Foods commonly consumed as

part of a Mediterranean diet

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Foods commonly consumed as

part of a Mediterranean diet

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Foods commonly consumed as

part of a Mediterranean diet

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Saline solution

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

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

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

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

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

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

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

Saline solution

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

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

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

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

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

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

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

Saline solution

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

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

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

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

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

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

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

Thrombus

Credit: Andre E.X. Brown

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Thrombus

Credit: Andre E.X. Brown

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Thrombus

Credit: Andre E.X. Brown

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

VASCULAR DEMENTIA

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

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

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

Sudden onset and stepwise decline

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

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

Deficits depend on vascular areas affected

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

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

Focal neurologic deficits may be found on clinical examination.

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

Treat symptoms and manage risk factors

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

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

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

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

DEMENTIA WITH LEWY BODIES

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

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

Visual hallucinations are typical

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

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

Parkinsonism develops with or after dementia with Lewy bodies

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

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

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

Cognitive deficits fluctuate

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

Specialized imaging provides clues

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

Alzheimer medications may help in dementia with Lewy bodies

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

Treating hallucinations of dementia with Lewy bodies

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

PROGRESSIVE SUPRANUCLEAR PALSY

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

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

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

Gait and balance problems predominate early in progressive supranuclear palsy

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

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

Apathy and extreme mood swings

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

Vertical gaze palsy

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

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

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

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

MRI shows ‘hummingbird sign’

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

Levodopa ineffective for supranuclear palsy

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

CORTICOBASAL DEGENERATION

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

Asymmetric movement disorder with cognitive dysfunction

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

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

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

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

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

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

Asymmetric cortical atrophy

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

Levodopa ineffective in corticobasal degeneration

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

MULTIPLE SYSTEM ATROPHY

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

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

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

A neurologic examination provides clues

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

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

Pyramidal features include extensor plantar responses and hyperreflexia.

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

Electromyography may demonstrate decreased anal sphincter tone.

MRI shows atrophy of putamen and pons

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

Multiple system atrophy typically responds poorly to levodopa

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

PARKINSON DISEASE DEMENTIA

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

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

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

MRI shows characteristic brain atrophy in Parkinson disease dementia

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

Rivastigmine effective for dementia

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

FRONTOTEMPORAL DEMENTIA

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

Gradual onset of uncharacteristic behaviors

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

Language sometimes affected in frontotemporal dementia

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

MRI shows frontotemporal lobes affected

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

Treat symptoms

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

PRIMARY PROGRESSIVE APHASIA

Language impairment predominates

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

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

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

Imaging shows focal degeneration in the left hemisphere

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

Other communication methods may help

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

NORMAL-PRESSURE HYDROCEPHALUS

Classic triad: Gait, cognition, incontinence

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

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

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

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

Enlarged ventricles seen on imaging in normal-pressure hydrocephalus

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

Treat with cerebrospinal fluid drainage

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

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

RAPIDLY PROGRESSIVE DEMENTIAS

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

Creutzfeldt-Jakob disease

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

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

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

Autoimmune diseases

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

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

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

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

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

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

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

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

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

VASCULAR DEMENTIA

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

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

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

Sudden onset and stepwise decline

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

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

Deficits depend on vascular areas affected

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

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

Focal neurologic deficits may be found on clinical examination.

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

Treat symptoms and manage risk factors

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

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

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

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

DEMENTIA WITH LEWY BODIES

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

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

Visual hallucinations are typical

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

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

Parkinsonism develops with or after dementia with Lewy bodies

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

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

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

Cognitive deficits fluctuate

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

Specialized imaging provides clues

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

Alzheimer medications may help in dementia with Lewy bodies

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

Treating hallucinations of dementia with Lewy bodies

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

PROGRESSIVE SUPRANUCLEAR PALSY

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

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

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

Gait and balance problems predominate early in progressive supranuclear palsy

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

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

Apathy and extreme mood swings

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

Vertical gaze palsy

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

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

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

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

MRI shows ‘hummingbird sign’

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

Levodopa ineffective for supranuclear palsy

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

CORTICOBASAL DEGENERATION

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

Asymmetric movement disorder with cognitive dysfunction

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

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

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

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

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

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

Asymmetric cortical atrophy

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

Levodopa ineffective in corticobasal degeneration

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

MULTIPLE SYSTEM ATROPHY

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

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

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

A neurologic examination provides clues

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

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

Pyramidal features include extensor plantar responses and hyperreflexia.

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

Electromyography may demonstrate decreased anal sphincter tone.

