity 95%.

Of note, the ranges of the published values were extremely broad. For example, the ranges in sensitivity were:

• Cornell voltage—2% to 41%
• Cornell product—8% to 32%
• Sokolow-Lyon voltage—4% to 51%
• Romhilt-Estes point score—0% to 41%.

While the studies with the extreme values may have had issues of small sample size or poor study quality, the wide range in values may primarily be the result of diverse study populations as well as different validation methods and cutoff values to define LVH. Regardless, the overall message of high specificity and low sensitivity is indisputable.

Electrocardiography is insensitive for diagnosing LVH because it relies on measuring the electrical activity of the heart by electrodes on the surface of the skin to predict the left ventricular mass. The intracardiac electrical activity is problematic to measure externally because the measurements are affected by everything between the myocardium and the electrodes, most notably fat, fluid, and air. Because of this effect, electrocardiography underdiagnoses LVH in patients with obesity, pleural effusions, pericardial effusions, anasarca, or chronic obstructive pulmonary disease. In addition, the diagnosis of LVH by electrocardiography is strongly influenced by age and ethnicity.^25–26

While electrocardiography is not sensitive and cannot be used to rule out LVH, it still has a role in its diagnosis and management. In the landmark Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, regression of LVH (diagnosed electrocardiographically by the Sokolow-Lyon index or the Cornell product criteria) in response to losartan (Cozaar) improved cardiovascular outcomes independent of blood pressure.¹⁰ Based on this, it is reasonable that all hypertensive patients and other patients at risk of LVH who undergo electrocardiography be screened with these two criteria.

Echocardiography, if available, should be the test of choice to assess for LVH. It is much more sensitive than electrocardiography and can also detect other abnormalities such as left ventricular dysfunction and valvular disease.

This test uses transthoracic or transesophageal ultrasonography to measure the left ventricular end-diastolic diameter, posterior wall thickness, and interventricular septum thickness. From these measurements and the patient’s height and weight, the left ventricular mass index can be calculated.²⁷

Several different cutoff values for the left ventricular mass index have been proposed; the LIFE study used values of > 104 g/m² in women and > 116 g/m² in men to define LVH.

When using echocardiography to assess for LVH, it is imperative that the left ventricular mass index be used and not just the left ventricular wall thickness, as often happens in clinical practice. This is necessary because diagnosis by wall thickness alone is not a good indicator of LVH, with a concordance between wall thickness and a left ventricular mass index of only 60%.²⁸ In addition, wall thickness tends to underestimate LVH in women and overestimate it in men.

Is echocardiography cost-effective?

Despite its clear advantages, an important consideration about echocardiography as a screening test for all hypertensive patients is its cost.

A suggested way to reduce cost is to measure the left ventricular mass index only.²⁹ A limited echocardiographic examination is much less expensive than a complete two-dimensional echocardiogram ($255 vs $431 per the 2009 Medicare Ambulatory Payment Classification³⁰) and should be the examination performed if the patient has no other clinical indication for echocardiography.

Another way to control cost is to stratify patients by risk and to do echocardiography only in those who would benefit most from it. Based on the prevalence of LVH, one study concluded that echocardiography is most cost-effective in men 50 years or older.³¹

Further study is necessary to more precisely define the cost-effectiveness of echocardiographic screening for LVH in terms of potentially preventable cardiovascular morbidity and death.

Cardiac MRI: The costly gold standard

Cardiac MRI is the gold standard test for LVH, as it is even more accurate and reproducible than echocardiography.³² It can precisely estimate a patient's left ventricular mass and assess for other structural cardiac abnormalities.

MRI’s use, however, is severely restricted in clinical practice due to its high cost and limited availability. While it may never be used for general screening for LVH, it certainly has a role in clinical research and for assessing cardiac anatomy in special clinical situations.

TREATMENT SHOULD INCLUDE AN ACE INHIBITOR OR ARB

Once LVH has been diagnosed, the next step is to decide on an appropriate treatment plan.

While the choice of therapy will always depend on other comorbidities, a 2003 metaanalysis of antihypertensive medications in the treatment of LVH (controlling for the degree of blood pressure lowering) showed that ARBs were the most efficacious class of agents for reducing the left ventricular mass.³³ Specifically, ARBs decreased the mass by 13%, followed by calcium-channel blockers at 11%, ACE inhibitors at 10%, diuretics at 8%, and beta-blockers at 6%. In pairwise comparison, ARBs, calcium-channel blockers, and ACE inhibitors were all significantly more effective in reducing the left ventricular mass than beta-blockers.

As previously discussed, LVH appears to be pathophysiologically linked to myocardial fibrosis and the renin-angiotensin-aldosterone system. For this reason and based on the data presented above regarding the degree of LVH regression, ACE inhibitors or ARBs should be used as the first-line agents for LVH unless they are contraindicated in the individual patient.

The LIFE study

The LIFE study offers the strongest evidence that treating LVH is beneficial. It showed that in hypertensive patients with electrocardiographic LVH by the Cornell product or Sokolow-Lyon criteria, treatment with antihypertensive drugs that resulted in less-severe LVH on electrocardiography was associated with lower rates of cardiovascular morbidity and death, independent of the blood pressure achieved or the drug used.¹⁰

The end point in this study was a composite of stroke, myocardial infarction, and cardiovascular death. Regression of electrocardiographic LVH in hypertensive patients has also been shown to decrease the incidence of diabetes mellitus,³⁴ atrial fibrillation,³⁵ and hospitalizations for heart failure.³⁶

The LIFE study also examined the prognostic implications of treating LVH detected by echocardiography. In this prospective cohort substudy, patients who had a lower left ventricular mass index during treatment with antihypertensive drugs had lower rates of cardiovascular morbidity and all-cause mortality, independent of the effects of blood pressure and treatment used.¹¹

These results suggest that there may be a role not only for treating LVH, but also for monitoring for a reduction in the left ventricular mass index as a goal of therapy (similar to the way hemoglobin A_1c is used in diabetic patients). If the index is used in this way, one could potentially adjust the dose of current drugs, switch classes, or add an additional drug based on a persistently elevated left ventricular mass index in order to optimize the patient's overall cardiovascular risk. A randomized controlled trial of therapy directed by the mass index vs conventional therapy of LVH would be necessary to assess the clinical utility of this approach.

RECOMMENDATIONS

LVH is a common and potentially modifiable cardiovascular risk factor often overlooked in clinical practice. Ideally, all hypertensive patients should be screened with echocardiography to look for LVH, using the calculated left ventricular mass index rather than wall thickness alone to make the diagnosis. While electrocardiography is specific and also has prognostic implications, it is not sensitive enough to be used alone to screen for LVH.

Once the diagnosis of LVH is made, the initial therapy should be an ARB or an ACE inhibitor. Response to therapy can be assessed by monitoring for a reduction in left ventricular mass index or regression of electrocardiographic LVH.

Treatment-induced regression of LVH decreases adverse cardiovascular events and improves overall survival. When modifying medications in hypertensive patients, it is important to remember that the treatment of LVH is not synonymous with blood pressure control.

Left ventricular hypertrophy (LVH) strongly predicts cardiovascular morbidity and overall mortality in hypertensive patients. ^1–7 Antihypertensive treatment that causes LVH to regress decreases the rates of adverse cardiovascular events and improves survival, independent of how much the blood pressure is lowered.^8–11 It is clinically important to recognize that LVH is a modifiable risk factor and that management is more complex than just blood pressure control.

This paper reviews the definition of LVH, compares the diagnostic tests for it, and discusses the current evidence-based approach to managing this dangerous risk factor.

A CHRONICALLY ELEVATED CARDIAC WORKLOAD CAUSES LVH

LVH is an abnormal increase in the mass of the left ventricular myocardium caused by a chronically increased workload on the heart.¹² This most commonly results from the heart pumping against an elevated afterload, as in hypertension and aortic stenosis. Another notable cause is increased filling of the left ventricle (ie, diastolic overload), which is the underlying mechanism for LVH in patients with aortic or mitral regurgitation and dilated cardiomyopathy. Coronary artery disease can also play a role in the pathogenesis of LVH, as the normal myocardium attempts to compensate for the ischemic or infarcted tissue.¹³

The development of myocardial fibrosis appears to be pathophysiologically linked to the renin-angiotensin-aldosterone system. Specifically, there is evidence that angiotensin II has a profibrotic effect on the myocardium of hypertensive patients.¹⁵ This may explain why angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are among the most potent agents for treating LVH, as we will discuss later in this review.

DIAGNOSIS BY ELECTROCARDIOGRAPHY, ECHOCARDIOGRAPHY, OR MRI

Many different criteria for electrocardiographic LVH have been proposed over the years. Most use the voltage in one or more leads, with or without additional factors such as QRS duration, secondary ST-T wave abnormalities, or left atrial abnormalities. The most well known electrocardiographic criteria are the Cornell voltage,²¹ the Cornell product,²² the Sokolow-Lyon index,²³ and the Romhilt-Estes point score system (Table 1).²⁴

• Cornell voltage—median sensitivity 15%, median specificity 96%
• Cornell product—median sensitivity 19.5%, median specificity 91%
• Sokolow-Lyon voltage—median sensitivity 21%, median specificity 89%
• Romhilt-Estes point score—median sensitivity 17%, median specificity 95%.

Of note, the ranges of the published values were extremely broad. For example, the ranges in sensitivity were:

• Cornell voltage—2% to 41%
• Cornell product—8% to 32%
• Sokolow-Lyon voltage—4% to 51%
• Romhilt-Estes point score—0% to 41%.

While the studies with the extreme values may have had issues of small sample size or poor study quality, the wide range in values may primarily be the result of diverse study populations as well as different validation methods and cutoff values to define LVH. Regardless, the overall message of high specificity and low sensitivity is indisputable.

Electrocardiography is insensitive for diagnosing LVH because it relies on measuring the electrical activity of the heart by electrodes on the surface of the skin to predict the left ventricular mass. The intracardiac electrical activity is problematic to measure externally because the measurements are affected by everything between the myocardium and the electrodes, most notably fat, fluid, and air. Because of this effect, electrocardiography underdiagnoses LVH in patients with obesity, pleural effusions, pericardial effusions, anasarca, or chronic obstructive pulmonary disease. In addition, the diagnosis of LVH by electrocardiography is strongly influenced by age and ethnicity.^25–26

While electrocardiography is not sensitive and cannot be used to rule out LVH, it still has a role in its diagnosis and management. In the landmark Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, regression of LVH (diagnosed electrocardiographically by the Sokolow-Lyon index or the Cornell product criteria) in response to losartan (Cozaar) improved cardiovascular outcomes independent of blood pressure.¹⁰ Based on this, it is reasonable that all hypertensive patients and other patients at risk of LVH who undergo electrocardiography be screened with these two criteria.

Echocardiography, if available, should be the test of choice to assess for LVH. It is much more sensitive than electrocardiography and can also detect other abnormalities such as left ventricular dysfunction and valvular disease.

This test uses transthoracic or transesophageal ultrasonography to measure the left ventricular end-diastolic diameter, posterior wall thickness, and interventricular septum thickness. From these measurements and the patient’s height and weight, the left ventricular mass index can be calculated.²⁷

Several different cutoff values for the left ventricular mass index have been proposed; the LIFE study used values of > 104 g/m² in women and > 116 g/m² in men to define LVH.

When using echocardiography to assess for LVH, it is imperative that the left ventricular mass index be used and not just the left ventricular wall thickness, as often happens in clinical practice. This is necessary because diagnosis by wall thickness alone is not a good indicator of LVH, with a concordance between wall thickness and a left ventricular mass index of only 60%.²⁸ In addition, wall thickness tends to underestimate LVH in women and overestimate it in men.

Is echocardiography cost-effective?

Despite its clear advantages, an important consideration about echocardiography as a screening test for all hypertensive patients is its cost.

A suggested way to reduce cost is to measure the left ventricular mass index only.²⁹ A limited echocardiographic examination is much less expensive than a complete two-dimensional echocardiogram ($255 vs $431 per the 2009 Medicare Ambulatory Payment Classification³⁰) and should be the examination performed if the patient has no other clinical indication for echocardiography.

Another way to control cost is to stratify patients by risk and to do echocardiography only in those who would benefit most from it. Based on the prevalence of LVH, one study concluded that echocardiography is most cost-effective in men 50 years or older.³¹

Further study is necessary to more precisely define the cost-effectiveness of echocardiographic screening for LVH in terms of potentially preventable cardiovascular morbidity and death.

Cardiac MRI: The costly gold standard

Cardiac MRI is the gold standard test for LVH, as it is even more accurate and reproducible than echocardiography.³² It can precisely estimate a patient's left ventricular mass and assess for other structural cardiac abnormalities.

MRI’s use, however, is severely restricted in clinical practice due to its high cost and limited availability. While it may never be used for general screening for LVH, it certainly has a role in clinical research and for assessing cardiac anatomy in special clinical situations.

TREATMENT SHOULD INCLUDE AN ACE INHIBITOR OR ARB

Once LVH has been diagnosed, the next step is to decide on an appropriate treatment plan.

While the choice of therapy will always depend on other comorbidities, a 2003 metaanalysis of antihypertensive medications in the treatment of LVH (controlling for the degree of blood pressure lowering) showed that ARBs were the most efficacious class of agents for reducing the left ventricular mass.³³ Specifically, ARBs decreased the mass by 13%, followed by calcium-channel blockers at 11%, ACE inhibitors at 10%, diuretics at 8%, and beta-blockers at 6%. In pairwise comparison, ARBs, calcium-channel blockers, and ACE inhibitors were all significantly more effective in reducing the left ventricular mass than beta-blockers.

As previously discussed, LVH appears to be pathophysiologically linked to myocardial fibrosis and the renin-angiotensin-aldosterone system. For this reason and based on the data presented above regarding the degree of LVH regression, ACE inhibitors or ARBs should be used as the first-line agents for LVH unless they are contraindicated in the individual patient.

The LIFE study

The LIFE study offers the strongest evidence that treating LVH is beneficial. It showed that in hypertensive patients with electrocardiographic LVH by the Cornell product or Sokolow-Lyon criteria, treatment with antihypertensive drugs that resulted in less-severe LVH on electrocardiography was associated with lower rates of cardiovascular morbidity and death, independent of the blood pressure achieved or the drug used.¹⁰

The end point in this study was a composite of stroke, myocardial infarction, and cardiovascular death. Regression of electrocardiographic LVH in hypertensive patients has also been shown to decrease the incidence of diabetes mellitus,³⁴ atrial fibrillation,³⁵ and hospitalizations for heart failure.³⁶

The LIFE study also examined the prognostic implications of treating LVH detected by echocardiography. In this prospective cohort substudy, patients who had a lower left ventricular mass index during treatment with antihypertensive drugs had lower rates of cardiovascular morbidity and all-cause mortality, independent of the effects of blood pressure and treatment used.¹¹

These results suggest that there may be a role not only for treating LVH, but also for monitoring for a reduction in the left ventricular mass index as a goal of therapy (similar to the way hemoglobin A_1c is used in diabetic patients). If the index is used in this way, one could potentially adjust the dose of current drugs, switch classes, or add an additional drug based on a persistently elevated left ventricular mass index in order to optimize the patient's overall cardiovascular risk. A randomized controlled trial of therapy directed by the mass index vs conventional therapy of LVH would be necessary to assess the clinical utility of this approach.

RECOMMENDATIONS

LVH is a common and potentially modifiable cardiovascular risk factor often overlooked in clinical practice. Ideally, all hypertensive patients should be screened with echocardiography to look for LVH, using the calculated left ventricular mass index rather than wall thickness alone to make the diagnosis. While electrocardiography is specific and also has prognostic implications, it is not sensitive enough to be used alone to screen for LVH.

Once the diagnosis of LVH is made, the initial therapy should be an ARB or an ACE inhibitor. Response to therapy can be assessed by monitoring for a reduction in left ventricular mass index or regression of electrocardiographic LVH.

Treatment-induced regression of LVH decreases adverse cardiovascular events and improves overall survival. When modifying medications in hypertensive patients, it is important to remember that the treatment of LVH is not synonymous with blood pressure control.

