The Journal of Family Practice

Alzheimer’s disease (AD), the most common form of dementia, affects more than 5 million Americans.¹ Estimates suggest that by 2050, the prevalence could triple, reaching 13 to 16 million.¹ To effectively care for patients with AD and their families, family physicians need to be familiar with the latest evidence on all facets of care, from initial detection to patient management and end-of-life care.

This evidence-based review will help you toward that end by answering common questions regarding Alzheimer’s care, including whether routine screening is advisable, what tests should be ordered, which interventions (including nonpharmacologic options) are worth considering, and how best to counsel patients and families about end-of-life care.

Routine screening? Still subject to debate

In considering routine dementia screening in primary care, the key question is whether screening improves outcomes. Advocates note that individuals with dementia may appear unimpaired during office visits and may not report symptoms due to lack of insight; they point out, too, that waiting for an event that makes cognitive impairment obvious, such as a driving mishap, is risky.² Those who advocate routine screening also note that only about half of those who have dementia are ever diagnosed.³

Others, including the US Preventive Services Task Force (USPSTF), disagree. In its 2014 evidence review, the USPSTF indicated that there is “insufficient evidence to assess the balance of benefits and harms of screening for cognitive impairment in older adults.”⁴

Mixed messages

The dearth of evidence is also reflected in the conflicting recommendations of the Affordable Care Act (ACA) and the Centers for Medicare and Medicaid Services (CMS). The ACA requires physicians to assess the cognitive function of Medicare patients during their annual wellness visits. CMS, however, instructs providers to screen for dementia only if observation or concerns raised by the patient or family suggest the possibility of impairment, and does not recommend any particular test.⁵

Cost-effectiveness analyses raise questions about the value of routine screening, as well. Evidence suggests that if a primary care physician screens 300 older patients, 39 will have a positive screen. But only about half of those 39 will agree to a diagnostic evaluation, and no more than 9 will ultimately be diagnosed with dementia. The estimated cost of identifying 9 cases is nearly $40,000—all in the absence of a treatment to cure or stop the progression of the disorder.⁶

The bottom line: Evidence does not support routine dementia screening of older adults. When cognitive impairment is suspected, however, physicians should conduct a diagnostic evaluation—and consider educating patients and families about the Alzheimer’s Association (AA)’s 10 warning signs of AD.⁷ (See “Is it Alzheimer’s? 10 warning signs”⁷ below.) A longer version, available at http://www.alz.org/national/documents/checklist_10signs.pdf, outlines the cognitive changes that are characteristic of healthy aging and compares them to changes suggestive of early dementia.⁷

How to proceed when you suspect AD

Step 1: Screening instrument. The first step in the diagnostic evaluation of a patient with suspected AD is to determine if, in fact, cognitive impairment is present. This can be done by screening with in-office screening instruments, such as the Mini-Cog (available at alz.org/documents_custom/minicog.pdf) or Mini-Mental State Examination (MMSE; health.gov.bc.ca/pharmacare/adti/clinician/pdf/ADTI%20SMMSE-GDS%20Reference%20Card.pdf), among others.⁸

Step 2: Clinical evaluation. If observation and test results suggest cognitive impairment, the next step is to determine whether clinical findings are consistent with the diagnostic criteria for AD (TABLE 1)⁹ developed by workgroups from the National Institute on Aging (NIA)/AA in 2011. A work-up is necessary to identify conditions that can mimic dementia (eg, depression) and behaviors that suggest another type of dementia, such as frontotemporal or Lewy body dementia.¹⁰ Lab testing should be included to rule out potentially reversible causes of cognitive dysfunction (eg, hypothyroidism, vitamin D deficiency).