MRI shows atrophy of putamen and pons

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

Multiple system atrophy typically responds poorly to levodopa

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

PARKINSON DISEASE DEMENTIA

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

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

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

MRI shows characteristic brain atrophy in Parkinson disease dementia

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

Rivastigmine effective for dementia

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

FRONTOTEMPORAL DEMENTIA

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

Gradual onset of uncharacteristic behaviors

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

Language sometimes affected in frontotemporal dementia

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

MRI shows frontotemporal lobes affected

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

Treat symptoms

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

PRIMARY PROGRESSIVE APHASIA

Language impairment predominates

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

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

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

Imaging shows focal degeneration in the left hemisphere

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

Other communication methods may help

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

NORMAL-PRESSURE HYDROCEPHALUS

Classic triad: Gait, cognition, incontinence

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

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

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

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

Enlarged ventricles seen on imaging in normal-pressure hydrocephalus

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

Treat with cerebrospinal fluid drainage

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

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

RAPIDLY PROGRESSIVE DEMENTIAS

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

Creutzfeldt-Jakob disease

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

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

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

Autoimmune diseases

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

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

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

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

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

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

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

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

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

VASCULAR DEMENTIA

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

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

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

Sudden onset and stepwise decline

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

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

Deficits depend on vascular areas affected

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

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

Focal neurologic deficits may be found on clinical examination.

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

Treat symptoms and manage risk factors

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

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

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

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

DEMENTIA WITH LEWY BODIES

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

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

Visual hallucinations are typical

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

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

Parkinsonism develops with or after dementia with Lewy bodies

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

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

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

Cognitive deficits fluctuate

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

Specialized imaging provides clues

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

Alzheimer medications may help in dementia with Lewy bodies

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

Treating hallucinations of dementia with Lewy bodies

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

PROGRESSIVE SUPRANUCLEAR PALSY

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

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

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

Gait and balance problems predominate early in progressive supranuclear palsy

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

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

Apathy and extreme mood swings

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

Vertical gaze palsy

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

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

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

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

MRI shows ‘hummingbird sign’

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

Levodopa ineffective for supranuclear palsy

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

CORTICOBASAL DEGENERATION

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

Asymmetric movement disorder with cognitive dysfunction

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

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

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

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

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

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

Asymmetric cortical atrophy

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

Levodopa ineffective in corticobasal degeneration

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

MULTIPLE SYSTEM ATROPHY

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

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

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

A neurologic examination provides clues

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

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

Pyramidal features include extensor plantar responses and hyperreflexia.

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

Electromyography may demonstrate decreased anal sphincter tone.

MRI shows atrophy of putamen and pons

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

Multiple system atrophy typically responds poorly to levodopa

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

PARKINSON DISEASE DEMENTIA

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

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

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

MRI shows characteristic brain atrophy in Parkinson disease dementia

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

Rivastigmine effective for dementia

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

FRONTOTEMPORAL DEMENTIA

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

Gradual onset of uncharacteristic behaviors

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

Language sometimes affected in frontotemporal dementia

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

MRI shows frontotemporal lobes affected

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

Treat symptoms

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

PRIMARY PROGRESSIVE APHASIA

Language impairment predominates

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

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

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

Imaging shows focal degeneration in the left hemisphere

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

Other communication methods may help

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

NORMAL-PRESSURE HYDROCEPHALUS

Classic triad: Gait, cognition, incontinence

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

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

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

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

Enlarged ventricles seen on imaging in normal-pressure hydrocephalus

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

Treat with cerebrospinal fluid drainage

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

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

RAPIDLY PROGRESSIVE DEMENTIAS

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

Creutzfeldt-Jakob disease

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

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

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

Autoimmune diseases

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

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

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

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

Most decisions for managing acute coronary syndromes can be based on ample data from large randomized trials with hard clinical end points, so there is little reason to provide care that is not evidence-based.

This article reviews some of the trials that provide guidance on diagnosing and managing acute coronary syndromes, including the timing of reperfusion and adjunctive therapies in different situations.

MOST ACUTE CORONARY SYNDROMES ARE NON-ST-ELEVATION CONDITIONS

Acute coronary syndromes range from unstable angina and non-ST-elevation myocardial infarction (NSTEMI) to ST-elevation MI (STEMI), reflecting a continuum of severity of coronary stenosis. The degree of coronary occlusion may ultimately determine whether a patient has unstable angina or MI with or without ST elevation.¹

The substrate for all of these is vulnerable plaque. Angiographic studies have indicated that in many cases medium-size plaques (30%–40% stenosis) are more likely to rupture than larger, more obstructive ones. Moderate plaques may be vulnerable because they are less mature, with a large lipid core and a thin cap prone to rupture or erode, exposing the thrombogenic subendothelial components.²

Because the vulnerability of a coronary plaque may not correlate with the severity of stenosis before the plaque ruptures, stress tests and symptoms may not predict the risk of MI. The key role of thrombosis in the pathogenesis also highlights the importance of antithrombotic therapy in the acute phases of acute coronary syndromes, which can significantly reduce mortality and morbidity rates.