Left ventricular hypertrophy (LVH) strongly predicts cardiovascular morbidity and overall mortality in hypertensive patients. ^1–7 Antihypertensive treatment that causes LVH to regress decreases the rates of adverse cardiovascular events and improves survival, independent of how much the blood pressure is lowered.^8–11 It is clinically important to recognize that LVH is a modifiable risk factor and that management is more complex than just blood pressure control.

This paper reviews the definition of LVH, compares the diagnostic tests for it, and discusses the current evidence-based approach to managing this dangerous risk factor.

A CHRONICALLY ELEVATED CARDIAC WORKLOAD CAUSES LVH

LVH is an abnormal increase in the mass of the left ventricular myocardium caused by a chronically increased workload on the heart.¹² This most commonly results from the heart pumping against an elevated afterload, as in hypertension and aortic stenosis. Another notable cause is increased filling of the left ventricle (ie, diastolic overload), which is the underlying mechanism for LVH in patients with aortic or mitral regurgitation and dilated cardiomyopathy. Coronary artery disease can also play a role in the pathogenesis of LVH, as the normal myocardium attempts to compensate for the ischemic or infarcted tissue.¹³

The development of myocardial fibrosis appears to be pathophysiologically linked to the renin-angiotensin-aldosterone system. Specifically, there is evidence that angiotensin II has a profibrotic effect on the myocardium of hypertensive patients.¹⁵ This may explain why angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are among the most potent agents for treating LVH, as we will discuss later in this review.

DIAGNOSIS BY ELECTROCARDIOGRAPHY, ECHOCARDIOGRAPHY, OR MRI

Many different criteria for electrocardiographic LVH have been proposed over the years. Most use the voltage in one or more leads, with or without additional factors such as QRS duration, secondary ST-T wave abnormalities, or left atrial abnormalities. The most well known electrocardiographic criteria are the Cornell voltage,²¹ the Cornell product,²² the Sokolow-Lyon index,²³ and the Romhilt-Estes point score system (Table 1).²⁴

• Cornell voltage—median sensitivity 15%, median specificity 96%
• Cornell product—median sensitivity 19.5%, median specificity 91%
• Sokolow-Lyon voltage—median sensitivity 21%, median specificity 89%
• Romhilt-Estes point score—median sensitivity 17%, median specificity 95%.

Of note, the ranges of the published values were extremely broad. For example, the ranges in sensitivity were:

• Cornell voltage—2% to 41%
• Cornell product—8% to 32%
• Sokolow-Lyon voltage—4% to 51%
• Romhilt-Estes point score—0% to 41%.

While the studies with the extreme values may have had issues of small sample size or poor study quality, the wide range in values may primarily be the result of diverse study populations as well as different validation methods and cutoff values to define LVH. Regardless, the overall message of high specificity and low sensitivity is indisputable.

Electrocardiography is insensitive for diagnosing LVH because it relies on measuring the electrical activity of the heart by electrodes on the surface of the skin to predict the left ventricular mass. The intracardiac electrical activity is problematic to measure externally because the measurements are affected by everything between the myocardium and the electrodes, most notably fat, fluid, and air. Because of this effect, electrocardiography underdiagnoses LVH in patients with obesity, pleural effusions, pericardial effusions, anasarca, or chronic obstructive pulmonary disease. In addition, the diagnosis of LVH by electrocardiography is strongly influenced by age and ethnicity.^25–26

While electrocardiography is not sensitive and cannot be used to rule out LVH, it still has a role in its diagnosis and management. In the landmark Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, regression of LVH (diagnosed electrocardiographically by the Sokolow-Lyon index or the Cornell product criteria) in response to losartan (Cozaar) improved cardiovascular outcomes independent of blood pressure.¹⁰ Based on this, it is reasonable that all hypertensive patients and other patients at risk of LVH who undergo electrocardiography be screened with these two criteria.

Echocardiography, if available, should be the test of choice to assess for LVH. It is much more sensitive than electrocardiography and can also detect other abnormalities such as left ventricular dysfunction and valvular disease.

This test uses transthoracic or transesophageal ultrasonography to measure the left ventricular end-diastolic diameter, posterior wall thickness, and interventricular septum thickness. From these measurements and the patient’s height and weight, the left ventricular mass index can be calculated.²⁷

Several different cutoff values for the left ventricular mass index have been proposed; the LIFE study used values of > 104 g/m² in women and > 116 g/m² in men to define LVH.

When using echocardiography to assess for LVH, it is imperative that the left ventricular mass index be used and not just the left ventricular wall thickness, as often happens in clinical practice. This is necessary because diagnosis by wall thickness alone is not a good indicator of LVH, with a concordance between wall thickness and a left ventricular mass index of only 60%.²⁸ In addition, wall thickness tends to underestimate LVH in women and overestimate it in men.

Is echocardiography cost-effective?

Despite its clear advantages, an important consideration about echocardiography as a screening test for all hypertensive patients is its cost.

A suggested way to reduce cost is to measure the left ventricular mass index only.²⁹ A limited echocardiographic examination is much less expensive than a complete two-dimensional echocardiogram ($255 vs $431 per the 2009 Medicare Ambulatory Payment Classification³⁰) and should be the examination performed if the patient has no other clinical indication for echocardiography.

Another way to control cost is to stratify patients by risk and to do echocardiography only in those who would benefit most from it. Based on the prevalence of LVH, one study concluded that echocardiography is most cost-effective in men 50 years or older.³¹

Further study is necessary to more precisely define the cost-effectiveness of echocardiographic screening for LVH in terms of potentially preventable cardiovascular morbidity and death.

Cardiac MRI: The costly gold standard

Cardiac MRI is the gold standard test for LVH, as it is even more accurate and reproducible than echocardiography.³² It can precisely estimate a patient's left ventricular mass and assess for other structural cardiac abnormalities.

MRI’s use, however, is severely restricted in clinical practice due to its high cost and limited availability. While it may never be used for general screening for LVH, it certainly has a role in clinical research and for assessing cardiac anatomy in special clinical situations.

TREATMENT SHOULD INCLUDE AN ACE INHIBITOR OR ARB

Once LVH has been diagnosed, the next step is to decide on an appropriate treatment plan.

While the choice of therapy will always depend on other comorbidities, a 2003 metaanalysis of antihypertensive medications in the treatment of LVH (controlling for the degree of blood pressure lowering) showed that ARBs were the most efficacious class of agents for reducing the left ventricular mass.³³ Specifically, ARBs decreased the mass by 13%, followed by calcium-channel blockers at 11%, ACE inhibitors at 10%, diuretics at 8%, and beta-blockers at 6%. In pairwise comparison, ARBs, calcium-channel blockers, and ACE inhibitors were all significantly more effective in reducing the left ventricular mass than beta-blockers.

As previously discussed, LVH appears to be pathophysiologically linked to myocardial fibrosis and the renin-angiotensin-aldosterone system. For this reason and based on the data presented above regarding the degree of LVH regression, ACE inhibitors or ARBs should be used as the first-line agents for LVH unless they are contraindicated in the individual patient.

The LIFE study

The LIFE study offers the strongest evidence that treating LVH is beneficial. It showed that in hypertensive patients with electrocardiographic LVH by the Cornell product or Sokolow-Lyon criteria, treatment with antihypertensive drugs that resulted in less-severe LVH on electrocardiography was associated with lower rates of cardiovascular morbidity and death, independent of the blood pressure achieved or the drug used.¹⁰

The end point in this study was a composite of stroke, myocardial infarction, and cardiovascular death. Regression of electrocardiographic LVH in hypertensive patients has also been shown to decrease the incidence of diabetes mellitus,³⁴ atrial fibrillation,³⁵ and hospitalizations for heart failure.³⁶

The LIFE study also examined the prognostic implications of treating LVH detected by echocardiography. In this prospective cohort substudy, patients who had a lower left ventricular mass index during treatment with antihypertensive drugs had lower rates of cardiovascular morbidity and all-cause mortality, independent of the effects of blood pressure and treatment used.¹¹

These results suggest that there may be a role not only for treating LVH, but also for monitoring for a reduction in the left ventricular mass index as a goal of therapy (similar to the way hemoglobin A_1c is used in diabetic patients). If the index is used in this way, one could potentially adjust the dose of current drugs, switch classes, or add an additional drug based on a persistently elevated left ventricular mass index in order to optimize the patient's overall cardiovascular risk. A randomized controlled trial of therapy directed by the mass index vs conventional therapy of LVH would be necessary to assess the clinical utility of this approach.

RECOMMENDATIONS

LVH is a common and potentially modifiable cardiovascular risk factor often overlooked in clinical practice. Ideally, all hypertensive patients should be screened with echocardiography to look for LVH, using the calculated left ventricular mass index rather than wall thickness alone to make the diagnosis. While electrocardiography is specific and also has prognostic implications, it is not sensitive enough to be used alone to screen for LVH.

Once the diagnosis of LVH is made, the initial therapy should be an ARB or an ACE inhibitor. Response to therapy can be assessed by monitoring for a reduction in left ventricular mass index or regression of electrocardiographic LVH.

Treatment-induced regression of LVH decreases adverse cardiovascular events and improves overall survival. When modifying medications in hypertensive patients, it is important to remember that the treatment of LVH is not synonymous with blood pressure control.

An 80-year-old Mandarin-speaking Chinese woman was referred to a mental health outpatient clinic for evaluation and treatment. The patient had a history of mild depression, for which she had been treated for many years with sertraline.

Five years earlier at age 75, the patient had been evaluated by a psychiatrist after she began to experience psychotic symptoms, including frequent repetitive auditory hallucinations of people counting, alternating with music from her childhood. At that time, she also had persecutory paranoid thoughts and delusional thinking that she was receiving messages in Mandarin while watching American TV programs. Initially, her only cognitive disturbance was an inability to differentiate among numbers on a calendar or a telephone keypad. No reports of memory problems were noted. Although the patient acknowledged auditory hallucinations, she denied experiencing command auditory hallucinations or hallucinations of other forms. The patient had no history of suicide attempts and denied suicidal or homicidal ideation. She had no history of psychiatric hospitalization.

The psychiatrist made a diagnosis of major depressive disorder with psychotic features, not otherwise specified¹ and prescribed sertraline 50 mg/d. The patient was also started on risperidone 0.25 mg/d for management of her psychotic symptoms, with the dosage gradually increased to 2.0 mg/d over five years. While taking this combination, the patient experienced stable mood and fewer paranoid thoughts, although her auditory hallucinations continued.

Two months before the current visit, the patient moved into a retirement living facility, and she reported having adapted well to the new setting. She was sleeping well and had a good appetite. Her BMI was within normal range.

The patient described herself as a single parent for nearly 40 years, raising one daughter. Formerly high functioning, she had held a full-time clerical job until age 70. She appeared well-groomed, polite but anxious, and oriented to time, person, and place. Her speech was normal, her thought processes were coherent, and her mood was stable. However, her affect was constricted; she acknowledged auditory hallucinations, which impaired her thought content. The patient reported feeling increased anxiety prior to any nonroutine activity, such as a doctor’s appointment; this, she said, would cause insomnia, leaving her to pace in her room.

During the examination, fine tremors on upper and lower extremities were noted. The patient’s Abnormal Involuntary Movement Scale (AIMS) score² was 13, which placed her in the highest risk category for antipsychotic-induced dopamine-blockade extrapyramidal symptoms (EPS). The patient was found to be negative for tardive dyskinesia, with no abnormal facial movements. She was aware of the tremors in her limbs and said she felt bothered by them.

The patient had an unsteady gait and used a four-point walker. Her Mini-Mental State Exam (MMSE) score³ was 28/30, which was normal for her age and education level (high school completed).

Apart from the described symptoms, the patient was healthy for her age and had no other medical diagnosis. Her vital signs were within normal range. The medical work-up to rule out other causes of dementia yielded negative results. Lab values were normal, including electrolyte levels and thyroid tests. The patient’s hearing test showed age-related hearing loss of full range, not limited to high pitch. She was able to engage in a meaningful conversation at a normal volume. Clinically, however, it was concerning to observe the possible signs of EPS and the relatively high risperidone dosage, considering the patient’s advanced age.

After the meeting with the patient, a treatment plan was created to 1) gradually reduce the dosage of antipsychotic medication, and 2) refer her to a neurologist for a complete work-up to rule out underlying neurologic disorders, such as dementia. Risperidone was tapered by increments of 0.25 mg/d every three to four weeks; throughout this process, the patient was closely monitored by the nursing staff at the retirement living facility. Monthly appointments were scheduled at the outpatient mental health clinic for evaluation and medication management.

Two months after the initial mental health clinic visit, the patient’s condition was pronounced stable on the current regimen of sertraline 50 mg/d and risperidone 1.0 mg/d. She was later seen by a neurologist, who made a diagnosis of Parkinson’s disease and placed her on carbidopa-­levodopa (1 1/2 tablets, 25/100 mg, tid). The patient’s auditory hallucinations continued with the same intensity as at baseline, but fewer tremors were noted in her extremities. By six months into the tapering process (with risperidone reduced at that time to 0.25 mg/d and carbidopa-levodopa to 25/100 mg tid), the patient had begun to experience dissipation of the tremors, and her AIMS score² was 0. She was able to replace her four-point walker with a cane.

One year after her initial visit to the mental health clinic, the patient’s neurologist suggested replacing risperidone with quetia­pine (12.5 mg/d) for its improved tolerability and lower adverse effect profile.⁴ She continued to take sertraline and carbidopa-levodopa.

Improvement of symptoms was noted following the switch. After one month on the revised regimen, the patient reported that the number of auditory hallucinations persisted, but that their intensity had decreased dramatically. She had a brighter affect and appeared to feel uplifted and more energetic. She became involved in the social activities offered at the retirement living facility and the mental health clinic. She also maintained a steady gait without her cane. According to the patient’s daughter, her mother was at her best psychological state since the onset of psychotic symptoms six years earlier. The pharmacologic regimen had reached its maximum benefit.

At a mental health appointment at the outpatient clinic 18 months after her initial visit there, it was evident that the patient’s auditory hallucinations persisted as a major stressor. She began to complain about other residents in her facility. She said she disliked the resident with whom she shared meals, and she claimed that other residents often spit on the floor in front of her room. The nursing staff did not confirm these incidents, which they considered a delusion despite the patient’s “evidence” (the tissues she said she had used to clean up).

Additionally, a new theme had emerged in the patient’s auditory hallucinations. She reported hearing a male voice that announced changes in meal times. Although she knew there was no public address system in her room or in the hallway, the “announcement” was so convincing that she would go to the dining room and once there, realize that nothing had changed. She seemed to drift between reality and her hallucinations/delusions. According to her daughter, the patient’s independent and reserved personality forced her to internalize her stressors—in this case, her frustration about the other residents—which fed into her hallucinations and delusions.

In response to her worsening psychotic symptoms, the patient’s provider increased her quetia­pine dosage from 12.5 mg/d to 25 mg/d. Her MMSE score³ at this visit was 25/30.

Two months later, the patient exhibited increasing symptoms of paranoia, delusions, and auditory hallucinations. She continued to respond to the “broadcast” messages about meal times, and she voiced her frustrations to others who spoke Mandarin. She became agitated in response to out-of-the-ordinary events. When her alarm clock battery ran out, for example, she insisted that “a man’s voice” kept reminding her to replace the battery; in response, she placed the alarm clock in the refrigerator, later explaining, “Now I don’t need to worry about it.”

Her cognitive status began to show obvious, progressive deterioration, with an MMSE score³ of 22/30 at this visit—a significant reduction from previous scores. Worsening of her short-term memory became apparent when she had difficulty playing bingo and was unable to remember her appointment or the current date. She became upset when others corrected her.

In a review of the trends in this patient’s clinical presentation, it became increasingly evident to the patient’s mental health care providers that she had Lewy body dementia.