Step 3: Neuropsychological evaluation. The NIA/AA recommends neuropsychological testing when the brief cognitive tests, history, and clinical work-up are not sufficient for a definitive diagnosis of dementia.⁹When brief cognitive tests, history, and clinical work-up are inconclusive, refer patients for neuropsychological testing.This generally involves a referral to a neuropsychologist, who conducts a battery of standardized tests to evaluate attention, memory, language, visual-spatial abilities, and executive functions, among others. Neuropsychological testing can confirm the presence of cognitive impairment and aid in the differential diagnosis by comparing the patient’s performance in these domains with characteristic features of different dementia syndromes.

Step 4: Brain imaging with either computed tomography or magnetic resonance imaging can be included in the work-up for patients with suspected AD to rule out abnormalities—eg, metastatic cancer, hydrocephalus, or occult chronic subdural hematoma—that could be causing cognitive impairment.^9,10 Clinical features that generally warrant brain imaging include onset of cognitive impairment before age 60; unexplained focal neurologic signs or symptoms; abrupt onset or rapid decline; and/or predisposing conditions, such as cancer or anticoagulant treatment.¹⁰

The role of biomarkers and advanced brain imaging

Biomarkers that might provide confirmation of AD in patients who exhibit early symptoms of dementia have been studied extensively.¹¹ The NIA/AA identified 2 categories of AD biomarkers:

• tests for β-amyloid deposition in the brain, including spinal fluid assays for β-amyloid (Aβ₄₂) and positron emission tomography (PET) scans after intravenous injection of florbetapir or flutemetamol, which bind to amyloid in the brain; and
• tests for neuronal degeneration, which would include spinal fluid assays for tau protein and PET scans after injection of fluorodeoxyglucose (FDG), which shows decreased uptake in patients with AD.⁹

Research reveals the promise of these biomarkers as diagnostic tools, particularly in patients with an atypical presentation of dementia or mild cognitive impairment (MCI) that may be associated with early AD.¹² (More on MCI in a moment.) However, the NIA/AA concluded that additional research is needed to validate these tests for routine diagnostic purposes. Medicare covers PET scans with FDG only for the differential diagnosis of AD vs frontotemporal dementia.¹³

Mild cognitive impairment: How likely that it will progress?

Along with diagnostic criteria for AD, the NIA/AA developed criteria for a symptomatic predementia phase of AD—often referred to as MCI.¹⁴ According to the workgroup, MCI is diagnosed when:

Progression: Less likely than you might think

Patients with MCI are at risk for progression to overt dementia, with an overall annual conversion rate from MCI to dementia estimated at 10% to 15%.^15,16 This estimate must be interpreted with caution, however, because most studies were conducted prior to the 2011 guidelines, when different diagnostic criteria were used. Observers have noted, too, that the numbers largely reflect data collected in specialty clinics and that community-based studies reveal substantially lower conversion rates (3%-6% per year).¹⁶ In addition, evidence suggests that many patients with MCI demonstrate long-term stability or even reversal of deficits.¹⁷

While there is some consideration of the use of biomarkers and amyloid imaging tests to help determine which patients with MCI will progress to AD, practice guidelines do not currently recommend such testing and it is not covered by Medicare.

When evidence indicates an AD diagnosis

When faced with the need to communicate an AD diagnosis, follow the general recommendations for delivering any bad news or discouraging prognosis:

Prioritize and limit the information you provide, determining not only what the patient and family want to hear, but also how much they are able to comprehend.

Confirm that the patient and family understand the information you’ve provided.

Offer emotional support and recommend additional resources¹⁸ (TABLE 2).

Given the progressive cognitive decline that characterizes AD, it is important to address the primary caregiver’s understanding of, and ability to cope with, the disease. It is also important to explore beliefs and attitudes regarding AD. Keep in mind that different cultural groups tend to differ in their beliefs about the nature, cause, and appropriate management of AD, as well as the role of spirituality, help-seeking, and stigma.^19,20

When communicating an Alzheimer's disease diagnosis, prioritize information and offer emotional support. The progressive and ultimately fatal nature of AD also makes planning for the future a priority. Ideally, patients should be engaged in discussions regarding end-of-life care as early as possible, while they are still able to make informed decisions and express their preferences. Discussing end-of-life care can be overwhelming for newly diagnosed patients and their families, however, so it is important that you address issues—medical, financial, and legal planning, for example—that families should be considering.