Perhaps because of the widespread use of aspirin and statins, most patients who currently present with an acute coronary syndrome have either unstable angina or NSTEMI: of about 1.57 million hospital admissions in 2004 for acute coronary syndromes, for example, only 330,000 (21%) were for STEMI.³

DIAGNOSING ACUTE CORONARY SYNDROME

Symptoms may not be classic

The classic symptoms of acute coronary syndromes are intense, oppressive chest pressure radiating to the left arm, but nearly any discomfort “between the nose and navel” (eg, including the jaw, arm, and epigastric and abdominal areas) may be an acute coronary syndrome. Associated symptoms may include chest heaviness or burning, radiation to the jaw, neck, shoulder, back, or arms, and dyspnea.

Particularly in older, female, postoperative, or diabetic patients, the presentation may be atypical or “silent,” including nausea or vomiting; breathlessness; sweating; arrhythmias; or light-headedness. Especially in these groups, symptoms may be mild or subtle, and acute coronary syndrome may manifest only as “not feeling well.”

The differential diagnosis of acute coronary syndromes is broad. Most important to immediately consider are pulmonary embolism and aortic dissection, as they are life-threatening and are treated differently from acute coronary syndromes. Otherwise, it is best to err on the side of caution and treat for an acute coronary syndrome until it is proven otherwise.

Electrocardiography is critical

Electrocardiography (ECG) gives valuable information about the location, extent, and prognosis of infarction, and it is critically important for distinguishing STEMI from NSTEMI, with ST elevation classically diagnostic of complete coronary occlusion. Q waves can occur early and do not necessarily signify completed infarction, as traditionally thought. ST depression or T inversion indicates that total coronary occlusion is unlikely unless they are in a pattern of circumflex infarct associated with an enlarging R wave in lead V₁. An ST elevation in RV₄ indicates right ventricular infarction.

The appearance on ECG may evolve over time, so a patient with atypical symptoms and a nonspecific electrocardiogram should be observed for 24 hours or until more specific criteria develop.

Biomarkers in NSTEMI

In MI, cardiac troponin levels begin to rise about 3 hours after the onset of chest pain, and elevations can last for up to 14 days. Levels can also be mildly elevated chronically in patients with renal dysfunction, so positive biomarker tests in that population should be interpreted cautiously.

For STEMI, the opportunity to reperfuse is lost if one waits for cardiac biomarkers to become elevated. But for NSTEMI, they are highly sensitive and specific for identifying patients at high risk and determining who should be treated aggressively. Patients who are biomarker-negative have a better prognosis than patients with identical symptoms and electrocardiograms who are biomarker-positive.

MI is currently defined as a rise in any biomarker (usually troponin) above the 99th percentile for a reference population, with at least one of the following:

• Ischemic symptoms
• New ST/T changes or left bundle branch block
• Pathologic Q waves
• Loss of myocardium or abnormal wall motion seen by imaging
• Intracoronary thrombus.

REPERFUSION FOR ACUTE STEMI

Because acute coronary syndromes have a common pathophysiology, for the most part, lessons from clinical trials in one syndrome are relevant to the others. However, important differences exist regarding the need for immediate reperfusion in STEMI, since in most cases these patients have total rather than partial occlusion.

Fibrinolysis has limitations

The standard of management for STEMI is immediate reperfusion. The goal is to interrupt the wave front of myocardial necrosis, salvage threatened myocardium, and ultimately improve survival.

Five placebo-controlled trials showed a 30% reduction in the death rate in patients who received fibrinolytic therapy within 6 to 12 hours of presentation.⁴

Patients with ST elevation or with new bundle branch block benefit most from fibrinolytic therapy. Those with ST depression, T inversion, or nonspecific changes on ECG do not benefit; they probably do not have complete coronary occlusion, so the prothrombotic or platelet-activating effects of fibrinolytic therapy may make them worse.⁵ Further, fibrinolytic therapy poses the risk of intracranial hemorrhage, which, although rare (occurring in up to 1% of cases depending on the drug regimen), is a devastating complication.