DISCUSSION
Dementia with Lewy bodies (DLB), a progressive disease, is the second most common cause of neurodegenerative dementia after Alzheimer’s disease.^5-7 It is estimated that DLB accounts for 20% of US cases of dementia (ie, about 800,000 patients).^8,9 Although public awareness of DLB is on the rise, the disorder is still underrecognized and underdiagnosed because its clinical manifestations so closely resemble those of Alzheimer’s disease, Parkinson’s disease, and psychosis.^10,11

Clinical symptoms of DLB include progressive cognitive decline, cognitive fluctuation, EPS, and parkinsonism; hallucinations involving all five senses, particularly sight; delusions; REM sleep disturbance, with or without vivid and frightening dreams; changes in mood and behavior; impaired judgment and insight; and autonomic dysfunction, such as orthostatic hypotension and carotid-sinus hypersensitivity.^5,11-15

The symptoms of DLB are caused by the accumulations of Lewy bodies, that is, deposits of alpha-synuclein protein in the nuclei of neurons. Lewy bodies destroy neurons over time, resulting in the destruction of dopaminergic and acetylcholinergic pathways from the brain stem to areas of the cerebral cortex associated with cognition and motor functions.^4,5,16

DLB is a spectrum disorder; it often coexists with Parkinson’s disease or Alzheimer’s disease, as Lewy bodies are also found in patients with these illnesses.⁷ This poses a challenge for formulating a differential diagnosis, particularly in patients with fluctuating cognition,¹⁰ and for attempting to establish disease prevalence.

Diagnosis
Currently, a conclusive diagnosis of DLB can be confirmed only through postmortem autopsy, although use of medial temporal lobe volume (via structural MRI) and regional blood flow (via single photon emission CT [SPECT] tracers) is being investigated.¹⁷

The diagnosis of DLB is currently based on the presenting clinical symptoms and the exclusion of other medical conditions whose symptoms mimic those of DLB.⁷ The screening assessment may include a neurologic/psychiatric assessment (MMSE, psychiatric evaluation, and interviews with family members or caretakers), neuroimaging such as MRI to rule out other organic causes, and laboratory evaluation to rule out potentially reversible causes of dementia, including electrolyte imbalance, vitamin deficiency (specifically vitamin B12), anemia, thyroid dysfunction, and kidney or liver impairment.¹⁸

The American Psychiatric Assocation¹ categorizes DLB under “Dementia Due to Other General Medical Conditions” (294.1x). The World Health Organization¹⁹ includes it among “Other specified degenerative diseases of the nervous system” (G31.8).

Treatment
Lewy body dementia is an irreversible neurologic degenerative disorder. Treatment for DLB comprises symptom management, primarily through pharmacology; however, the response to medication is highly individualized. Treatment includes management of the following symptoms:

Cognitive impairment. Cholinesterase inhibitors, such as rivastigmine (3 to 12 mg/d), donepezil (10 mg/d), or galantamine (titrated up to 12 mg bid),^20-23 improve attention and behavior and reduce apathy, anxiety, delusions, and hallucinations. As cognitive impairment worsens, memantine (10 mg bid) may be effective.²⁴ The potential for anticholinergic adverse effects requires close monitoring in patients taking these agents.

Parkinsonian symptoms. Medications indicated for Parkinson’s disease and syndrome, such as carbidopa-levodopa (25/100 mg tid), can be effective; dosage may be slowly titrated upward as tolerated and if needed for symptom management.^25,26 The dopaminergic effect of antiparkinson medications may intensify the psychotic symptoms and worsen the REM sleep pattern. In this case, a low-dose atypical antipsychotic is suggested^27,28 (see below).

Psychotic symptoms. An atypical antipsychotic agent, such as quetiapine (12.5 mg), risperidone (0.25 mg), olanzapine (2.5 mg), ziprasidone (20 mg), aripiprazole (2 mg), or paliperidone (1.5 mg), may be used. Because of the DLB-associated risk of neuroleptic sensitivity, atypical antipsychotic agents should be initiated at a low dose with slow upward titration^17,26,29; quetiapine appears less likely than risperidone or olanzapine to cause neuroleptic sensitivity or to trigger EPS.⁴ For Asian patients, who often respond to lower doses of these medications (and are more easily affected by associated adverse effects), Chen et al³⁰ recommend a starting dose of about one-half the recommended dose.

Depression. An SSRI antidepressant with relatively simple pharmacologic properties and moderate half-life may be used to manage symptoms of depression.^26,31,32 Long–half-life SSRIs (eg, fluoxetine) should be avoided in elderly patients; in response to SNRIs (serotonin-norepinephrine reuptake inhibitors), these patients may experience elevated blood pressures and pulses, with subsequent morbidity.³³

REM sleep disturbances. Clo­nazepam (0.25 mg), melatonin (3.0 mg), or quetiapine (12.5 mg) may be administered at bedtime.³⁴

Important Lessons
In general, providers should consider the benefits and risks of any pharmacologic treatment and avoid polypharmacy, if possible. Family and caretakers should be included in the treatment planning, with a focus on prioritizing and managing the most debilitating symptoms or dysfunctions that prompt concerns for safety.

For optimal homeostasis, some DLB patients may require joint pharmacologic modalities that appear counterintuitive—for example, an antiparkinsonism (dopaminergic) agent for parkinsonian symptoms or neuroleptic-induced EPS, versus an antipsychotic (eg, a dopamine antagonist) to treat profound hallucinations.²⁶

As the response to treatment for DLB is highly individualized, it is essential to titrate and augment with care.

CONCLUSION
In DLB, as with other dementing illnesses, the onset of symptoms can be gradual and insidious, posing a great challenge to the clinician who seeks to confirm the diagnosis. In the illness’s early stages, the clinician may have to treat targeted symptoms and adjust the treatment plan once signs of the pathologic origins emerge.

It is critical to understand the mechanisms of psychotropic medications and targeted neurotransmitters when evaluating treatment for DLB. Titrating or augmenting these medications in elderly patients requires the clinician to follow a principle of start low and go slow, making only one change at a time.

It is always helpful to include family members in the patient’s care and to gather information on previous history, personality traits, family history, and cultural components. It is also important to communicate with other specialists to implement collaborative care.

An 80-year-old Mandarin-speaking Chinese woman was referred to a mental health outpatient clinic for evaluation and treatment. The patient had a history of mild depression, for which she had been treated for many years with sertraline.

Five years earlier at age 75, the patient had been evaluated by a psychiatrist after she began to experience psychotic symptoms, including frequent repetitive auditory hallucinations of people counting, alternating with music from her childhood. At that time, she also had persecutory paranoid thoughts and delusional thinking that she was receiving messages in Mandarin while watching American TV programs. Initially, her only cognitive disturbance was an inability to differentiate among numbers on a calendar or a telephone keypad. No reports of memory problems were noted. Although the patient acknowledged auditory hallucinations, she denied experiencing command auditory hallucinations or hallucinations of other forms. The patient had no history of suicide attempts and denied suicidal or homicidal ideation. She had no history of psychiatric hospitalization.

The psychiatrist made a diagnosis of major depressive disorder with psychotic features, not otherwise specified¹ and prescribed sertraline 50 mg/d. The patient was also started on risperidone 0.25 mg/d for management of her psychotic symptoms, with the dosage gradually increased to 2.0 mg/d over five years. While taking this combination, the patient experienced stable mood and fewer paranoid thoughts, although her auditory hallucinations continued.

Two months before the current visit, the patient moved into a retirement living facility, and she reported having adapted well to the new setting. She was sleeping well and had a good appetite. Her BMI was within normal range.

The patient described herself as a single parent for nearly 40 years, raising one daughter. Formerly high functioning, she had held a full-time clerical job until age 70. She appeared well-groomed, polite but anxious, and oriented to time, person, and place. Her speech was normal, her thought processes were coherent, and her mood was stable. However, her affect was constricted; she acknowledged auditory hallucinations, which impaired her thought content. The patient reported feeling increased anxiety prior to any nonroutine activity, such as a doctor’s appointment; this, she said, would cause insomnia, leaving her to pace in her room.

During the examination, fine tremors on upper and lower extremities were noted. The patient’s Abnormal Involuntary Movement Scale (AIMS) score² was 13, which placed her in the highest risk category for antipsychotic-induced dopamine-blockade extrapyramidal symptoms (EPS). The patient was found to be negative for tardive dyskinesia, with no abnormal facial movements. She was aware of the tremors in her limbs and said she felt bothered by them.

The patient had an unsteady gait and used a four-point walker. Her Mini-Mental State Exam (MMSE) score³ was 28/30, which was normal for her age and education level (high school completed).

Apart from the described symptoms, the patient was healthy for her age and had no other medical diagnosis. Her vital signs were within normal range. The medical work-up to rule out other causes of dementia yielded negative results. Lab values were normal, including electrolyte levels and thyroid tests. The patient’s hearing test showed age-related hearing loss of full range, not limited to high pitch. She was able to engage in a meaningful conversation at a normal volume. Clinically, however, it was concerning to observe the possible signs of EPS and the relatively high risperidone dosage, considering the patient’s advanced age.

After the meeting with the patient, a treatment plan was created to 1) gradually reduce the dosage of antipsychotic medication, and 2) refer her to a neurologist for a complete work-up to rule out underlying neurologic disorders, such as dementia. Risperidone was tapered by increments of 0.25 mg/d every three to four weeks; throughout this process, the patient was closely monitored by the nursing staff at the retirement living facility. Monthly appointments were scheduled at the outpatient mental health clinic for evaluation and medication management.

Two months after the initial mental health clinic visit, the patient’s condition was pronounced stable on the current regimen of sertraline 50 mg/d and risperidone 1.0 mg/d. She was later seen by a neurologist, who made a diagnosis of Parkinson’s disease and placed her on carbidopa-­levodopa (1 1/2 tablets, 25/100 mg, tid). The patient’s auditory hallucinations continued with the same intensity as at baseline, but fewer tremors were noted in her extremities. By six months into the tapering process (with risperidone reduced at that time to 0.25 mg/d and carbidopa-levodopa to 25/100 mg tid), the patient had begun to experience dissipation of the tremors, and her AIMS score² was 0. She was able to replace her four-point walker with a cane.

One year after her initial visit to the mental health clinic, the patient’s neurologist suggested replacing risperidone with quetia­pine (12.5 mg/d) for its improved tolerability and lower adverse effect profile.⁴ She continued to take sertraline and carbidopa-levodopa.

Improvement of symptoms was noted following the switch. After one month on the revised regimen, the patient reported that the number of auditory hallucinations persisted, but that their intensity had decreased dramatically. She had a brighter affect and appeared to feel uplifted and more energetic. She became involved in the social activities offered at the retirement living facility and the mental health clinic. She also maintained a steady gait without her cane. According to the patient’s daughter, her mother was at her best psychological state since the onset of psychotic symptoms six years earlier. The pharmacologic regimen had reached its maximum benefit.

At a mental health appointment at the outpatient clinic 18 months after her initial visit there, it was evident that the patient’s auditory hallucinations persisted as a major stressor. She began to complain about other residents in her facility. She said she disliked the resident with whom she shared meals, and she claimed that other residents often spit on the floor in front of her room. The nursing staff did not confirm these incidents, which they considered a delusion despite the patient’s “evidence” (the tissues she said she had used to clean up).

Additionally, a new theme had emerged in the patient’s auditory hallucinations. She reported hearing a male voice that announced changes in meal times. Although she knew there was no public address system in her room or in the hallway, the “announcement” was so convincing that she would go to the dining room and once there, realize that nothing had changed. She seemed to drift between reality and her hallucinations/delusions. According to her daughter, the patient’s independent and reserved personality forced her to internalize her stressors—in this case, her frustration about the other residents—which fed into her hallucinations and delusions.

In response to her worsening psychotic symptoms, the patient’s provider increased her quetia­pine dosage from 12.5 mg/d to 25 mg/d. Her MMSE score³ at this visit was 25/30.

Two months later, the patient exhibited increasing symptoms of paranoia, delusions, and auditory hallucinations. She continued to respond to the “broadcast” messages about meal times, and she voiced her frustrations to others who spoke Mandarin. She became agitated in response to out-of-the-ordinary events. When her alarm clock battery ran out, for example, she insisted that “a man’s voice” kept reminding her to replace the battery; in response, she placed the alarm clock in the refrigerator, later explaining, “Now I don’t need to worry about it.”

Her cognitive status began to show obvious, progressive deterioration, with an MMSE score³ of 22/30 at this visit—a significant reduction from previous scores. Worsening of her short-term memory became apparent when she had difficulty playing bingo and was unable to remember her appointment or the current date. She became upset when others corrected her.

In a review of the trends in this patient’s clinical presentation, it became increasingly evident to the patient’s mental health care providers that she had Lewy body dementia.

DISCUSSION
Dementia with Lewy bodies (DLB), a progressive disease, is the second most common cause of neurodegenerative dementia after Alzheimer’s disease.^5-7 It is estimated that DLB accounts for 20% of US cases of dementia (ie, about 800,000 patients).^8,9 Although public awareness of DLB is on the rise, the disorder is still underrecognized and underdiagnosed because its clinical manifestations so closely resemble those of Alzheimer’s disease, Parkinson’s disease, and psychosis.^10,11

Clinical symptoms of DLB include progressive cognitive decline, cognitive fluctuation, EPS, and parkinsonism; hallucinations involving all five senses, particularly sight; delusions; REM sleep disturbance, with or without vivid and frightening dreams; changes in mood and behavior; impaired judgment and insight; and autonomic dysfunction, such as orthostatic hypotension and carotid-sinus hypersensitivity.^5,11-15

The symptoms of DLB are caused by the accumulations of Lewy bodies, that is, deposits of alpha-synuclein protein in the nuclei of neurons. Lewy bodies destroy neurons over time, resulting in the destruction of dopaminergic and acetylcholinergic pathways from the brain stem to areas of the cerebral cortex associated with cognition and motor functions.^4,5,16

DLB is a spectrum disorder; it often coexists with Parkinson’s disease or Alzheimer’s disease, as Lewy bodies are also found in patients with these illnesses.⁷ This poses a challenge for formulating a differential diagnosis, particularly in patients with fluctuating cognition,¹⁰ and for attempting to establish disease prevalence.

Diagnosis
Currently, a conclusive diagnosis of DLB can be confirmed only through postmortem autopsy, although use of medial temporal lobe volume (via structural MRI) and regional blood flow (via single photon emission CT [SPECT] tracers) is being investigated.¹⁷

The diagnosis of DLB is currently based on the presenting clinical symptoms and the exclusion of other medical conditions whose symptoms mimic those of DLB.⁷ The screening assessment may include a neurologic/psychiatric assessment (MMSE, psychiatric evaluation, and interviews with family members or caretakers), neuroimaging such as MRI to rule out other organic causes, and laboratory evaluation to rule out potentially reversible causes of dementia, including electrolyte imbalance, vitamin deficiency (specifically vitamin B12), anemia, thyroid dysfunction, and kidney or liver impairment.¹⁸

The American Psychiatric Assocation¹ categorizes DLB under “Dementia Due to Other General Medical Conditions” (294.1x). The World Health Organization¹⁹ includes it among “Other specified degenerative diseases of the nervous system” (G31.8).

Treatment
Lewy body dementia is an irreversible neurologic degenerative disorder. Treatment for DLB comprises symptom management, primarily through pharmacology; however, the response to medication is highly individualized. Treatment includes management of the following symptoms:

Cognitive impairment. Cholinesterase inhibitors, such as rivastigmine (3 to 12 mg/d), donepezil (10 mg/d), or galantamine (titrated up to 12 mg bid),^20-23 improve attention and behavior and reduce apathy, anxiety, delusions, and hallucinations. As cognitive impairment worsens, memantine (10 mg bid) may be effective.²⁴ The potential for anticholinergic adverse effects requires close monitoring in patients taking these agents.

Parkinsonian symptoms. Medications indicated for Parkinson’s disease and syndrome, such as carbidopa-levodopa (25/100 mg tid), can be effective; dosage may be slowly titrated upward as tolerated and if needed for symptom management.^25,26 The dopaminergic effect of antiparkinson medications may intensify the psychotic symptoms and worsen the REM sleep pattern. In this case, a low-dose atypical antipsychotic is suggested^27,28 (see below).

Psychotic symptoms. An atypical antipsychotic agent, such as quetiapine (12.5 mg), risperidone (0.25 mg), olanzapine (2.5 mg), ziprasidone (20 mg), aripiprazole (2 mg), or paliperidone (1.5 mg), may be used. Because of the DLB-associated risk of neuroleptic sensitivity, atypical antipsychotic agents should be initiated at a low dose with slow upward titration^17,26,29; quetiapine appears less likely than risperidone or olanzapine to cause neuroleptic sensitivity or to trigger EPS.⁴ For Asian patients, who often respond to lower doses of these medications (and are more easily affected by associated adverse effects), Chen et al³⁰ recommend a starting dose of about one-half the recommended dose.