TABLE 2

Drugs address cognitive and behavioral function

No current treatments
 can cure 
or significantly alter the progression of AD, but 2 classes of medications are used to improve cognitive function. No currently available treatments can cure or significantly alter the progression of AD, but 2 classes of medications are used in an attempt to improve cognitive function. One is cholinesterase inhibitors (ChEIs), which potentiate acetylcholine synaptic transmission. The other is N-methyl-D-aspartate (NMDA) glutamate receptor blockers. Other classes of drugs are sometimes used to treat behavioral symptoms of dementia, such as agitation, aggression, mood disorders, and psychosis (eg, delusions and hallucinations).

Cognitive function. Results from studies of pharmacologic management of MCI vary widely, but recent reviews have found no convincing evidence that either ChEIs or NMDA receptor blockers have an effect on progression from MCI to dementia.^21,22 Neither class is FDA-approved for treating MCI.

In patients with dementia, the effects of ChEIs and NMDA receptor blockers on cognition are statistically significant but modest, and often of questionable clinical relevance.²³ Nonetheless, among ChEIs, donepezil is approved by the US Food and Drug Administration (FDA) for mild, moderate, and severe dementia and galantamine and rivastigmine are approved for mild and moderate dementia. There is no evidence that any one ChEI is more effective than any other,²⁴ and the choice of drugs is often guided by cost, adverse effects, and health plan formularies. Memantine, the only FDA-approved NMDA receptor blocker, is approved for moderate to severe dementia and can be used alone or in combination with a ChEI.

In patients with dementia, the effects of ChEIs and NMDA receptor blockers on cognition are statistically significant but modest, and are often of questionable clinical relevance. If these drugs are used in an attempt to improve cognition in AD, guidelines recommend the following approach for initial therapy: Prescribe a ChEI for the mild stage, a ChEI plus memantine for the moderate stage, and memantine (with or without a ChEI) for the severe stage.²⁵ The recommendations also include monitoring every 6 months.

There is no consensus about when to discontinue medication. Various published recommendations call for continuing treatment until the patient has “lost all cognitive and functional abilities;”²² until the patient’s MMSE score falls below 10 and there is no indication that the drug is having a “worthwhile effect;”²¹ or until he or she has reached stage 7 on the Reisberg Functional Assessment Staging scale, indicating nonambulatory status with speech limited to one to 5 words a day.¹⁰

Behavioral function. A variety of drugs are used to treat behavioral symptoms in AD. While not FDA-approved for this use, the most widely prescribed agents are second-generation antipsychotics (aripiprazole, olanzapine, quetiapine, and risperidone). The main effect of these drugs is often nothing more than sedation, and one large multi­site clinical trial concluded that the adverse effects offset the benefits for patients with AD.²⁶ Indeed, the FDA has issued an advisory on the use of second-generation antipsychotics in AD patients, stating that they are associated with an increased risk of death.²⁷ The recently updated Beers Criteria strongly recommend avoiding these drugs for treating behavioral disturbances in AD unless nonpharmacologic options have failed and the patient is a threat to self or others.²⁸

The FDA has issued an advisory on the use of second-generation antipsychotics in Alzheimer’s patients, stating that they are associated with an increased risk of death. Because of the black-box warning that antipsychotics increase the risk of death, some physicians have advocated obtaining informed consent prior to prescribing such medications.²⁹ At the very least, when family or guardians are involved, a conversation about risks vs benefits should take place and be documented in the medical record.

Other drug classes are also sometimes used in an attempt to improve behavioral function, including anti-seizure medications (valproic acid, carbamazepine), antidepressants (trazodone and selective serotonin reuptake inhibitors), and anxiolytics (benzodiazepines and buspirone). Other than their sedating effects, there is no strong evidence that these drugs are effective for treating dementia-related behavioral disorders. If used, caution is required due to potential adverse effects.