In general, absolute contraindications to fibrinolysis include intracranial abnormalities, hemorrhage, and head trauma. An important relative contraindication is uncontrolled blood pressure (> 180/110 mm Hg at any point during hospitalization, including during the immediate presentation). Studies show that even if blood pressure can be controlled, the risk of intracranial hemorrhage is substantially higher, although the risk may not outweigh the benefit of reperfusion, particularly for large infarctions when percutaneous coronary intervention (PCI) is not available as an alternative to fibrinolysis.

Prompt PCI is preferable to fibrinolysis

If PCI is available on site, there is nearly no role for fibrinolytic therapy. PCI is better than fibrinolytic therapy in terms of the degree of reperfusion, reocclusion, MI recurrence, and mortality rate, and it poses little or no risk of intracranial hemorrhage.⁶

For either fibrinolytic therapy or percutaneous therapy, “time is muscle”: the longer the ischemic time, the higher the mortality rate (relative risk = 1.075 for every 30 minutes of delay, P = .041).⁷

At centers that do not have PCI on site, studies (mainly from Europe) have shown that it is better to transport the patient for PCI than to give immediate fibrinolytic therapy.^7,8 But because the centers studied tended to have short transport times (usually 40 minutes or less), it is uncertain whether the results are applicable throughout the United States.

The delay between symptom onset and presentation is also relevant. Reperfusion within the first 1 to 2 hours after the onset of symptoms provides the greatest degree of myocardial salvage and of reduction in the risk of death; the extent of benefit thereafter is substantially less. As a result, patients who present very early after symptom onset have the most to lose if their reperfusion is delayed by even a few more hours, whereas patients who have already experienced several hours of pain are affected less by additional delay.⁹ Thus, patients presenting within the “golden” 1 or 2 hours after symptoms begin should be considered for fibrinolytic therapy if transfer for PCI cannot be done expeditiously. It is important for hospitals without PCI available on site to have a system in place for rapid transport of patients when needed.

Guidelines advise that patients with STEMI should undergo PCI rather than receive fibrinolytic therapy as long as PCI is available within 90 minutes of first medical contact. Otherwise, fibrinolysis should be started within 30 minutes.¹⁰ For patients who present several hours after symptom onset, PCI may still be preferable even if the transport time is somewhat longer.

PCI after fibrinolytic therapy

In prior decades, PCI immediately after fibrinolytic therapy was associated with an increased risk of bleeding complications and reinfarction. That has changed with improvements in equipment and antithrombotic therapy.

Two large trials conclusively found that routinely transferring high-risk patients for PCI immediately after receiving fibrinolytic therapy (combined half-dose reteplase [Retavase] and abciximab [ReoPro]¹¹ or full-dose tenecteplase [TNKase]¹²) resulted in much lower rates of ischemic end points without an increase in bleeding complications compared with transferring patients only for rescue PCI after fibrinolytic therapy.

Routine transfer is now the standard of care for high-risk patients after fibrinolytic therapy and probably is best for all patients after an MI.

MANAGING NSTEMI AND UNSTABLE ANGINA

For patients with NSTEMI, immediate reperfusion is usually not required, although initial triage for “early invasive” vs “initial conservative” management must be done early in the hospital course. Randomized trials have evaluated these two approaches, with most studies in the contemporary era reporting improved outcomes with an early invasive approach.

The TACTICS trial,¹³ the most important of these, enrolled more than 2,200 patients with unstable angina or NSTEMI and randomized them to an early invasive strategy or a conservative strategy. Overall, results were better with the early invasive strategy.

The ICTUS trial.¹⁴ Although several studies showed that an early invasive approach was better, the most recent study using the most modern practices—the ICTUS trial—did not find that it reduced death rates. Most patients eventually underwent angiography and revascularization, but not early on. However, all studies showed that rates of recurrent unstable angina and hospitalization were reduced by an early invasive approach, so revascularization does have a role in stabilizing the patient. But in situations of aggressive medical management with antithrombotic and other therapies, an early conservative approach may be an appropriate alternative for many patients.¹⁵

The selection of an invasive vs a conservative approach should include a consideration of risk, which can be estimated using a number of criteria, including the Thrombolysis in Myocardial Infarction (TIMI) or the GRACE risk score. When risk was stratified using the TIMI risk score,¹⁶ in the TACTICS trial, the higher the risk score, the more likely patients were to benefit from early revascularization.

When an invasive approach is chosen, it does not appear necessary to take patients to catheterization immediately (within 2–24 hours) compared with later during the hospital course.