Depression. An SSRI antidepressant with relatively simple pharmacologic properties and moderate half-life may be used to manage symptoms of depression.^26,31,32 Long–half-life SSRIs (eg, fluoxetine) should be avoided in elderly patients; in response to SNRIs (serotonin-norepinephrine reuptake inhibitors), these patients may experience elevated blood pressures and pulses, with subsequent morbidity.³³

REM sleep disturbances. Clo­nazepam (0.25 mg), melatonin (3.0 mg), or quetiapine (12.5 mg) may be administered at bedtime.³⁴

Important Lessons
In general, providers should consider the benefits and risks of any pharmacologic treatment and avoid polypharmacy, if possible. Family and caretakers should be included in the treatment planning, with a focus on prioritizing and managing the most debilitating symptoms or dysfunctions that prompt concerns for safety.

For optimal homeostasis, some DLB patients may require joint pharmacologic modalities that appear counterintuitive—for example, an antiparkinsonism (dopaminergic) agent for parkinsonian symptoms or neuroleptic-induced EPS, versus an antipsychotic (eg, a dopamine antagonist) to treat profound hallucinations.²⁶

As the response to treatment for DLB is highly individualized, it is essential to titrate and augment with care.

CONCLUSION
In DLB, as with other dementing illnesses, the onset of symptoms can be gradual and insidious, posing a great challenge to the clinician who seeks to confirm the diagnosis. In the illness’s early stages, the clinician may have to treat targeted symptoms and adjust the treatment plan once signs of the pathologic origins emerge.

It is critical to understand the mechanisms of psychotropic medications and targeted neurotransmitters when evaluating treatment for DLB. Titrating or augmenting these medications in elderly patients requires the clinician to follow a principle of start low and go slow, making only one change at a time.

It is always helpful to include family members in the patient’s care and to gather information on previous history, personality traits, family history, and cultural components. It is also important to communicate with other specialists to implement collaborative care.

An 80-year-old Mandarin-speaking Chinese woman was referred to a mental health outpatient clinic for evaluation and treatment. The patient had a history of mild depression, for which she had been treated for many years with sertraline.

Five years earlier at age 75, the patient had been evaluated by a psychiatrist after she began to experience psychotic symptoms, including frequent repetitive auditory hallucinations of people counting, alternating with music from her childhood. At that time, she also had persecutory paranoid thoughts and delusional thinking that she was receiving messages in Mandarin while watching American TV programs. Initially, her only cognitive disturbance was an inability to differentiate among numbers on a calendar or a telephone keypad. No reports of memory problems were noted. Although the patient acknowledged auditory hallucinations, she denied experiencing command auditory hallucinations or hallucinations of other forms. The patient had no history of suicide attempts and denied suicidal or homicidal ideation. She had no history of psychiatric hospitalization.

The psychiatrist made a diagnosis of major depressive disorder with psychotic features, not otherwise specified¹ and prescribed sertraline 50 mg/d. The patient was also started on risperidone 0.25 mg/d for management of her psychotic symptoms, with the dosage gradually increased to 2.0 mg/d over five years. While taking this combination, the patient experienced stable mood and fewer paranoid thoughts, although her auditory hallucinations continued.

Two months before the current visit, the patient moved into a retirement living facility, and she reported having adapted well to the new setting. She was sleeping well and had a good appetite. Her BMI was within normal range.

The patient described herself as a single parent for nearly 40 years, raising one daughter. Formerly high functioning, she had held a full-time clerical job until age 70. She appeared well-groomed, polite but anxious, and oriented to time, person, and place. Her speech was normal, her thought processes were coherent, and her mood was stable. However, her affect was constricted; she acknowledged auditory hallucinations, which impaired her thought content. The patient reported feeling increased anxiety prior to any nonroutine activity, such as a doctor’s appointment; this, she said, would cause insomnia, leaving her to pace in her room.

During the examination, fine tremors on upper and lower extremities were noted. The patient’s Abnormal Involuntary Movement Scale (AIMS) score² was 13, which placed her in the highest risk category for antipsychotic-induced dopamine-blockade extrapyramidal symptoms (EPS). The patient was found to be negative for tardive dyskinesia, with no abnormal facial movements. She was aware of the tremors in her limbs and said she felt bothered by them.

The patient had an unsteady gait and used a four-point walker. Her Mini-Mental State Exam (MMSE) score³ was 28/30, which was normal for her age and education level (high school completed).

Apart from the described symptoms, the patient was healthy for her age and had no other medical diagnosis. Her vital signs were within normal range. The medical work-up to rule out other causes of dementia yielded negative results. Lab values were normal, including electrolyte levels and thyroid tests. The patient’s hearing test showed age-related hearing loss of full range, not limited to high pitch. She was able to engage in a meaningful conversation at a normal volume. Clinically, however, it was concerning to observe the possible signs of EPS and the relatively high risperidone dosage, considering the patient’s advanced age.

After the meeting with the patient, a treatment plan was created to 1) gradually reduce the dosage of antipsychotic medication, and 2) refer her to a neurologist for a complete work-up to rule out underlying neurologic disorders, such as dementia. Risperidone was tapered by increments of 0.25 mg/d every three to four weeks; throughout this process, the patient was closely monitored by the nursing staff at the retirement living facility. Monthly appointments were scheduled at the outpatient mental health clinic for evaluation and medication management.

Two months after the initial mental health clinic visit, the patient’s condition was pronounced stable on the current regimen of sertraline 50 mg/d and risperidone 1.0 mg/d. She was later seen by a neurologist, who made a diagnosis of Parkinson’s disease and placed her on carbidopa-­levodopa (1 1/2 tablets, 25/100 mg, tid). The patient’s auditory hallucinations continued with the same intensity as at baseline, but fewer tremors were noted in her extremities. By six months into the tapering process (with risperidone reduced at that time to 0.25 mg/d and carbidopa-levodopa to 25/100 mg tid), the patient had begun to experience dissipation of the tremors, and her AIMS score² was 0. She was able to replace her four-point walker with a cane.

One year after her initial visit to the mental health clinic, the patient’s neurologist suggested replacing risperidone with quetia­pine (12.5 mg/d) for its improved tolerability and lower adverse effect profile.⁴ She continued to take sertraline and carbidopa-levodopa.

Improvement of symptoms was noted following the switch. After one month on the revised regimen, the patient reported that the number of auditory hallucinations persisted, but that their intensity had decreased dramatically. She had a brighter affect and appeared to feel uplifted and more energetic. She became involved in the social activities offered at the retirement living facility and the mental health clinic. She also maintained a steady gait without her cane. According to the patient’s daughter, her mother was at her best psychological state since the onset of psychotic symptoms six years earlier. The pharmacologic regimen had reached its maximum benefit.

At a mental health appointment at the outpatient clinic 18 months after her initial visit there, it was evident that the patient’s auditory hallucinations persisted as a major stressor. She began to complain about other residents in her facility. She said she disliked the resident with whom she shared meals, and she claimed that other residents often spit on the floor in front of her room. The nursing staff did not confirm these incidents, which they considered a delusion despite the patient’s “evidence” (the tissues she said she had used to clean up).

Additionally, a new theme had emerged in the patient’s auditory hallucinations. She reported hearing a male voice that announced changes in meal times. Although she knew there was no public address system in her room or in the hallway, the “announcement” was so convincing that she would go to the dining room and once there, realize that nothing had changed. She seemed to drift between reality and her hallucinations/delusions. According to her daughter, the patient’s independent and reserved personality forced her to internalize her stressors—in this case, her frustration about the other residents—which fed into her hallucinations and delusions.

In response to her worsening psychotic symptoms, the patient’s provider increased her quetia­pine dosage from 12.5 mg/d to 25 mg/d. Her MMSE score³ at this visit was 25/30.

Two months later, the patient exhibited increasing symptoms of paranoia, delusions, and auditory hallucinations. She continued to respond to the “broadcast” messages about meal times, and she voiced her frustrations to others who spoke Mandarin. She became agitated in response to out-of-the-ordinary events. When her alarm clock battery ran out, for example, she insisted that “a man’s voice” kept reminding her to replace the battery; in response, she placed the alarm clock in the refrigerator, later explaining, “Now I don’t need to worry about it.”

Her cognitive status began to show obvious, progressive deterioration, with an MMSE score³ of 22/30 at this visit—a significant reduction from previous scores. Worsening of her short-term memory became apparent when she had difficulty playing bingo and was unable to remember her appointment or the current date. She became upset when others corrected her.

In a review of the trends in this patient’s clinical presentation, it became increasingly evident to the patient’s mental health care providers that she had Lewy body dementia.

DISCUSSION
Dementia with Lewy bodies (DLB), a progressive disease, is the second most common cause of neurodegenerative dementia after Alzheimer’s disease.^5-7 It is estimated that DLB accounts for 20% of US cases of dementia (ie, about 800,000 patients).^8,9 Although public awareness of DLB is on the rise, the disorder is still underrecognized and underdiagnosed because its clinical manifestations so closely resemble those of Alzheimer’s disease, Parkinson’s disease, and psychosis.^10,11

Clinical symptoms of DLB include progressive cognitive decline, cognitive fluctuation, EPS, and parkinsonism; hallucinations involving all five senses, particularly sight; delusions; REM sleep disturbance, with or without vivid and frightening dreams; changes in mood and behavior; impaired judgment and insight; and autonomic dysfunction, such as orthostatic hypotension and carotid-sinus hypersensitivity.^5,11-15

The symptoms of DLB are caused by the accumulations of Lewy bodies, that is, deposits of alpha-synuclein protein in the nuclei of neurons. Lewy bodies destroy neurons over time, resulting in the destruction of dopaminergic and acetylcholinergic pathways from the brain stem to areas of the cerebral cortex associated with cognition and motor functions.^4,5,16

DLB is a spectrum disorder; it often coexists with Parkinson’s disease or Alzheimer’s disease, as Lewy bodies are also found in patients with these illnesses.⁷ This poses a challenge for formulating a differential diagnosis, particularly in patients with fluctuating cognition,¹⁰ and for attempting to establish disease prevalence.

Diagnosis
Currently, a conclusive diagnosis of DLB can be confirmed only through postmortem autopsy, although use of medial temporal lobe volume (via structural MRI) and regional blood flow (via single photon emission CT [SPECT] tracers) is being investigated.¹⁷

The diagnosis of DLB is currently based on the presenting clinical symptoms and the exclusion of other medical conditions whose symptoms mimic those of DLB.⁷ The screening assessment may include a neurologic/psychiatric assessment (MMSE, psychiatric evaluation, and interviews with family members or caretakers), neuroimaging such as MRI to rule out other organic causes, and laboratory evaluation to rule out potentially reversible causes of dementia, including electrolyte imbalance, vitamin deficiency (specifically vitamin B12), anemia, thyroid dysfunction, and kidney or liver impairment.¹⁸

The American Psychiatric Assocation¹ categorizes DLB under “Dementia Due to Other General Medical Conditions” (294.1x). The World Health Organization¹⁹ includes it among “Other specified degenerative diseases of the nervous system” (G31.8).

Treatment
Lewy body dementia is an irreversible neurologic degenerative disorder. Treatment for DLB comprises symptom management, primarily through pharmacology; however, the response to medication is highly individualized. Treatment includes management of the following symptoms:

Cognitive impairment. Cholinesterase inhibitors, such as rivastigmine (3 to 12 mg/d), donepezil (10 mg/d), or galantamine (titrated up to 12 mg bid),^20-23 improve attention and behavior and reduce apathy, anxiety, delusions, and hallucinations. As cognitive impairment worsens, memantine (10 mg bid) may be effective.²⁴ The potential for anticholinergic adverse effects requires close monitoring in patients taking these agents.

Parkinsonian symptoms. Medications indicated for Parkinson’s disease and syndrome, such as carbidopa-levodopa (25/100 mg tid), can be effective; dosage may be slowly titrated upward as tolerated and if needed for symptom management.^25,26 The dopaminergic effect of antiparkinson medications may intensify the psychotic symptoms and worsen the REM sleep pattern. In this case, a low-dose atypical antipsychotic is suggested^27,28 (see below).

Psychotic symptoms. An atypical antipsychotic agent, such as quetiapine (12.5 mg), risperidone (0.25 mg), olanzapine (2.5 mg), ziprasidone (20 mg), aripiprazole (2 mg), or paliperidone (1.5 mg), may be used. Because of the DLB-associated risk of neuroleptic sensitivity, atypical antipsychotic agents should be initiated at a low dose with slow upward titration^17,26,29; quetiapine appears less likely than risperidone or olanzapine to cause neuroleptic sensitivity or to trigger EPS.⁴ For Asian patients, who often respond to lower doses of these medications (and are more easily affected by associated adverse effects), Chen et al³⁰ recommend a starting dose of about one-half the recommended dose.

Depression. An SSRI antidepressant with relatively simple pharmacologic properties and moderate half-life may be used to manage symptoms of depression.^26,31,32 Long–half-life SSRIs (eg, fluoxetine) should be avoided in elderly patients; in response to SNRIs (serotonin-norepinephrine reuptake inhibitors), these patients may experience elevated blood pressures and pulses, with subsequent morbidity.³³

REM sleep disturbances. Clo­nazepam (0.25 mg), melatonin (3.0 mg), or quetiapine (12.5 mg) may be administered at bedtime.³⁴

Important Lessons
In general, providers should consider the benefits and risks of any pharmacologic treatment and avoid polypharmacy, if possible. Family and caretakers should be included in the treatment planning, with a focus on prioritizing and managing the most debilitating symptoms or dysfunctions that prompt concerns for safety.

For optimal homeostasis, some DLB patients may require joint pharmacologic modalities that appear counterintuitive—for example, an antiparkinsonism (dopaminergic) agent for parkinsonian symptoms or neuroleptic-induced EPS, versus an antipsychotic (eg, a dopamine antagonist) to treat profound hallucinations.²⁶

As the response to treatment for DLB is highly individualized, it is essential to titrate and augment with care.

CONCLUSION
In DLB, as with other dementing illnesses, the onset of symptoms can be gradual and insidious, posing a great challenge to the clinician who seeks to confirm the diagnosis. In the illness’s early stages, the clinician may have to treat targeted symptoms and adjust the treatment plan once signs of the pathologic origins emerge.

It is critical to understand the mechanisms of psychotropic medications and targeted neurotransmitters when evaluating treatment for DLB. Titrating or augmenting these medications in elderly patients requires the clinician to follow a principle of start low and go slow, making only one change at a time.

It is always helpful to include family members in the patient’s care and to gather information on previous history, personality traits, family history, and cultural components. It is also important to communicate with other specialists to implement collaborative care.

How to reduce malpractice risk with better documentation.

Tips to make documentation easier, faster, and more satisfying” (Current Psychiatry, February 2008), I discussed documentation techniques at length. Table 3 reprints principles that may be especially helpful in practices that consist primarily of med checks.

Table 3

Keys to better documentation

Acknowledgment

Thanks to James Knoll IV, MD for his helpful input on this article.

How to reduce malpractice risk with better documentation.

Tips to make documentation easier, faster, and more satisfying” (Current Psychiatry, February 2008), I discussed documentation techniques at length. Table 3 reprints principles that may be especially helpful in practices that consist primarily of med checks.

Table 3

Keys to better documentation

Acknowledgment

Thanks to James Knoll IV, MD for his helpful input on this article.

How to reduce malpractice risk with better documentation.

Tips to make documentation easier, faster, and more satisfying” (Current Psychiatry, February 2008), I discussed documentation techniques at length. Table 3 reprints principles that may be especially helpful in practices that consist primarily of med checks.

Table 3

Keys to better documentation

Acknowledgment

Thanks to James Knoll IV, MD for his helpful input on this article.

CASE: Self-destructive behaviors

After being acquitted of 4 counts of second-degree forgery for writing checks from her mother’s bank account, Ms. L, age 52, is sent to the state hospital for a forensic examination to determine competency. Two years later she is granted conditional release from the hospital, transferred to our not-for-profit community mental health center, and enrolled in an intensive inpatient treatment program to monitor forensic patients. She is legally required to comply with treatment recommendations.