Nonpharmacologic management is “promising”

A recent systematic review of nonpharmacologic interventions for MCI evaluated exercise, training in compensatory strategies, and engagement in cognitively stimulating activities and found “promising but inconclusive” results. The researchers found that studies show mostly positive effects on cognition but have significant methodologic limitations.³⁰ Importantly, there is no evidence of delayed or reduced conversion to dementia.

For patients who already have mild-to-moderate dementia, cognitive stimulation seems to help in the short term.³¹ There is also some evidence that exercise and occupational therapy may slow functional decline,³² but the effects are small to modest and their actual clinical significance (eg, the ability to delay institutionalization) is unclear. There is promising but preliminary evidence that cognitive rehabilitation (helping patients devise strategies to complete daily activities) may improve functioning in everyday life.³³

While behavioral symptoms are often due to the dementia itself, it is important to identify and treat medical and environmental causes that may be contributing, such as infection, pain, and loud or unsafe environments.Interventions such as massage therapy, aromatherapy, exercise, and music therapy may be effective in the short term for agitated behavior. As noted before, nonpharmacologic treatments are generally preferred for behavioral problems and should be considered prior to drug therapy. Approaches that identify and modify both the antecedents and consequences of problem behaviors and increase pleasant events have empirical support for the management of behavioral symptoms.³⁴ Interventions including massage therapy, aromatherapy, exercise, and music therapy may also be effective in the short term for agitated behavior.³⁵

Caregivers should be encouraged to receive training in these strategies through organizations like AA. Caregiver education and support can reduce caregivers’ distress and increase their self-efficacy and coping skills.³⁶

End-of-life care must be addressed

Perhaps the most important aspect of end-of-life care in AD is assuring that families (or health care proxies) understand that AD is a fatal illness, with most patients dying within 4 to 8 years of diagnosis.¹ Evidence indicates that patients whose proxies have a clear recognition of this are less likely to experience “burdensome” interventions such as parenteral therapy, emergency department visits, hospital admissions, and tube feedings in their last 3 months of life.³⁷

Overall, decisions regarding discontinuing medical treatments in advanced AD should be made by balancing the likelihood of benefit with the potential for adverse effects.³⁸The progressive and ultimately fatal nature of Alzheimer's disease makes planning for the future a priority. For example, the American Geriatrics Society recently recommended against feeding tubes because they often result in discomfort due to agitation, use of restraints, and worsening pressure ulcers.³⁹

Unfortunately, only a minority of families receives straightforward information on the course and prognosis of AD, including the fact that patients eventually stop eating and that the natural cause of death is often an acute infection. Studies also show that patients with dementia are at risk for inadequate treatment of pain.⁴⁰ Assuring adequate pain control is an essential component of end-of-life care.

Hospice. End-of-life care can often be improved with hospice care. This service is underused by patients with dementia, even though hospice care is available at no cost through Medicare. Hospice eligibility criteria for patients with AD are shown in
TABLE 3.^41,42

Finally, a word about prevention

Numerous risk factors have been associated with an increased risk of AD (TABLE 4)^2,3. Some, like age and genetics, are nonmodifiable, while others—particularly cardiovascular risk factors—can be modified.¹ There are also factors associated with decreased risk, most notably, physical exercise and participating in cognitively stimulating activities.³ Identification of these factors has led to the hope that addressing them can prevent AD.

But association does not equal causation. In 2010, a report from the National Institutes of Health concluded that, although there are modifiable factors associated with AD, there is insufficient evidence that addressing any of them will actually prevent AD.⁴³ In fact, there is good evidence that some of these factors (eg, statin therapy) are not effective in reducing the incidence of dementia, and that others (eg, vitamin E and estrogen therapy) are potentially harmful.⁴⁴

The absence of empirically supported preventive interventions does not mean, however, that we should disregard these risks and protective factors. Encouraging social engagement, for example, may improve both emotional health and quality of life. Addressing cardiovascular risk factors can reduce the rate of coronary and cerebrovascular disease, potentially including vascular dementia, even if it does not reduce the rate of AD.