The TIMACS trial,¹⁷ with more than 3,000 patients, tested the benefits of very early vs later revascularization for patients with NSTEMI and unstable angina. Early intervention did not significantly improve outcomes for the primary composite end point of death, MI, and stroke in the overall population enrolled in the trial, but when the secondary end point of refractory ischemia was added in, early intervention was found to be beneficial overall. Moreover, when stratified by risk, high-risk patients significantly benefited from early intervention for the primary end point.

Guidelines for NSTEMI and unstable angina continue to prefer an early invasive strategy, particularly for high-risk patients, although a conservative strategy is considered acceptable if patients receive intensive evidence-based medical therapy and remain clinically stable.¹⁸

ANTITHROMBOTIC THERAPIES

Once a revascularization strategy has been chosen, adjunctive therapies should be considered. The most important are the antithrombotic therapies.

Many drugs target platelet activity. Most important are the thromboxane inhibitor aspirin, the adenosine diphosphate (ADP) receptor antagonists clopidogrel (Plavix), prasugrel (Effient), and ticagrelor (Brilinta), and the glycoprotein (GP) IIb/IIIa antagonists abciximab and eptifibatide (Integrilin). Others, such as thrombin receptor antagonists, are under investigation.¹⁹

Aspirin for secondary prevention

Evidence is unequivocal for the benefit of aspirin therapy in patients with established or suspected vascular disease.

The ISIS-2 trial²⁰ compared 35-day mortality rates in 16,000 patients with STEMI who were given aspirin, streptokinase, combined streptokinase and aspirin, or placebo. Mortality rates were reduced by aspirin compared with placebo by an extent similar to that achieved with streptokinase, with a further reduction when aspirin and streptokinase were given together.

Therefore, patients with STEMI should be given aspirin daily indefinitely unless they have true aspirin allergy. The dose is 165 to 325 mg initially and 75 to 162 mg daily thereafter.

For NSTEMI and even for secondary prevention in less-acute situations, a number of smaller trials also provide clear evidence of benefit from aspirin therapy.

The CURRENT-OASIS 7 trial²¹ showed that low maintenance dosages of aspirin (75–100 mg per day) resulted in the same incidence of ischemic end points (cardiovascular death, MI, or stroke) as higher dosages. Although rates of major bleeding events did not differ, a higher rate of gastrointestinal bleeding was evident at just 30 days in patients taking the higher doses. This large trial clearly established that there is no advantage to daily aspirin doses of more than 100 mg.

DUAL ANTIPLATELET THERAPY IS STANDARD

Standard practice now is to use aspirin plus another antiplatelet agent that acts by inhibiting either the ADP receptor (for which there is the most evidence) or the GP IIb/IIIa receptor (which is becoming less used). Dual therapy should begin early in patients with acute coronary syndrome.

Clopidogrel: Well studied with aspirin

The most commonly used ADP antagonist is clopidogrel, a thienopyridine. Much evidence exists for its benefit.

The CURE trial²² randomized more than 12,000 patients with NSTEMI or unstable angina to aspirin plus either clopidogrel or placebo. The incidence of the combined end point of MI, stroke, and cardiovascular death was 20% lower in the clopidogrel group than in the placebo group over 12 months of follow-up. The benefit of clopidogrel began to occur within the first 24 hours after randomization, with a 33% relative risk reduction in the combined end point of cardiovascular death, MI, stroke, and severe ischemia, demonstrating the importance of starting this agent early in the hospital course.

COMMIT²³ found a benefit in adding clopidogrel to aspirin in patients with acute STEMI. Although it was only a 30-day trial, significant risk reduction was found in the dual-therapy group for combined death, stroke, or reinfarction. The results of this brief trial were less definitive, but the pathophysiology was similar to non-ST-elevation acute coronary syndromes, so it is reasonable to extrapolate the long-term findings to this setting.

The CURRENT-OASIS 7 trial²¹ randomized more than 25,000 patients to either clopidogrel in a double dosage (600 mg load, 150 mg/day for 6 days, then 75 mg/day) or standard dosage (300 mg load, 75 mg/day thereafter). Although no overall benefit was found for the higher dosage, a subgroup of more than 17,000 patients who underwent PCI after randomization had a lower risk of developing stent thrombosis. On the other hand, higher doses of clopidogrel caused more major bleeding events.

Ticagrelor and prasugrel: New alternatives to clopidogrel

The principal limitation of clopidogrel is its metabolism. It is a prodrug, ie, it is not active as taken and must be converted to its active state by cytochrome P450 enzymes in the liver. Patients who bear certain polymorphisms in the genes for these enzymes or who are taking other medications that affect this enzymatic pathway may derive less platelet inhibition from the drug, leading to considerable patient-to-patient variability in the degree of antiplatelet effect.