At admission, Ms. L is diagnosed with major depression, recurrent, and borderline personality disorder (BPD). She has no history of antisocial behavior or criminal acts other than forging checks and has never spent time in prison, which makes it unlikely she has co morbid antisocial personality disorder (Table 1).¹

Over the next 5 years Ms. L tests limits with the treatment team and acts out by engaging in self-harming behaviors. In 1 instance, she cuts her forearm deeply, stuffs the wound with mayonnaise and paper towels, and wraps her arm with a bandage. She wears a long-sleeved shirt to hide her wound, which is not discovered until a severe infection develops.

Ms. L has difficulty with coping skills and interpersonal relationships. She approaches others with ambivalence and mistrust and consistently expects them to demean or take advantage of her. Ms. L is manipulative, at times injuring herself after perceived wrongdoings by staff. For example, after her therapist reschedules a meeting because of an emergency, Ms. L pours scalding water on her foot.

Table 1

Cluster B personality disorders: Differential diagnosis

The authors’ observations

Ms. L consistently displays 3 common constructs of BPD:

• primitive defense mechanisms
• identity diffusion
• generally intact reality testing.²

Defense mechanisms are psychological attempts to deal with intrapsychic stress. Splitting—vacillating between extremes of idealization and devaluation—is a fundamental primitive defense mechanism that is the root of BPD.² Identity diffusion causes confusion about life goals and values and feelings of boredom and emptiness. This internal world leads a patient to have the same perception of the external world, which explains many symptoms of BPD, such as rapidly shifting moods, intense anger, lack of clear sense of self, fear of abandonment, and unstable and intense interpersonal relationships.²

Early in treatment, Ms. L had difficulty breaking a cycle of self-defeating behavior, such as destroying personal items, trying to hang herself, and gluing an ear plug in her ear. During an argument with a staff member, Ms. L punched a wall and fractured her left hand. BPD patients sometimes will “up the ante” when acting out. For example, one of our patients claimed to have planted a bomb in an elementary school and another swallowed inedible objects, including spoons, forks, and butter knives. In Ms. L’s case, we addressed her self-harm behavior by helping her:

• develop less destructive coping skills such as drawing or painting
• identify irrational thoughts that contribute to self harm.

HISTORY: Troubled past

Raised by her biologic parents, Ms. L met all developmental milestones. She denies a history of childhood abuse but reports experiencing “depression and memory loss” and relationship problems with her parents during adolescence. As a child she often missed school because she “did not want anyone to know what a disgusting person I was” and “I should have my head cut open and cut into little pieces for thinking such mean thoughts.” Ms. L dropped out of school in the twelfth grade but obtained her general educational development certificate.

Notes and letters Ms. L wrote while in treatment consistently refer to her negative self-image. Ms. L writes that she feels she does not deserve to “be a part of this world,” is “never good enough for anyone,” and “should be thrown away with the garbage.”

Ms. L vacillates between desiring a closer relationship with her parents, especially her mother, and wanting to “cut them out of my life for good.” She has minimal contact with her older sister. Ms. L is divorced and has 2 adult sons. She was involved sporadically in her sons’ lives when they were children, but now has no contact with them.

BPD and crime

Ms. L is enrolled in the “911 program,” which monitors individuals who have been found not guilty by reason of mental defect. Individuals with BPD often are convicted of serious and violent crimes, which may be because of BPD features such as interpersonal hostility and self-harm. Impulsivity, substance abuse, and parental neglect—all of which are associated with BPD—can increase risk of criminality.³ There is no evidence to suggest a direct link between BPD and criminality; however, over-representation of BPD in prison populations suggest that in severe cases it may increase criminogenic risk.^1,3

TREATMENT: Worsened depression

When Ms. L arrives at our facility, her medication regimen includes fluoxetine, 80 mg/d, risperidone, 2 mg/d, and buspirone, 20 mg/d. Risperidone and buspirone are discontinued because of perceived lack of efficacy. Venlafaxine XR is added and titrated to 300 mg/d, and Ms. L receives lorazepam, 1 and 2 mg as needed. However, lorazepam carries risks because impulsivity and impaired judgment—which are common in BPD—can lead to dependence and abuse. We feel that in a supervised setting the risks can be managed.

Recently, staff witnessed Ms. L experiencing an episode that appeared to be a grand mal seizure. After Ms. L is evaluated at the local emergency room, her EEG is normal, but a neurologic consult recommends discontinuing fluoxetine or venlafaxine XR because they may have contributed to the seizure. We taper and discontinue venlafaxine XR but Ms. L complains bitterly that she is getting increasingly depressed. On several occasions she attempts to pit team members against each other.

Ms. L falls, injures her back, and begins to abuse opiates. After her prescription runs out, she obtains more from an intellectually limited patient in her treatment program. Ms. L says she is getting more depressed, threatens suicide, and is placed in a more restrictive in-patient setting. We consider adding pregabalin to address her pain and help with anxiety and impulse control but the consulting neurologist prescribes carbamazepine, 400 mg/d, and her pain improves.^5,6

The authors’ observations

BPD treatment primarily is psychotherapeutic and emphasizes skill building (Table 2) with focused, symptom-targeted pharmacotherapy as indicated.⁴ Pharmacotherapy typically targets 3 domains:

• affective dysregulation
• impulsive-behavioral dyscontrol symptoms
• cognitive-perceptual symptoms.

Patients with prominent anxiety may benefit from benzodiazepines, although research on these agents for BPD is limited. Recent studies show efficacy with fluoxetine, olanzapine, or a combination of both,⁷ and divalproex.⁸ Preliminary data supports the use of topiramate, quetiapine, risperidone, ziprasidone, lamotrigine, and clonidine (Table 3).^9-14 A recent review and meta-analysis showed efficacy with topira-mate, lamotrigine, valproate, aripiprazole, and olanzapine.¹⁵

For Ms. L, we restart venlafaxine at a lower dose of 50 mg/d and titrate it to 150 mg/d, which is still lower than her previous dose of 300 mg/d. She has no recurrence of seizures and her depression improves.

Table 2

Features of psychotherapeutic modalities for BPD

Table 3

Pharmacotherapy for BPD: What the evidence says

OUTCOME: Some improvement

Ms. L has no dramatic suicidal gestures for 3 years. Although she continues to engage in self-injurious behaviors, the intensity and frequency are reduced and she does not inflict any serious injury for 18 months. Her mood and behavior continue to oscillate; she is relatively calm and satisfied 1 week, angry and assaultive the next. This stormy course is expected given her BPD diagnosis.

Initially, Ms. L resided in a locked residential unit and was minimally compliant with treatment recommendations and unit policies. As treatment progressed she moved to a different locked unit and eventually to an apartment. Recently, she was placed in a more restrictive setting because her hostile and self-destructive behavior escalated.

The authors’ observations

Ms. L is no different from most Axis II Cluster B disordered patients. During treatment she shows improvement by refraining from self-destructive behaviors for up to 18 months, but she then briefly reverts back to maladaptive behaviors. Ms. L resides in a very structured treatment setting. It is not clear if the gains she made in treatment would have been possible if she was living on her own in the community.

One year after finishing the court-mandated “911 program,” Ms. L lives in the community, draws and paints quite well, attends weekly individual and group therapy, and refrains from self-mutilation. She still experiences volatile moods, but can handle them without inflicting self injury.

Related resources

• Oldham JM. Guideline watch: practice guideline for the treatment of patients with borderline personality disorder. Arlington, VA: American Psychiatric Association; 2005. www.psychiatryonline.com/content.aspx?aID=148722.
• Koenigsberg HW, Kernberg OF, Stone MH, et al. Borderline patients: extending the limits of treatability. New York, NY: Basic Books; 2000.

Drug brand names

• Aripiprazole • Abilify
• Buspirone • Buspar
• Carbamazepine • Tegretol
• Clonidine • Catapres
• Divalproex • Depakote
• Fluoxetine • Prozac
• Fluoxetine-olanzapine • Symbyax
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Lorazepam • Ativan
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Pregabalin • Lyrica
• Risperidone • Risperdal
• Topiramate • Topamax
• Valproic acid • Depakene
• Venlafaxine XR • Effexor XR
• Ziprasidone • Geodon

Disclosures

Dr. Hashmi is on the speakers bureau for AstraZeneca, Eli Lilly and Company, and Janssen.

Dr. Vowell reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Self-destructive behaviors

After being acquitted of 4 counts of second-degree forgery for writing checks from her mother’s bank account, Ms. L, age 52, is sent to the state hospital for a forensic examination to determine competency. Two years later she is granted conditional release from the hospital, transferred to our not-for-profit community mental health center, and enrolled in an intensive inpatient treatment program to monitor forensic patients. She is legally required to comply with treatment recommendations.

At admission, Ms. L is diagnosed with major depression, recurrent, and borderline personality disorder (BPD). She has no history of antisocial behavior or criminal acts other than forging checks and has never spent time in prison, which makes it unlikely she has co morbid antisocial personality disorder (Table 1).¹

Over the next 5 years Ms. L tests limits with the treatment team and acts out by engaging in self-harming behaviors. In 1 instance, she cuts her forearm deeply, stuffs the wound with mayonnaise and paper towels, and wraps her arm with a bandage. She wears a long-sleeved shirt to hide her wound, which is not discovered until a severe infection develops.

Ms. L has difficulty with coping skills and interpersonal relationships. She approaches others with ambivalence and mistrust and consistently expects them to demean or take advantage of her. Ms. L is manipulative, at times injuring herself after perceived wrongdoings by staff. For example, after her therapist reschedules a meeting because of an emergency, Ms. L pours scalding water on her foot.

Table 1

Cluster B personality disorders: Differential diagnosis

The authors’ observations

Ms. L consistently displays 3 common constructs of BPD:

• primitive defense mechanisms
• identity diffusion
• generally intact reality testing.²

Defense mechanisms are psychological attempts to deal with intrapsychic stress. Splitting—vacillating between extremes of idealization and devaluation—is a fundamental primitive defense mechanism that is the root of BPD.² Identity diffusion causes confusion about life goals and values and feelings of boredom and emptiness. This internal world leads a patient to have the same perception of the external world, which explains many symptoms of BPD, such as rapidly shifting moods, intense anger, lack of clear sense of self, fear of abandonment, and unstable and intense interpersonal relationships.²

Early in treatment, Ms. L had difficulty breaking a cycle of self-defeating behavior, such as destroying personal items, trying to hang herself, and gluing an ear plug in her ear. During an argument with a staff member, Ms. L punched a wall and fractured her left hand. BPD patients sometimes will “up the ante” when acting out. For example, one of our patients claimed to have planted a bomb in an elementary school and another swallowed inedible objects, including spoons, forks, and butter knives. In Ms. L’s case, we addressed her self-harm behavior by helping her:

• develop less destructive coping skills such as drawing or painting
• identify irrational thoughts that contribute to self harm.

HISTORY: Troubled past

Raised by her biologic parents, Ms. L met all developmental milestones. She denies a history of childhood abuse but reports experiencing “depression and memory loss” and relationship problems with her parents during adolescence. As a child she often missed school because she “did not want anyone to know what a disgusting person I was” and “I should have my head cut open and cut into little pieces for thinking such mean thoughts.” Ms. L dropped out of school in the twelfth grade but obtained her general educational development certificate.

Notes and letters Ms. L wrote while in treatment consistently refer to her negative self-image. Ms. L writes that she feels she does not deserve to “be a part of this world,” is “never good enough for anyone,” and “should be thrown away with the garbage.”

Ms. L vacillates between desiring a closer relationship with her parents, especially her mother, and wanting to “cut them out of my life for good.” She has minimal contact with her older sister. Ms. L is divorced and has 2 adult sons. She was involved sporadically in her sons’ lives when they were children, but now has no contact with them.

BPD and crime

Ms. L is enrolled in the “911 program,” which monitors individuals who have been found not guilty by reason of mental defect. Individuals with BPD often are convicted of serious and violent crimes, which may be because of BPD features such as interpersonal hostility and self-harm. Impulsivity, substance abuse, and parental neglect—all of which are associated with BPD—can increase risk of criminality.³ There is no evidence to suggest a direct link between BPD and criminality; however, over-representation of BPD in prison populations suggest that in severe cases it may increase criminogenic risk.^1,3

TREATMENT: Worsened depression

When Ms. L arrives at our facility, her medication regimen includes fluoxetine, 80 mg/d, risperidone, 2 mg/d, and buspirone, 20 mg/d. Risperidone and buspirone are discontinued because of perceived lack of efficacy. Venlafaxine XR is added and titrated to 300 mg/d, and Ms. L receives lorazepam, 1 and 2 mg as needed. However, lorazepam carries risks because impulsivity and impaired judgment—which are common in BPD—can lead to dependence and abuse. We feel that in a supervised setting the risks can be managed.

Recently, staff witnessed Ms. L experiencing an episode that appeared to be a grand mal seizure. After Ms. L is evaluated at the local emergency room, her EEG is normal, but a neurologic consult recommends discontinuing fluoxetine or venlafaxine XR because they may have contributed to the seizure. We taper and discontinue venlafaxine XR but Ms. L complains bitterly that she is getting increasingly depressed. On several occasions she attempts to pit team members against each other.

Ms. L falls, injures her back, and begins to abuse opiates. After her prescription runs out, she obtains more from an intellectually limited patient in her treatment program. Ms. L says she is getting more depressed, threatens suicide, and is placed in a more restrictive in-patient setting. We consider adding pregabalin to address her pain and help with anxiety and impulse control but the consulting neurologist prescribes carbamazepine, 400 mg/d, and her pain improves.^5,6

The authors’ observations

BPD treatment primarily is psychotherapeutic and emphasizes skill building (Table 2) with focused, symptom-targeted pharmacotherapy as indicated.⁴ Pharmacotherapy typically targets 3 domains:

• affective dysregulation
• impulsive-behavioral dyscontrol symptoms
• cognitive-perceptual symptoms.

Patients with prominent anxiety may benefit from benzodiazepines, although research on these agents for BPD is limited. Recent studies show efficacy with fluoxetine, olanzapine, or a combination of both,⁷ and divalproex.⁸ Preliminary data supports the use of topiramate, quetiapine, risperidone, ziprasidone, lamotrigine, and clonidine (Table 3).^9-14 A recent review and meta-analysis showed efficacy with topira-mate, lamotrigine, valproate, aripiprazole, and olanzapine.¹⁵

For Ms. L, we restart venlafaxine at a lower dose of 50 mg/d and titrate it to 150 mg/d, which is still lower than her previous dose of 300 mg/d. She has no recurrence of seizures and her depression improves.

Table 2

Features of psychotherapeutic modalities for BPD

Table 3

Pharmacotherapy for BPD: What the evidence says

OUTCOME: Some improvement

Ms. L has no dramatic suicidal gestures for 3 years. Although she continues to engage in self-injurious behaviors, the intensity and frequency are reduced and she does not inflict any serious injury for 18 months. Her mood and behavior continue to oscillate; she is relatively calm and satisfied 1 week, angry and assaultive the next. This stormy course is expected given her BPD diagnosis.

Initially, Ms. L resided in a locked residential unit and was minimally compliant with treatment recommendations and unit policies. As treatment progressed she moved to a different locked unit and eventually to an apartment. Recently, she was placed in a more restrictive setting because her hostile and self-destructive behavior escalated.

The authors’ observations

Ms. L is no different from most Axis II Cluster B disordered patients. During treatment she shows improvement by refraining from self-destructive behaviors for up to 18 months, but she then briefly reverts back to maladaptive behaviors. Ms. L resides in a very structured treatment setting. It is not clear if the gains she made in treatment would have been possible if she was living on her own in the community.

One year after finishing the court-mandated “911 program,” Ms. L lives in the community, draws and paints quite well, attends weekly individual and group therapy, and refrains from self-mutilation. She still experiences volatile moods, but can handle them without inflicting self injury.

Related resources

• Oldham JM. Guideline watch: practice guideline for the treatment of patients with borderline personality disorder. Arlington, VA: American Psychiatric Association; 2005. www.psychiatryonline.com/content.aspx?aID=148722.
• Koenigsberg HW, Kernberg OF, Stone MH, et al. Borderline patients: extending the limits of treatability. New York, NY: Basic Books; 2000.