Studies are evaluating the use of monoclonal antibodies with anti-amyloid properties for preventing AD in individuals who have APOE ε4 genotypes or high amyloid loads on neuroimaging.⁴⁵ It will be several years before results are available, however, and the outcome of these studies is uncertain as the use of anti-amyloid agents for treating established dementia has not been effective.^46,47

CORRESPONDENCE
Marisa Menchola, PhD, Department of Psychiatry, University of Arizona College of Medicine, 1501 N. Campbell Ave., 7OPC. Tucson, AZ 85724; marisam@psychiatry.arizona.edu

Alzheimer’s disease (AD), the most common form of dementia, affects more than 5 million Americans.¹ Estimates suggest that by 2050, the prevalence could triple, reaching 13 to 16 million.¹ To effectively care for patients with AD and their families, family physicians need to be familiar with the latest evidence on all facets of care, from initial detection to patient management and end-of-life care.

This evidence-based review will help you toward that end by answering common questions regarding Alzheimer’s care, including whether routine screening is advisable, what tests should be ordered, which interventions (including nonpharmacologic options) are worth considering, and how best to counsel patients and families about end-of-life care.

Routine screening? Still subject to debate

In considering routine dementia screening in primary care, the key question is whether screening improves outcomes. Advocates note that individuals with dementia may appear unimpaired during office visits and may not report symptoms due to lack of insight; they point out, too, that waiting for an event that makes cognitive impairment obvious, such as a driving mishap, is risky.² Those who advocate routine screening also note that only about half of those who have dementia are ever diagnosed.³

Others, including the US Preventive Services Task Force (USPSTF), disagree. In its 2014 evidence review, the USPSTF indicated that there is “insufficient evidence to assess the balance of benefits and harms of screening for cognitive impairment in older adults.”⁴

Mixed messages

The dearth of evidence is also reflected in the conflicting recommendations of the Affordable Care Act (ACA) and the Centers for Medicare and Medicaid Services (CMS). The ACA requires physicians to assess the cognitive function of Medicare patients during their annual wellness visits. CMS, however, instructs providers to screen for dementia only if observation or concerns raised by the patient or family suggest the possibility of impairment, and does not recommend any particular test.⁵

Cost-effectiveness analyses raise questions about the value of routine screening, as well. Evidence suggests that if a primary care physician screens 300 older patients, 39 will have a positive screen. But only about half of those 39 will agree to a diagnostic evaluation, and no more than 9 will ultimately be diagnosed with dementia. The estimated cost of identifying 9 cases is nearly $40,000—all in the absence of a treatment to cure or stop the progression of the disorder.⁶

The bottom line: Evidence does not support routine dementia screening of older adults. When cognitive impairment is suspected, however, physicians should conduct a diagnostic evaluation—and consider educating patients and families about the Alzheimer’s Association (AA)’s 10 warning signs of AD.⁷ (See “Is it Alzheimer’s? 10 warning signs”⁷ below.) A longer version, available at http://www.alz.org/national/documents/checklist_10signs.pdf, outlines the cognitive changes that are characteristic of healthy aging and compares them to changes suggestive of early dementia.⁷

How to proceed when you suspect AD

Step 1: Screening instrument. The first step in the diagnostic evaluation of a patient with suspected AD is to determine if, in fact, cognitive impairment is present. This can be done by screening with in-office screening instruments, such as the Mini-Cog (available at alz.org/documents_custom/minicog.pdf) or Mini-Mental State Examination (MMSE; health.gov.bc.ca/pharmacare/adti/clinician/pdf/ADTI%20SMMSE-GDS%20Reference%20Card.pdf), among others.⁸

Step 2: Clinical evaluation. If observation and test results suggest cognitive impairment, the next step is to determine whether clinical findings are consistent with the diagnostic criteria for AD (TABLE 1)⁹ developed by workgroups from the National Institute on Aging (NIA)/AA in 2011. A work-up is necessary to identify conditions that can mimic dementia (eg, depression) and behaviors that suggest another type of dementia, such as frontotemporal or Lewy body dementia.¹⁰ Lab testing should be included to rule out potentially reversible causes of cognitive dysfunction (eg, hypothyroidism, vitamin D deficiency).