Alternatives to clopidogrel have been developed that inhibit platelets more intensely, are activated more rapidly, and have less interpatient variability. Available now are ticagrelor and prasugrel.²⁴ Like clopidogrel, prasugrel is absorbed as an inactive prodrug, but it is efficiently metabolized by esterases to an active form, and then by a simpler step within the liver to its fully active metabolite.²⁵ Ticagrelor is active as absorbed.²⁶

Pharmacodynamically, the two drugs perform almost identically and much faster than clopidogrel, with equilibrium platelet inhibition reached in less than 1 hour. The degree of platelet inhibition is also more—sometimes twice as much—with the new drugs compared with clopidogrel, and the effect is much more consistent between patients.

Both clopidogrel and prasugrel permanently inhibit the platelet ADP receptor, and 3 to 7 days are therefore required for their antiplatelet effects to completely wear off. In contrast, ticagrelor is a reversible inhibitor and its effects wear off more rapidly. Despite achieving a much higher level of platelet inhibition than clopidogrel, ticagrelor’s activity falls below that of clopidogrel’s by 48 hours of discontinuing the drugs.

The TRITON-TIMI 38 trial²⁷ enrolled more than 13,000 patients with acute coronary syndromes, randomized to receive, either prasugrel or clopidogrel, in addition to aspirin. The patients were all undergoing PCI, so the findings do not apply to patients treated medically with an early conservative approach. The study drug was given only after the decision was made to perform PCI in patients with non-ST-elevation acute coronary syndrome (but given immediately for patients with STEMI, because nearly all those patients undergo PCI).

Prasugrel was clearly beneficial, with a significant 20% lower rate of the combined end point of cardiovascular death, MI, and stroke at 15 months. However, bleeding risk was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% confidence interval 1.02–1.68, P = .03). Looking at individual end points, the advantages of prasugrel were primarily in reducing rates of stent thrombosis and nonfatal MI. Death rates with the two drugs were equivalent, possibly because of the higher risk of bleeding with prasugrel. Bleeding in the prasugrel group was particularly increased in patients who underwent bypass surgery; more patients also needed transfusion.

Subgroup analysis showed that patients with a history of stroke or transient ischemic attack had higher rates of ischemic and bleeding events with prasugrel than with clopidogrel, leading to these being labeled as absolute contraindications to prasugrel. Patients over age 75 or who weighed less than 60 kg experienced excess bleeding risk that closely matched the reduction in ischemic event rates and thus did not have a net benefit with prasugrel.

Trial of ticagrelor vs clopidogrel

The PLATO trial²⁸ included 18,000 patients, of whom 65% underwent revascularization and 35% were treated medically. The drug—clopidogrel or ticagrelor—was given in addition to aspirin at randomization (within 24 hours of symptom onset); this more closely follows clinical practice, in which dual antiplatelet therapy is started as soon as possible. This difference makes the PLATO study more relevant to practice for patients with non-ST-elevation acute coronary syndrome. Also, because they gave the drugs to all patients regardless of whether they were to undergo PCI, this study likely had a higher-risk population, which may be refected in the higher mortality rate at 30 days (5.9% in the clopidogrel group in the PLATO study vs 3.2% in the clopidogrel group in the TRITON study).

Another important difference between the trials testing prasugrel and ticagrelor is that patients who had already received a thienopyridine were excluded from the prasugrel trial but not from the ticagrelor trial. Nearly half the patients in the ticagrelor group were already taking clopidogrel. The clinical implication is that for patients who arrive from another facility and already have been given clopidogrel, it is safe to give ticagrelor. There is limited information about whether that is also true for prasugrel, although there is no known reason why the safety of adding prasugrel to clopidogrel should be different from that of ticagrelor.

The rate of ischemic events was 20% lower in the ticagrelor group than in the clopidogrel group, importantly including reductions in the incidence of death, MI, and stent thrombosis. There was no increase with ticagrelor compared with clopidogrel in bleeding associated with coronary artery bypass graft surgery, likely because of the more rapid washout of the ticagrelor effect, or in the need for blood transfusions. However, the rate of bleeding unrelated to coronary artery bypass was about 20% higher with ticagrelor.