Drug brand names

• Aripiprazole • Abilify
• Buspirone • Buspar
• Carbamazepine • Tegretol
• Clonidine • Catapres
• Divalproex • Depakote
• Fluoxetine • Prozac
• Fluoxetine-olanzapine • Symbyax
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Lorazepam • Ativan
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Pregabalin • Lyrica
• Risperidone • Risperdal
• Topiramate • Topamax
• Valproic acid • Depakene
• Venlafaxine XR • Effexor XR
• Ziprasidone • Geodon

Disclosures

Dr. Hashmi is on the speakers bureau for AstraZeneca, Eli Lilly and Company, and Janssen.

Dr. Vowell reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Self-destructive behaviors

After being acquitted of 4 counts of second-degree forgery for writing checks from her mother’s bank account, Ms. L, age 52, is sent to the state hospital for a forensic examination to determine competency. Two years later she is granted conditional release from the hospital, transferred to our not-for-profit community mental health center, and enrolled in an intensive inpatient treatment program to monitor forensic patients. She is legally required to comply with treatment recommendations.

At admission, Ms. L is diagnosed with major depression, recurrent, and borderline personality disorder (BPD). She has no history of antisocial behavior or criminal acts other than forging checks and has never spent time in prison, which makes it unlikely she has co morbid antisocial personality disorder (Table 1).¹

Over the next 5 years Ms. L tests limits with the treatment team and acts out by engaging in self-harming behaviors. In 1 instance, she cuts her forearm deeply, stuffs the wound with mayonnaise and paper towels, and wraps her arm with a bandage. She wears a long-sleeved shirt to hide her wound, which is not discovered until a severe infection develops.

Ms. L has difficulty with coping skills and interpersonal relationships. She approaches others with ambivalence and mistrust and consistently expects them to demean or take advantage of her. Ms. L is manipulative, at times injuring herself after perceived wrongdoings by staff. For example, after her therapist reschedules a meeting because of an emergency, Ms. L pours scalding water on her foot.

Table 1

Cluster B personality disorders: Differential diagnosis

The authors’ observations

Ms. L consistently displays 3 common constructs of BPD:

• primitive defense mechanisms
• identity diffusion
• generally intact reality testing.²

Defense mechanisms are psychological attempts to deal with intrapsychic stress. Splitting—vacillating between extremes of idealization and devaluation—is a fundamental primitive defense mechanism that is the root of BPD.² Identity diffusion causes confusion about life goals and values and feelings of boredom and emptiness. This internal world leads a patient to have the same perception of the external world, which explains many symptoms of BPD, such as rapidly shifting moods, intense anger, lack of clear sense of self, fear of abandonment, and unstable and intense interpersonal relationships.²

Early in treatment, Ms. L had difficulty breaking a cycle of self-defeating behavior, such as destroying personal items, trying to hang herself, and gluing an ear plug in her ear. During an argument with a staff member, Ms. L punched a wall and fractured her left hand. BPD patients sometimes will “up the ante” when acting out. For example, one of our patients claimed to have planted a bomb in an elementary school and another swallowed inedible objects, including spoons, forks, and butter knives. In Ms. L’s case, we addressed her self-harm behavior by helping her:

• develop less destructive coping skills such as drawing or painting
• identify irrational thoughts that contribute to self harm.

HISTORY: Troubled past

Raised by her biologic parents, Ms. L met all developmental milestones. She denies a history of childhood abuse but reports experiencing “depression and memory loss” and relationship problems with her parents during adolescence. As a child she often missed school because she “did not want anyone to know what a disgusting person I was” and “I should have my head cut open and cut into little pieces for thinking such mean thoughts.” Ms. L dropped out of school in the twelfth grade but obtained her general educational development certificate.

Notes and letters Ms. L wrote while in treatment consistently refer to her negative self-image. Ms. L writes that she feels she does not deserve to “be a part of this world,” is “never good enough for anyone,” and “should be thrown away with the garbage.”

Ms. L vacillates between desiring a closer relationship with her parents, especially her mother, and wanting to “cut them out of my life for good.” She has minimal contact with her older sister. Ms. L is divorced and has 2 adult sons. She was involved sporadically in her sons’ lives when they were children, but now has no contact with them.

BPD and crime

Ms. L is enrolled in the “911 program,” which monitors individuals who have been found not guilty by reason of mental defect. Individuals with BPD often are convicted of serious and violent crimes, which may be because of BPD features such as interpersonal hostility and self-harm. Impulsivity, substance abuse, and parental neglect—all of which are associated with BPD—can increase risk of criminality.³ There is no evidence to suggest a direct link between BPD and criminality; however, over-representation of BPD in prison populations suggest that in severe cases it may increase criminogenic risk.^1,3

TREATMENT: Worsened depression

When Ms. L arrives at our facility, her medication regimen includes fluoxetine, 80 mg/d, risperidone, 2 mg/d, and buspirone, 20 mg/d. Risperidone and buspirone are discontinued because of perceived lack of efficacy. Venlafaxine XR is added and titrated to 300 mg/d, and Ms. L receives lorazepam, 1 and 2 mg as needed. However, lorazepam carries risks because impulsivity and impaired judgment—which are common in BPD—can lead to dependence and abuse. We feel that in a supervised setting the risks can be managed.

Recently, staff witnessed Ms. L experiencing an episode that appeared to be a grand mal seizure. After Ms. L is evaluated at the local emergency room, her EEG is normal, but a neurologic consult recommends discontinuing fluoxetine or venlafaxine XR because they may have contributed to the seizure. We taper and discontinue venlafaxine XR but Ms. L complains bitterly that she is getting increasingly depressed. On several occasions she attempts to pit team members against each other.

Ms. L falls, injures her back, and begins to abuse opiates. After her prescription runs out, she obtains more from an intellectually limited patient in her treatment program. Ms. L says she is getting more depressed, threatens suicide, and is placed in a more restrictive in-patient setting. We consider adding pregabalin to address her pain and help with anxiety and impulse control but the consulting neurologist prescribes carbamazepine, 400 mg/d, and her pain improves.^5,6

The authors’ observations

BPD treatment primarily is psychotherapeutic and emphasizes skill building (Table 2) with focused, symptom-targeted pharmacotherapy as indicated.⁴ Pharmacotherapy typically targets 3 domains:

• affective dysregulation
• impulsive-behavioral dyscontrol symptoms
• cognitive-perceptual symptoms.

Patients with prominent anxiety may benefit from benzodiazepines, although research on these agents for BPD is limited. Recent studies show efficacy with fluoxetine, olanzapine, or a combination of both,⁷ and divalproex.⁸ Preliminary data supports the use of topiramate, quetiapine, risperidone, ziprasidone, lamotrigine, and clonidine (Table 3).^9-14 A recent review and meta-analysis showed efficacy with topira-mate, lamotrigine, valproate, aripiprazole, and olanzapine.¹⁵

For Ms. L, we restart venlafaxine at a lower dose of 50 mg/d and titrate it to 150 mg/d, which is still lower than her previous dose of 300 mg/d. She has no recurrence of seizures and her depression improves.

Table 2

Features of psychotherapeutic modalities for BPD

Table 3

Pharmacotherapy for BPD: What the evidence says

OUTCOME: Some improvement

Ms. L has no dramatic suicidal gestures for 3 years. Although she continues to engage in self-injurious behaviors, the intensity and frequency are reduced and she does not inflict any serious injury for 18 months. Her mood and behavior continue to oscillate; she is relatively calm and satisfied 1 week, angry and assaultive the next. This stormy course is expected given her BPD diagnosis.

Initially, Ms. L resided in a locked residential unit and was minimally compliant with treatment recommendations and unit policies. As treatment progressed she moved to a different locked unit and eventually to an apartment. Recently, she was placed in a more restrictive setting because her hostile and self-destructive behavior escalated.

The authors’ observations

Ms. L is no different from most Axis II Cluster B disordered patients. During treatment she shows improvement by refraining from self-destructive behaviors for up to 18 months, but she then briefly reverts back to maladaptive behaviors. Ms. L resides in a very structured treatment setting. It is not clear if the gains she made in treatment would have been possible if she was living on her own in the community.

One year after finishing the court-mandated “911 program,” Ms. L lives in the community, draws and paints quite well, attends weekly individual and group therapy, and refrains from self-mutilation. She still experiences volatile moods, but can handle them without inflicting self injury.

Related resources

• Oldham JM. Guideline watch: practice guideline for the treatment of patients with borderline personality disorder. Arlington, VA: American Psychiatric Association; 2005. www.psychiatryonline.com/content.aspx?aID=148722.
• Koenigsberg HW, Kernberg OF, Stone MH, et al. Borderline patients: extending the limits of treatability. New York, NY: Basic Books; 2000.

Drug brand names

• Aripiprazole • Abilify
• Buspirone • Buspar
• Carbamazepine • Tegretol
• Clonidine • Catapres
• Divalproex • Depakote
• Fluoxetine • Prozac
• Fluoxetine-olanzapine • Symbyax
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Lorazepam • Ativan
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Pregabalin • Lyrica
• Risperidone • Risperdal
• Topiramate • Topamax
• Valproic acid • Depakene
• Venlafaxine XR • Effexor XR
• Ziprasidone • Geodon

Disclosures

Dr. Hashmi is on the speakers bureau for AstraZeneca, Eli Lilly and Company, and Janssen.

Dr. Vowell reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article

Pharmacologic treatments for Alzheimer’s disease (AD) may improve symptoms but have not been shown to prevent AD onset. Primary prevention therefore remains the goal. Although preventing AD by managing risk factors such as age or genetics is beyond our control (Box 1), we can do something about other factors.

This article summarizes the findings of many studies that address AD prevention and includes an online-only bibliography for readers seeking an in-depth review. The evidence does not support a firm recommendation for any specific form of primary prevention and has revealed hazards associated with estrogen therapy and nonsteroidal anti-inflammatory drugs (Box 2). Most important, it suggests that you could reduce your patients’ risk of developing AD by routinely supporting their mental, physical, and social health.

The potential benefits of modifying an individual’s AD risk factors likely will depend on his or her genetic makeup, environment, and lifestyle. Even so, counseling patients to exercise more and improve their diets—such as by eating more fish, fruits, and vegetables and less saturated fat—might help protect the brain. Your ongoing efforts to manage hypertension, hypercholesterolemia, and diabetes also may reduce their AD risk.

Box 1

Box 2

Cardiovascular risk factors

The risk of developing AD or vascular dementia appears to be increased by conditions that damage the heart or blood vessels. Recent evidence suggests that successfully managing cardiovascular risk factors may decrease the likelihood of dementia in later life.

Hypertension is associated with a higher risk of AD and all-cause dementia. Curiously, some studies have shown that low blood pressure also increases dementia risk, suggesting a U-shaped relationship between blood pressure and cognitive decline. Systolic hypertension in midlife may be associated with dementia 20 years later.

One might assume that antihypertensive therapy would help prevent dementia, but the data are conflicting. The Systolic Hypertension in Europe (SYST-EUR) study¹ showed a 53% reduction in vascular dementia or mixed dementia among patients receiving antihypertensive medication and a 60% reduction in AD. Similarly, the PROGRESS² clinical trial of prevention of recurrent stroke by antihypertensive treatment reported a 34% reduction in a composite measure of cognitive impairment and dementia. On the other hand, cognitive function neither improved nor worsened in the Hypertension in the Very Elderly Trial (HYVET-COG),³ whether patients received blood pressure treatment or placebo.

Hyperlipidemia. Lipid metabolism likely is an important pathway in amyloid beta-protein deposition, tau phosphorylation, and disruption of synaptic plasticity and neurodegenerative endpoints. Cognitive decline and incident dementia have been associated with higher dietary intake of saturated fats, partially hydrogenated unsaturated fatty acids (trans fats), and cholesterol. Not all studies have found this association, however. This could be because serum cholesterol levels may decrease in early dementia, limiting the ability to detect an effect of hypercholesterolemia on dementia risk when measurements are made later in life.

Using statins (3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors) to treat hypercholesterolemia has been hypothesized to impede large vessel atherosclerosis and its consequences and to trigger metabolic effects in the brain related to AD pathogenesis. Mechanisms by which statins might help prevent dementia include:

• a direct association between amyloid processing and cholesterol in the brain
• an indirect effect by decreasing the risk of stroke, as even small cerebral infarcts worsen AD severity.

Nonrandomized epidemiologic studies such as the Cardiovascular Health Study⁴ and MRC/BHF Heart Protection Study⁵ suggested that statin treatment might reduce the incidence of dementia, the degree of age-related cognitive decline, and AD’s neuropathologic burden. Large, randomized, controlled trials have not supported these observations, however. Statins failed to reduce the incidence of dementia in:

• the Heart Protection Study, testing simvastatin for 5 years in 20,536 subjects age 40 to 80⁵
• the 3-year Preventive Study of Pravastatin in the Elderly at Risk (PROSPER) of 5,800 subjects.⁶

Similarly, patients receiving adjunctive atorvastatin or placebo showed no significant differences in cognition assessments after 72 weeks in the Lipitor’s Effect in Alzheimer’s Dementia (LEADe) study. This trial enrolled 640 subjects age 50 to 90 with mild-to-moderate dementia who were treated with donepezil.⁷ A recent Cochrane review concluded that high serum cholesterol may contribute to the development of AD and vascular dementia, but lowering cholesterol levels with statins does not prevent these problems.⁸

Diabetes mellitus. Diabetes and cognitive decline are closely associated. Diabetes is associated with a 50% to 100% increase in risk of AD and dementia overall and a 100% to 150% increased risk of vascular dementia. The mechanism by which diabetes increases dementia risk is uncertain but does not appear to be mediated entirely through vascular disease. High and low insulin levels may increase the risk of dementia, independent of diabetes and blood glucose. Increased peripheral insulin levels are associated with reduced brain atrophy and cognitive impairment in patients with early AD, suggesting a role for insulin signaling in AD pathophysiology. A possible relationship between insulin and beta amyloid metabolism is being studied.

Elevated postprandial plasma glucose has been associated with accelerated declines in cognitive performance.⁹ An inverse correlation has been noted between some cognitive measures and hemoglobin A1C levels.¹⁰ It is not clear that treating diabetes reduces the risk of dementia. In addition, in the prospective, population-based Rotterdam study, elderly patients with type 2 diabetes treated with insulin had the highest incidence of dementia.¹¹

Tobacco smoke directly affects neuronal function, integrity, and survival. Chronic smoking has been linked to decreased global cerebral blood flow, accelerated cerebral atrophy, and ventricular enlargement.

Some studies suggest an increased risk of dementia in middle-aged and elderly smokers, possibly through a cerebrovascular mechanism such as stroke. Other studies found no association between smoking and dementia risk, and 1 suggested that nicotine may protect against AD by reducing senile plaque formation. Any protective effect of smoking would be offset by increased risks of lung cancer, chronic obstructive pulmonary disease, and vascular dementia.

The apolipoprotein E epsilon 4 (APOE e4) gene may explain, at least in part, the conflicting results of these studies. In 2 population-based cohorts,^12,13 smoking was associated with memory decline in patients without, but not with, the APOE e4 genotype.

Dietary factors

Antioxidants. The brains of patients with AD contain elevated levels of endogenous antioxidants. In vitro studies show exogenous antioxidants can reduce the toxicity of beta-amyloid in brain tissue of persons with AD. These findings have led to interest in assessing the role of dietary antioxidants such as vitamins E and C for AD prevention.

High-dose alpha-tocopherol (vitamin E, 2,000 IU/d) may slow disease progression in patients with AD, but this association is not consistently found. Furthermore, a meta-analysis of 19 randomized controlled trials (RCTs) totaling >135,000 patients found an association between vitamin E doses >400 IU/d and increased all-cause mortality.¹⁴ High-dose vitamin E supplementation for primary or secondary prevention of AD may be dangerous and is not recommended.

The lack of consistent efficacy data for vitamin C in preventing or treating AD may discourage its routine use for this purpose.¹⁵

Homocysteine is a risk factor for stroke and heart disease. It also could play a role in vascular dementia through its association with large- and small-vessel disease.

Low folate and hyperhomocysteinemia have been associated with dementia or cognitive impairment, although a cause-effect relationship is not clear. In non-demented elderly populations, plasma homocysteine is inversely associated with poor performance in tests of global cognitive function, particularly in measures of psychomotor speed.

In a recent double-blind RCT, folic acid supplementation for 3 years significantly improved domains of cognitive function that tend to decline with age, especially information processing and sensorimotor speed.¹⁶ No other good evidence, however, has shown that homocysteine-lowering therapy using folic acid or other vitamin B supplements improves cognitive function or prevents cognitive decline.

Fish and omega-3 fatty acids. High total fat, saturated fat, and total cholesterol intake increases the risk for incident dementia. In epidemiologic studies, low omega-3 fatty acid serum levels have been linked to increased dementia risk.

Fish consumption may be beneficial in reducing the risk of dementia or cognitive decline. A prospective study of 815 elderly persons found 60% less risk of developing AD in those who ate ≥1 fish meal per week, compared with those who rarely or never ate fish.¹⁷ In the Framingham study, individuals who at baseline were in the top quartile of docosahexaenoic acid consumption had lower dementia rates over 9 years of follow-up.¹⁸ Results from cross-sectional and longitudinal studies have been inconsistent; some have shown that high intake of n-3 polyunsaturated fatty acids is associated with less cognitive decline,¹⁹ whereas others have not.²⁰

Although we cannot offer unequivocal advice regarding seafood or omega-3 fatty acid intake for primary prevention of dementia without evidence from RCTs, these uncontrolled studies show promise.

Mediterranean diet (MeDi) components include abundant fruits and vegetables, fish or shellfish at least twice weekly, very limited red meat, olive oil or canola oil instead of butter or margarine, tree nuts such as walnuts or pecans, red wine in moderation, and using herbs and spices instead of salt to season food. High adherence to the MeDi has been associated with a significantly lower risk for incident AD. The MeDi may affect the risk of developing AD²¹ as well as subsequent disease course, with a possible dose-response relationship in lower mortality.²²

Eating fruits and vegetables has been associated with improved cognitive performance²² and decreased incident dementia in elderly subjects.¹⁸

Alcohol. A U-shaped relationship exists between alcohol consumption and dementia risk. High alcohol intake is associated with clinical problem drinking and alcoholism and can lead to cognitive decline. Conversely, moderate wine consumption (250 to 500 mL/d) may be protective—compared with more or less than this amount—and is associated with approximately 50% less risk of dementia.

Alcohol use may increase the risk of dementia in persons carrying the APOE e4 allele, according to the population-based Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study from Sweden.²³ After an average 21 years of follow-up of 1,449 individuals, researchers found that environmental factors—such as physical inactivity, dietary fat intake, alcohol consumption, and smoking at midlife—were associated with an increased risk of dementia at age 65 to 79 in APOE e4 carriers compared with noncarriers. The study also found that physical inactivity, dietary fat intake, and smoking at midlife increase AD risk, especially among APOE e4 carriers.

In the absence of evidence from RCTs, we cannot recommend alcohol to reduce the risk of AD.

Lifestyle and activity

Three components of lifestyle—social, mental, and physical activity—are inversely associated with the risk for dementia, AD, and cognitive impairment.

Physical exercise has been thought to enhance brain neurotrophic factor and modify apoptosis. Exercise can deter stroke and microvascular disease and improve regional cerebral blood flow. In the Cardiovascular Health Study, participants who expended the highest quartile of energy had a lower risk of all-cause dementia and AD compared with participants who expended the lowest quartile of energy.²⁴

Mental and social activity. Epidemiologic studies have shown associations between higher educational achievement and other socioeconomic factors and reduced AD risk. Advanced education is believed to represent a cognitive reserve that delays presentation of AD’s effects on memory and cognitive function, rather than providing a protective effect against accumulation of AD pathology. Higher-educated individuals appear to experience a somewhat more rapid rate of cognitive decline when AD does become apparent, perhaps because they have accumulated a greater degree of AD pathology at that point compared with less-educated persons.

Among 117 persons with dementia in the Bronx Aging Study, each additional year of formal education delayed the time of accelerated decline by 0.21 years. After accelerated decline began, each year of additional formal education was associated with a slightly faster rate of memory decline.²⁵

The longitudinal, population-based Kungsholmen Project in Stockholm, Sweden, found an association between daily mentally stimulating activities and decreased risk of all-cause dementia.²⁶ Similarly, higher levels of leisure activity were linked to reduced risk of all-cause dementia in a longitudinal study of 1,772 persons age ≥65 living in Manhattan, NY.²⁷ In a randomized, single-controlled study of the long-term effects of cognitive training, elderly individuals from 6 U.S. cities showed sustained improvement in specific cognitive performance up to 5 years after training sessions began, including memory, reasoning, and speed of processing.²⁸

It seems reasonable to encourage older patients to maintain or increase physical, cognitive, and leisure activities as well as social interaction. These interventions can improve the quality of life and lower the risk of depression, which may be a response to cognitive decline or an independent risk factor for dementia (Box 3). The Table lists “brain exercises” you can suggest to patients to increase their mental and social activity.

Head trauma. The Multi-Institutional Research in Alzheimer’s Genetic Epidemiology (MIRAGE) project found an association between AD risk and a history of head trauma, especially in persons with APOE e4 alleles.²⁹ Conversely, the Rotterdam Study showed no change in dementia risk for persons with a history of head trauma.³⁰

Even in the absence of conclusive evidence supporting AD prevention, protecting the head by buckling seat belts while driving, wearing helmets when participating in sports, and “fall-proofing” the home is recommended.

Box 3

Table

Brain exercises to suggest to patients

Related resource

• For an extensive bibliography of literature on Alzheimer’s disease risk factors and prevention, see this article at CurrentPsychiatry.com.

Drug brand names

• Atorvastatin • Lipitor
• Celecoxib • Celebrex
• Donepezil • Aricept
• Medroxyprogesterone • Provera
• Pravastatin • Pravachol
• Rofecoxib • Vioxx
• Simvastatin • Zocor

Disclosures

Dr. Bassil reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Dr. Grossberg receives research/grant support from and is a consultant to Bristol-Myers Squibb, Forest Pharmaceuticals, Novartis, Pfizer Inc., and Wyeth Pharmaceuticals. He also receives research/grant support from Baxter.

Discuss this article

Pharmacologic treatments for Alzheimer’s disease (AD) may improve symptoms but have not been shown to prevent AD onset. Primary prevention therefore remains the goal. Although preventing AD by managing risk factors such as age or genetics is beyond our control (Box 1), we can do something about other factors.

This article summarizes the findings of many studies that address AD prevention and includes an online-only bibliography for readers seeking an in-depth review. The evidence does not support a firm recommendation for any specific form of primary prevention and has revealed hazards associated with estrogen therapy and nonsteroidal anti-inflammatory drugs (Box 2). Most important, it suggests that you could reduce your patients’ risk of developing AD by routinely supporting their mental, physical, and social health.

The potential benefits of modifying an individual’s AD risk factors likely will depend on his or her genetic makeup, environment, and lifestyle. Even so, counseling patients to exercise more and improve their diets—such as by eating more fish, fruits, and vegetables and less saturated fat—might help protect the brain. Your ongoing efforts to manage hypertension, hypercholesterolemia, and diabetes also may reduce their AD risk.

Box 1

Box 2

Cardiovascular risk factors

The risk of developing AD or vascular dementia appears to be increased by conditions that damage the heart or blood vessels. Recent evidence suggests that successfully managing cardiovascular risk factors may decrease the likelihood of dementia in later life.

Hypertension is associated with a higher risk of AD and all-cause dementia. Curiously, some studies have shown that low blood pressure also increases dementia risk, suggesting a U-shaped relationship between blood pressure and cognitive decline. Systolic hypertension in midlife may be associated with dementia 20 years later.

One might assume that antihypertensive therapy would help prevent dementia, but the data are conflicting. The Systolic Hypertension in Europe (SYST-EUR) study¹ showed a 53% reduction in vascular dementia or mixed dementia among patients receiving antihypertensive medication and a 60% reduction in AD. Similarly, the PROGRESS² clinical trial of prevention of recurrent stroke by antihypertensive treatment reported a 34% reduction in a composite measure of cognitive impairment and dementia. On the other hand, cognitive function neither improved nor worsened in the Hypertension in the Very Elderly Trial (HYVET-COG),³ whether patients received blood pressure treatment or placebo.

Hyperlipidemia. Lipid metabolism likely is an important pathway in amyloid beta-protein deposition, tau phosphorylation, and disruption of synaptic plasticity and neurodegenerative endpoints. Cognitive decline and incident dementia have been associated with higher dietary intake of saturated fats, partially hydrogenated unsaturated fatty acids (trans fats), and cholesterol. Not all studies have found this association, however. This could be because serum cholesterol levels may decrease in early dementia, limiting the ability to detect an effect of hypercholesterolemia on dementia risk when measurements are made later in life.

Using statins (3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors) to treat hypercholesterolemia has been hypothesized to impede large vessel atherosclerosis and its consequences and to trigger metabolic effects in the brain related to AD pathogenesis. Mechanisms by which statins might help prevent dementia include:

• a direct association between amyloid processing and cholesterol in the brain
• an indirect effect by decreasing the risk of stroke, as even small cerebral infarcts worsen AD severity.

Nonrandomized epidemiologic studies such as the Cardiovascular Health Study⁴ and MRC/BHF Heart Protection Study⁵ suggested that statin treatment might reduce the incidence of dementia, the degree of age-related cognitive decline, and AD’s neuropathologic burden. Large, randomized, controlled trials have not supported these observations, however. Statins failed to reduce the incidence of dementia in:

• the Heart Protection Study, testing simvastatin for 5 years in 20,536 subjects age 40 to 80⁵
• the 3-year Preventive Study of Pravastatin in the Elderly at Risk (PROSPER) of 5,800 subjects.⁶

Similarly, patients receiving adjunctive atorvastatin or placebo showed no significant differences in cognition assessments after 72 weeks in the Lipitor’s Effect in Alzheimer’s Dementia (LEADe) study. This trial enrolled 640 subjects age 50 to 90 with mild-to-moderate dementia who were treated with donepezil.⁷ A recent Cochrane review concluded that high serum cholesterol may contribute to the development of AD and vascular dementia, but lowering cholesterol levels with statins does not prevent these problems.⁸

Diabetes mellitus. Diabetes and cognitive decline are closely associated. Diabetes is associated with a 50% to 100% increase in risk of AD and dementia overall and a 100% to 150% increased risk of vascular dementia. The mechanism by which diabetes increases dementia risk is uncertain but does not appear to be mediated entirely through vascular disease. High and low insulin levels may increase the risk of dementia, independent of diabetes and blood glucose. Increased peripheral insulin levels are associated with reduced brain atrophy and cognitive impairment in patients with early AD, suggesting a role for insulin signaling in AD pathophysiology. A possible relationship between insulin and beta amyloid metabolism is being studied.

Elevated postprandial plasma glucose has been associated with accelerated declines in cognitive performance.⁹ An inverse correlation has been noted between some cognitive measures and hemoglobin A1C levels.¹⁰ It is not clear that treating diabetes reduces the risk of dementia. In addition, in the prospective, population-based Rotterdam study, elderly patients with type 2 diabetes treated with insulin had the highest incidence of dementia.¹¹

Tobacco smoke directly affects neuronal function, integrity, and survival. Chronic smoking has been linked to decreased global cerebral blood flow, accelerated cerebral atrophy, and ventricular enlargement.

Some studies suggest an increased risk of dementia in middle-aged and elderly smokers, possibly through a cerebrovascular mechanism such as stroke. Other studies found no association between smoking and dementia risk, and 1 suggested that nicotine may protect against AD by reducing senile plaque formation. Any protective effect of smoking would be offset by increased risks of lung cancer, chronic obstructive pulmonary disease, and vascular dementia.

The apolipoprotein E epsilon 4 (APOE e4) gene may explain, at least in part, the conflicting results of these studies. In 2 population-based cohorts,^12,13 smoking was associated with memory decline in patients without, but not with, the APOE e4 genotype.

Dietary factors

Antioxidants. The brains of patients with AD contain elevated levels of endogenous antioxidants. In vitro studies show exogenous antioxidants can reduce the toxicity of beta-amyloid in brain tissue of persons with AD. These findings have led to interest in assessing the role of dietary antioxidants such as vitamins E and C for AD prevention.

High-dose alpha-tocopherol (vitamin E, 2,000 IU/d) may slow disease progression in patients with AD, but this association is not consistently found. Furthermore, a meta-analysis of 19 randomized controlled trials (RCTs) totaling >135,000 patients found an association between vitamin E doses >400 IU/d and increased all-cause mortality.¹⁴ High-dose vitamin E supplementation for primary or secondary prevention of AD may be dangerous and is not recommended.

The lack of consistent efficacy data for vitamin C in preventing or treating AD may discourage its routine use for this purpose.¹⁵

Homocysteine is a risk factor for stroke and heart disease. It also could play a role in vascular dementia through its association with large- and small-vessel disease.

Low folate and hyperhomocysteinemia have been associated with dementia or cognitive impairment, although a cause-effect relationship is not clear. In non-demented elderly populations, plasma homocysteine is inversely associated with poor performance in tests of global cognitive function, particularly in measures of psychomotor speed.

In a recent double-blind RCT, folic acid supplementation for 3 years significantly improved domains of cognitive function that tend to decline with age, especially information processing and sensorimotor speed.¹⁶ No other good evidence, however, has shown that homocysteine-lowering therapy using folic acid or other vitamin B supplements improves cognitive function or prevents cognitive decline.

Fish and omega-3 fatty acids. High total fat, saturated fat, and total cholesterol intake increases the risk for incident dementia. In epidemiologic studies, low omega-3 fatty acid serum levels have been linked to increased dementia risk.

Fish consumption may be beneficial in reducing the risk of dementia or cognitive decline. A prospective study of 815 elderly persons found 60% less risk of developing AD in those who ate ≥1 fish meal per week, compared with those who rarely or never ate fish.¹⁷ In the Framingham study, individuals who at baseline were in the top quartile of docosahexaenoic acid consumption had lower dementia rates over 9 years of follow-up.¹⁸ Results from cross-sectional and longitudinal studies have been inconsistent; some have shown that high intake of n-3 polyunsaturated fatty acids is associated with less cognitive decline,¹⁹ whereas others have not.²⁰

Although we cannot offer unequivocal advice regarding seafood or omega-3 fatty acid intake for primary prevention of dementia without evidence from RCTs, these uncontrolled studies show promise.

Mediterranean diet (MeDi) components include abundant fruits and vegetables, fish or shellfish at least twice weekly, very limited red meat, olive oil or canola oil instead of butter or margarine, tree nuts such as walnuts or pecans, red wine in moderation, and using herbs and spices instead of salt to season food. High adherence to the MeDi has been associated with a significantly lower risk for incident AD. The MeDi may affect the risk of developing AD²¹ as well as subsequent disease course, with a possible dose-response relationship in lower mortality.²²

Eating fruits and vegetables has been associated with improved cognitive performance²² and decreased incident dementia in elderly subjects.¹⁸

Alcohol. A U-shaped relationship exists between alcohol consumption and dementia risk. High alcohol intake is associated with clinical problem drinking and alcoholism and can lead to cognitive decline. Conversely, moderate wine consumption (250 to 500 mL/d) may be protective—compared with more or less than this amount—and is associated with approximately 50% less risk of dementia.

Alcohol use may increase the risk of dementia in persons carrying the APOE e4 allele, according to the population-based Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study from Sweden.²³ After an average 21 years of follow-up of 1,449 individuals, researchers found that environmental factors—such as physical inactivity, dietary fat intake, alcohol consumption, and smoking at midlife—were associated with an increased risk of dementia at age 65 to 79 in APOE e4 carriers compared with noncarriers. The study also found that physical inactivity, dietary fat intake, and smoking at midlife increase AD risk, especially among APOE e4 carriers.

In the absence of evidence from RCTs, we cannot recommend alcohol to reduce the risk of AD.

Lifestyle and activity

Three components of lifestyle—social, mental, and physical activity—are inversely associated with the risk for dementia, AD, and cognitive impairment.