In summary, more intense platelet inhibition reduces the risk of ischemic events, but, particularly for the irreversible inhibitor prasugrel, at the cost of a higher risk of bleeding. In general, the net benefit of these agents in preventing the irreversible complications of MI and (in the case of ticagrelor) death favor the use of the more intense ADP inhibitors in appropriate patients. Ticagrelor is indicated in patients with acute coronary syndromes undergoing invasive or conservative management; prasugrel is indicated in patients undergoing PCI, but contraindicated in patients with a previous stroke or transient ischemic event. Neither drug is indicated in patients undergoing elective PCI outside the setting of acute coronary syndromes, although these agents may be appropriate in patients with intolerance or allergy to clopidogrel.

Glycoprotein IIb/IIIa antagonists for select cases only

GP IIb/IIIa antagonists such as abciximab were previously used more commonly than they are today. Now, with routine pretreatment using thienopyridines, their role in acute coronary syndromes is less clear. They still play a role when routine dual antiplatelet therapy is not used, when prasugrel or ticagrelor is not used, and when heparin rather than an alternative antithrombin agent is used.

A meta-analysis²⁹ of 3,755 patients showed a clear reduction in ischemic complications with abciximab as an adjunct to primary PCI for STEMI in patients treated with heparin.

Kastrati et al³⁰ found that patients with non-ST-elevation acute coronary syndromes benefited from abciximab at the time of PCI with heparin, even though they had been routinely pretreated with clopidogrel. However, benefits were seen only in high-risk patients who had presented with elevated troponins.

On the other hand, the role of GP IIb/IIIa blockade for “upstream” medical management in patients with acute coronary syndromes has been eroded by several studies.

The ACUITY trial³¹ randomized more than 9,000 patients to receive either routine treatment with a GP IIb/IIIa inhibitor before angiography or deferred selective use in the catheterization laboratory only for patients undergoing PCI. No significant differences were found in rates of MI and death.

The Early ACS trial³² compared early routine eptifibatide vs delayed, provisional eptifibatide in 9,492 patients with acute coronary syndromes without ST elevation and who were assigned to an invasive strategy. The early-eptifibatide group received two boluses and an infusion of eptifibatide before angiography; the others received a placebo infusion, with provisional eptifibatide after angiography if the patient underwent PCI and was deemed at high risk. No significant difference in rates of death or MI were noted, and the early-eptifibatide group had significantly higher rates of bleeding and need for transfusion.

The FINESSE trial³³ also discredited “facilitating” PCI by giving GP IIb/IIIa antagonists in patients with STEMI before arrival in the catheterization laboratory, with no benefit to giving abciximab ahead of time vs in the catheterization laboratory, and with an increased risk of bleeding complications.

These studies have helped narrow the use of GP IIb/IIIa inhibitors to the catheterization laboratory in conjunction with heparin anticoagulation (as compared with bivalirudin [Angiomax]; see below) and only in select or high-risk cases. These drugs are indicated in the medical phase of management only if patients cannot be stabilized by aspirin or ADP inhibition.

NEWER ANTITHROMBOTICS: ADVANTAGES UNCLEAR

The complex coagulation cascade has a number of components, but only a few are targeted by drugs that are approved and recommended: fondaparinux (Arixtra) and oral factor Xa inhibitors affect the prothrombinase complex (including factor X); bivalirudin and oral factor IIa inhibitors affect thrombin; and heparin and the low-molecular-weight heparins inhibit both targets.

The SYNERGY trial³⁴ randomized nearly 10,000 patients with non-ST-elevation acute coronary syndromes at high risk for ischemic cardiac complications managed with an invasive approach to either the low-molecular-weight heparin enoxaparin (Lovenox) or intravenous unfractionated heparin immediately after enrollment. Most patients underwent catheterization and revascularization. No clinical advantage was found for enoxaparin, and bleeding complications were increased.

The EXTRACT-TIMI 25 trial³⁵ randomized more than 20,000 patients with STEMI who were about to undergo fibrinolysis to receive either enoxaparin throughout hospitalization (average of 8 days) or unfractionated heparin for at least 48 hours. The enoxaparin group had a lower rate of recurrent MI, but it was unclear if the difference was in part attributable to the longer therapy time. The enoxaparin group also had more bleeding.

Fondaparinux

The OASIS-5 trial^36,37 compared enoxaparin and fondaparinux, an exclusive factor Xa inhibitor, in more than 20,000 patients with unstable angina or NSTEMI. Fondaparinux was associated with a lower risk of death and reinfarction as well as fewer bleeding events. However, the benefits were almost exclusively in patients treated medically. In those undergoing PCI within the first 8 days, no benefit was found, although there was still a significant reduction in major bleeding events. Catheter thrombosis was also increased in patients taking fondaparinux, but only in those who did not receive adequate unfractionated heparin treatment before PCI.

Bivalirudin superior at time of catheterization

The most significant advance in antithrombotic therapy for patients with acute coronary syndromes is bivalirudin. This drug has a clear role only in the catheterization laboratory, where patients can be switched to it from heparin, low-molecular-weight heparin, or fondaparinux.

Three trials^38–40 evaluated the drug in a total of more than 20,000 patients receiving invasive management of coronary artery disease undergoing PCI for elective indications, NSTEMI, or STEMI.

Results were remarkably similar across the three trials. Patients who were treated with bivalirudin alone had the same rate of ischemic end points at 30 days as those receiving heparin plus a GP IIb/IIIa inhibitor, but bivalirudin was associated with a consistent and significant 40% to 50% lower bleeding risk. For the highest-risk patients, those with STEMI, the bivalirudin group also had a significantly lower risk of death at 1 year.⁴¹

OTHER DRUGS: EARLY TREATMENT NO LONGER ROUTINE

Most data for the use of therapies aside from antithrombotics are from studies of patients with STEMI, but findings can logically be extrapolated to those with non-ST-elevation acute coronary syndromes.

Beta-blockers: Cardiogenic shock a risk

For beta-blockers, many historical trials were done in stable coronary disease, but there are no large trials in the setting of NSTEMI or unstable angina, and only recently have there been large trials for STEMI. Before the availability of recent evidence, standard practice was to treat STEMI routinely with intravenous metoprolol (Lopressor) and then oral metoprolol.

When large studies were finally conducted, the results were sobering.

COMMIT.⁴² Nearly 46,000 patients with suspected acute MI were randomized to receive either metoprolol (up to 15 mg intravenously, then 200 mg by mouth daily until discharge or for up to 4 weeks in the hospital) or placebo. Surprisingly, although rates of reinfarction and ventricular fibrillation were lower with metoprolol, a higher risk of cardiogenic shock with early beta-blockade offset these benefits and the net mortality rate was not reduced. This study led to a reduction in the early use of beta-blockers in patients with STEMI.

The standard of care has now shifted from beta-blockers in everyone as early as possible after MI to being more cautious in patients with contraindications, including signs of heart failure or a low-output state, or even in those of advanced age or with borderline low blood pressure or a high heart rate. Patients who present late and therefore may have a larger infarct are also at higher risk.

Although the goal should be to ultimately discharge patients on beta-blocker therapy after an MI, there should be no rush to start one early.

Carvedilol now preferred after STEMI

The CAPRICORN trial⁴³ randomized nearly 2,000 patients following MI with left ventricular dysfunction (an ejection fraction of 40% or below) to either placebo or the beta-blocker carvedilol (Coreg). Patients taking the drug had a clear reduction in rates of death and reinfarction, leading to this drug becoming the beta-blocker of choice in patients with ventricular dysfunction after STEMI.

Angiotensin-converting enzyme inhibitors: Early risk of cardiogenic shock

The use of angiotensin-converting enzyme (ACE) inhibitors after MI is also supported by several studies.⁴⁴ Two very large studies, one of nearly 60,000 patients and one of nearly 20,000, showed a clear reduction in the mortality rate in those who received an ACE inhibitor. Most of the benefit was in patients with an ejection fraction of less than 40%. On the basis of these trials, ACE inhibitors are indicated for all patients for the first 30 days after MI and then indefinitely for those with left ventricular dysfunction. However, the trial in which an ACE inhibitor was given intravenously early on had to be stopped prematurely because of worse outcomes owing to cardiogenic shock.

These studies highlight again that for patients who are unstable in the first few days of an acute coronary syndrome, it is best to wait until their condition stabilizes and to start these therapies before hospital discharge.

Intensive statin therapy

In the last 20 years, unequivocal evidence has emerged to support the beneficial role of statins for secondary prevention in patients with established coronary artery disease. More-recent trials have also shown that intensive statin therapy (a high dose of a potent statin) improves outcomes better than lower doses.

The PROVE-IT TIMI 22 trial⁴⁵ randomized patients after an acute coronary syndrome to receive either standard therapy (pravastatin [Pravachol] 40 mg) or intensive therapy (atorvastatin [Lipitor] 80 mg). The intensive-therapy group had a significantly lower rate of major cardiovascular events, and the difference persisted and grew over 30 months of follow-up.

A number of studies confirmed this and broadened the patient population to those with unstable or stable coronary disease. Regardless of the risk profile, the effects were consistent and showed that high-dose statins were better in preventing coronary death and MI.⁴⁶

Guidelines are evolving toward recommendation of highest doses of statins independently of the target level of low-density lipoprotein cholesterol.