Physical exercise has been thought to enhance brain neurotrophic factor and modify apoptosis. Exercise can deter stroke and microvascular disease and improve regional cerebral blood flow. In the Cardiovascular Health Study, participants who expended the highest quartile of energy had a lower risk of all-cause dementia and AD compared with participants who expended the lowest quartile of energy.²⁴

Mental and social activity. Epidemiologic studies have shown associations between higher educational achievement and other socioeconomic factors and reduced AD risk. Advanced education is believed to represent a cognitive reserve that delays presentation of AD’s effects on memory and cognitive function, rather than providing a protective effect against accumulation of AD pathology. Higher-educated individuals appear to experience a somewhat more rapid rate of cognitive decline when AD does become apparent, perhaps because they have accumulated a greater degree of AD pathology at that point compared with less-educated persons.

Among 117 persons with dementia in the Bronx Aging Study, each additional year of formal education delayed the time of accelerated decline by 0.21 years. After accelerated decline began, each year of additional formal education was associated with a slightly faster rate of memory decline.²⁵

The longitudinal, population-based Kungsholmen Project in Stockholm, Sweden, found an association between daily mentally stimulating activities and decreased risk of all-cause dementia.²⁶ Similarly, higher levels of leisure activity were linked to reduced risk of all-cause dementia in a longitudinal study of 1,772 persons age ≥65 living in Manhattan, NY.²⁷ In a randomized, single-controlled study of the long-term effects of cognitive training, elderly individuals from 6 U.S. cities showed sustained improvement in specific cognitive performance up to 5 years after training sessions began, including memory, reasoning, and speed of processing.²⁸

It seems reasonable to encourage older patients to maintain or increase physical, cognitive, and leisure activities as well as social interaction. These interventions can improve the quality of life and lower the risk of depression, which may be a response to cognitive decline or an independent risk factor for dementia (Box 3). The Table lists “brain exercises” you can suggest to patients to increase their mental and social activity.

Head trauma. The Multi-Institutional Research in Alzheimer’s Genetic Epidemiology (MIRAGE) project found an association between AD risk and a history of head trauma, especially in persons with APOE e4 alleles.²⁹ Conversely, the Rotterdam Study showed no change in dementia risk for persons with a history of head trauma.³⁰

Even in the absence of conclusive evidence supporting AD prevention, protecting the head by buckling seat belts while driving, wearing helmets when participating in sports, and “fall-proofing” the home is recommended.

Box 3

Table

Brain exercises to suggest to patients

Related resource

• For an extensive bibliography of literature on Alzheimer’s disease risk factors and prevention, see this article at CurrentPsychiatry.com.

Drug brand names

• Atorvastatin • Lipitor
• Celecoxib • Celebrex
• Donepezil • Aricept
• Medroxyprogesterone • Provera
• Pravastatin • Pravachol
• Rofecoxib • Vioxx
• Simvastatin • Zocor

Disclosures

Dr. Bassil reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Dr. Grossberg receives research/grant support from and is a consultant to Bristol-Myers Squibb, Forest Pharmaceuticals, Novartis, Pfizer Inc., and Wyeth Pharmaceuticals. He also receives research/grant support from Baxter.

Discuss this article

Pharmacologic treatments for Alzheimer’s disease (AD) may improve symptoms but have not been shown to prevent AD onset. Primary prevention therefore remains the goal. Although preventing AD by managing risk factors such as age or genetics is beyond our control (Box 1), we can do something about other factors.

This article summarizes the findings of many studies that address AD prevention and includes an online-only bibliography for readers seeking an in-depth review. The evidence does not support a firm recommendation for any specific form of primary prevention and has revealed hazards associated with estrogen therapy and nonsteroidal anti-inflammatory drugs (Box 2). Most important, it suggests that you could reduce your patients’ risk of developing AD by routinely supporting their mental, physical, and social health.

The potential benefits of modifying an individual’s AD risk factors likely will depend on his or her genetic makeup, environment, and lifestyle. Even so, counseling patients to exercise more and improve their diets—such as by eating more fish, fruits, and vegetables and less saturated fat—might help protect the brain. Your ongoing efforts to manage hypertension, hypercholesterolemia, and diabetes also may reduce their AD risk.

Box 1

Box 2

Cardiovascular risk factors

The risk of developing AD or vascular dementia appears to be increased by conditions that damage the heart or blood vessels. Recent evidence suggests that successfully managing cardiovascular risk factors may decrease the likelihood of dementia in later life.

Hypertension is associated with a higher risk of AD and all-cause dementia. Curiously, some studies have shown that low blood pressure also increases dementia risk, suggesting a U-shaped relationship between blood pressure and cognitive decline. Systolic hypertension in midlife may be associated with dementia 20 years later.

One might assume that antihypertensive therapy would help prevent dementia, but the data are conflicting. The Systolic Hypertension in Europe (SYST-EUR) study¹ showed a 53% reduction in vascular dementia or mixed dementia among patients receiving antihypertensive medication and a 60% reduction in AD. Similarly, the PROGRESS² clinical trial of prevention of recurrent stroke by antihypertensive treatment reported a 34% reduction in a composite measure of cognitive impairment and dementia. On the other hand, cognitive function neither improved nor worsened in the Hypertension in the Very Elderly Trial (HYVET-COG),³ whether patients received blood pressure treatment or placebo.

Hyperlipidemia. Lipid metabolism likely is an important pathway in amyloid beta-protein deposition, tau phosphorylation, and disruption of synaptic plasticity and neurodegenerative endpoints. Cognitive decline and incident dementia have been associated with higher dietary intake of saturated fats, partially hydrogenated unsaturated fatty acids (trans fats), and cholesterol. Not all studies have found this association, however. This could be because serum cholesterol levels may decrease in early dementia, limiting the ability to detect an effect of hypercholesterolemia on dementia risk when measurements are made later in life.

Using statins (3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors) to treat hypercholesterolemia has been hypothesized to impede large vessel atherosclerosis and its consequences and to trigger metabolic effects in the brain related to AD pathogenesis. Mechanisms by which statins might help prevent dementia include:

• a direct association between amyloid processing and cholesterol in the brain
• an indirect effect by decreasing the risk of stroke, as even small cerebral infarcts worsen AD severity.

Nonrandomized epidemiologic studies such as the Cardiovascular Health Study⁴ and MRC/BHF Heart Protection Study⁵ suggested that statin treatment might reduce the incidence of dementia, the degree of age-related cognitive decline, and AD’s neuropathologic burden. Large, randomized, controlled trials have not supported these observations, however. Statins failed to reduce the incidence of dementia in:

• the Heart Protection Study, testing simvastatin for 5 years in 20,536 subjects age 40 to 80⁵
• the 3-year Preventive Study of Pravastatin in the Elderly at Risk (PROSPER) of 5,800 subjects.⁶

Similarly, patients receiving adjunctive atorvastatin or placebo showed no significant differences in cognition assessments after 72 weeks in the Lipitor’s Effect in Alzheimer’s Dementia (LEADe) study. This trial enrolled 640 subjects age 50 to 90 with mild-to-moderate dementia who were treated with donepezil.⁷ A recent Cochrane review concluded that high serum cholesterol may contribute to the development of AD and vascular dementia, but lowering cholesterol levels with statins does not prevent these problems.⁸

Diabetes mellitus. Diabetes and cognitive decline are closely associated. Diabetes is associated with a 50% to 100% increase in risk of AD and dementia overall and a 100% to 150% increased risk of vascular dementia. The mechanism by which diabetes increases dementia risk is uncertain but does not appear to be mediated entirely through vascular disease. High and low insulin levels may increase the risk of dementia, independent of diabetes and blood glucose. Increased peripheral insulin levels are associated with reduced brain atrophy and cognitive impairment in patients with early AD, suggesting a role for insulin signaling in AD pathophysiology. A possible relationship between insulin and beta amyloid metabolism is being studied.

Elevated postprandial plasma glucose has been associated with accelerated declines in cognitive performance.⁹ An inverse correlation has been noted between some cognitive measures and hemoglobin A1C levels.¹⁰ It is not clear that treating diabetes reduces the risk of dementia. In addition, in the prospective, population-based Rotterdam study, elderly patients with type 2 diabetes treated with insulin had the highest incidence of dementia.¹¹

Tobacco smoke directly affects neuronal function, integrity, and survival. Chronic smoking has been linked to decreased global cerebral blood flow, accelerated cerebral atrophy, and ventricular enlargement.

Some studies suggest an increased risk of dementia in middle-aged and elderly smokers, possibly through a cerebrovascular mechanism such as stroke. Other studies found no association between smoking and dementia risk, and 1 suggested that nicotine may protect against AD by reducing senile plaque formation. Any protective effect of smoking would be offset by increased risks of lung cancer, chronic obstructive pulmonary disease, and vascular dementia.

The apolipoprotein E epsilon 4 (APOE e4) gene may explain, at least in part, the conflicting results of these studies. In 2 population-based cohorts,^12,13 smoking was associated with memory decline in patients without, but not with, the APOE e4 genotype.

Dietary factors

Antioxidants. The brains of patients with AD contain elevated levels of endogenous antioxidants. In vitro studies show exogenous antioxidants can reduce the toxicity of beta-amyloid in brain tissue of persons with AD. These findings have led to interest in assessing the role of dietary antioxidants such as vitamins E and C for AD prevention.

High-dose alpha-tocopherol (vitamin E, 2,000 IU/d) may slow disease progression in patients with AD, but this association is not consistently found. Furthermore, a meta-analysis of 19 randomized controlled trials (RCTs) totaling >135,000 patients found an association between vitamin E doses >400 IU/d and increased all-cause mortality.¹⁴ High-dose vitamin E supplementation for primary or secondary prevention of AD may be dangerous and is not recommended.

The lack of consistent efficacy data for vitamin C in preventing or treating AD may discourage its routine use for this purpose.¹⁵

Homocysteine is a risk factor for stroke and heart disease. It also could play a role in vascular dementia through its association with large- and small-vessel disease.

Low folate and hyperhomocysteinemia have been associated with dementia or cognitive impairment, although a cause-effect relationship is not clear. In non-demented elderly populations, plasma homocysteine is inversely associated with poor performance in tests of global cognitive function, particularly in measures of psychomotor speed.

In a recent double-blind RCT, folic acid supplementation for 3 years significantly improved domains of cognitive function that tend to decline with age, especially information processing and sensorimotor speed.¹⁶ No other good evidence, however, has shown that homocysteine-lowering therapy using folic acid or other vitamin B supplements improves cognitive function or prevents cognitive decline.

Fish and omega-3 fatty acids. High total fat, saturated fat, and total cholesterol intake increases the risk for incident dementia. In epidemiologic studies, low omega-3 fatty acid serum levels have been linked to increased dementia risk.

Fish consumption may be beneficial in reducing the risk of dementia or cognitive decline. A prospective study of 815 elderly persons found 60% less risk of developing AD in those who ate ≥1 fish meal per week, compared with those who rarely or never ate fish.¹⁷ In the Framingham study, individuals who at baseline were in the top quartile of docosahexaenoic acid consumption had lower dementia rates over 9 years of follow-up.¹⁸ Results from cross-sectional and longitudinal studies have been inconsistent; some have shown that high intake of n-3 polyunsaturated fatty acids is associated with less cognitive decline,¹⁹ whereas others have not.²⁰

Although we cannot offer unequivocal advice regarding seafood or omega-3 fatty acid intake for primary prevention of dementia without evidence from RCTs, these uncontrolled studies show promise.

Mediterranean diet (MeDi) components include abundant fruits and vegetables, fish or shellfish at least twice weekly, very limited red meat, olive oil or canola oil instead of butter or margarine, tree nuts such as walnuts or pecans, red wine in moderation, and using herbs and spices instead of salt to season food. High adherence to the MeDi has been associated with a significantly lower risk for incident AD. The MeDi may affect the risk of developing AD²¹ as well as subsequent disease course, with a possible dose-response relationship in lower mortality.²²

Eating fruits and vegetables has been associated with improved cognitive performance²² and decreased incident dementia in elderly subjects.¹⁸

Alcohol. A U-shaped relationship exists between alcohol consumption and dementia risk. High alcohol intake is associated with clinical problem drinking and alcoholism and can lead to cognitive decline. Conversely, moderate wine consumption (250 to 500 mL/d) may be protective—compared with more or less than this amount—and is associated with approximately 50% less risk of dementia.

Alcohol use may increase the risk of dementia in persons carrying the APOE e4 allele, according to the population-based Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study from Sweden.²³ After an average 21 years of follow-up of 1,449 individuals, researchers found that environmental factors—such as physical inactivity, dietary fat intake, alcohol consumption, and smoking at midlife—were associated with an increased risk of dementia at age 65 to 79 in APOE e4 carriers compared with noncarriers. The study also found that physical inactivity, dietary fat intake, and smoking at midlife increase AD risk, especially among APOE e4 carriers.

In the absence of evidence from RCTs, we cannot recommend alcohol to reduce the risk of AD.

Lifestyle and activity

Three components of lifestyle—social, mental, and physical activity—are inversely associated with the risk for dementia, AD, and cognitive impairment.

Physical exercise has been thought to enhance brain neurotrophic factor and modify apoptosis. Exercise can deter stroke and microvascular disease and improve regional cerebral blood flow. In the Cardiovascular Health Study, participants who expended the highest quartile of energy had a lower risk of all-cause dementia and AD compared with participants who expended the lowest quartile of energy.²⁴

Mental and social activity. Epidemiologic studies have shown associations between higher educational achievement and other socioeconomic factors and reduced AD risk. Advanced education is believed to represent a cognitive reserve that delays presentation of AD’s effects on memory and cognitive function, rather than providing a protective effect against accumulation of AD pathology. Higher-educated individuals appear to experience a somewhat more rapid rate of cognitive decline when AD does become apparent, perhaps because they have accumulated a greater degree of AD pathology at that point compared with less-educated persons.

Among 117 persons with dementia in the Bronx Aging Study, each additional year of formal education delayed the time of accelerated decline by 0.21 years. After accelerated decline began, each year of additional formal education was associated with a slightly faster rate of memory decline.²⁵

The longitudinal, population-based Kungsholmen Project in Stockholm, Sweden, found an association between daily mentally stimulating activities and decreased risk of all-cause dementia.²⁶ Similarly, higher levels of leisure activity were linked to reduced risk of all-cause dementia in a longitudinal study of 1,772 persons age ≥65 living in Manhattan, NY.²⁷ In a randomized, single-controlled study of the long-term effects of cognitive training, elderly individuals from 6 U.S. cities showed sustained improvement in specific cognitive performance up to 5 years after training sessions began, including memory, reasoning, and speed of processing.²⁸

It seems reasonable to encourage older patients to maintain or increase physical, cognitive, and leisure activities as well as social interaction. These interventions can improve the quality of life and lower the risk of depression, which may be a response to cognitive decline or an independent risk factor for dementia (Box 3). The Table lists “brain exercises” you can suggest to patients to increase their mental and social activity.

Head trauma. The Multi-Institutional Research in Alzheimer’s Genetic Epidemiology (MIRAGE) project found an association between AD risk and a history of head trauma, especially in persons with APOE e4 alleles.²⁹ Conversely, the Rotterdam Study showed no change in dementia risk for persons with a history of head trauma.³⁰

Even in the absence of conclusive evidence supporting AD prevention, protecting the head by buckling seat belts while driving, wearing helmets when participating in sports, and “fall-proofing” the home is recommended.

Box 3

Table

Brain exercises to suggest to patients

Related resource

• For an extensive bibliography of literature on Alzheimer’s disease risk factors and prevention, see this article at CurrentPsychiatry.com.

Drug brand names

• Atorvastatin • Lipitor
• Celecoxib • Celebrex
• Donepezil • Aricept
• Medroxyprogesterone • Provera
• Pravastatin • Pravachol
• Rofecoxib • Vioxx
• Simvastatin • Zocor

Disclosures

Dr. Bassil reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Dr. Grossberg receives research/grant support from and is a consultant to Bristol-Myers Squibb, Forest Pharmaceuticals, Novartis, Pfizer Inc., and Wyeth Pharmaceuticals. He also receives research/grant support from Baxter.