Step 3: Neuropsychological evaluation. The NIA/AA recommends neuropsychological testing when the brief cognitive tests, history, and clinical work-up are not sufficient for a definitive diagnosis of dementia.⁹When brief cognitive tests, history, and clinical work-up are inconclusive, refer patients for neuropsychological testing.This generally involves a referral to a neuropsychologist, who conducts a battery of standardized tests to evaluate attention, memory, language, visual-spatial abilities, and executive functions, among others. Neuropsychological testing can confirm the presence of cognitive impairment and aid in the differential diagnosis by comparing the patient’s performance in these domains with characteristic features of different dementia syndromes.

Step 4: Brain imaging with either computed tomography or magnetic resonance imaging can be included in the work-up for patients with suspected AD to rule out abnormalities—eg, metastatic cancer, hydrocephalus, or occult chronic subdural hematoma—that could be causing cognitive impairment.^9,10 Clinical features that generally warrant brain imaging include onset of cognitive impairment before age 60; unexplained focal neurologic signs or symptoms; abrupt onset or rapid decline; and/or predisposing conditions, such as cancer or anticoagulant treatment.¹⁰

The role of biomarkers and advanced brain imaging

Biomarkers that might provide confirmation of AD in patients who exhibit early symptoms of dementia have been studied extensively.¹¹ The NIA/AA identified 2 categories of AD biomarkers:

• tests for β-amyloid deposition in the brain, including spinal fluid assays for β-amyloid (Aβ₄₂) and positron emission tomography (PET) scans after intravenous injection of florbetapir or flutemetamol, which bind to amyloid in the brain; and
• tests for neuronal degeneration, which would include spinal fluid assays for tau protein and PET scans after injection of fluorodeoxyglucose (FDG), which shows decreased uptake in patients with AD.⁹

Research reveals the promise of these biomarkers as diagnostic tools, particularly in patients with an atypical presentation of dementia or mild cognitive impairment (MCI) that may be associated with early AD.¹² (More on MCI in a moment.) However, the NIA/AA concluded that additional research is needed to validate these tests for routine diagnostic purposes. Medicare covers PET scans with FDG only for the differential diagnosis of AD vs frontotemporal dementia.¹³

Mild cognitive impairment: How likely that it will progress?

Along with diagnostic criteria for AD, the NIA/AA developed criteria for a symptomatic predementia phase of AD—often referred to as MCI.¹⁴ According to the workgroup, MCI is diagnosed when:

Progression: Less likely than you might think

Patients with MCI are at risk for progression to overt dementia, with an overall annual conversion rate from MCI to dementia estimated at 10% to 15%.^15,16 This estimate must be interpreted with caution, however, because most studies were conducted prior to the 2011 guidelines, when different diagnostic criteria were used. Observers have noted, too, that the numbers largely reflect data collected in specialty clinics and that community-based studies reveal substantially lower conversion rates (3%-6% per year).¹⁶ In addition, evidence suggests that many patients with MCI demonstrate long-term stability or even reversal of deficits.¹⁷

While there is some consideration of the use of biomarkers and amyloid imaging tests to help determine which patients with MCI will progress to AD, practice guidelines do not currently recommend such testing and it is not covered by Medicare.

When evidence indicates an AD diagnosis

When faced with the need to communicate an AD diagnosis, follow the general recommendations for delivering any bad news or discouraging prognosis:

Prioritize and limit the information you provide, determining not only what the patient and family want to hear, but also how much they are able to comprehend.

Confirm that the patient and family understand the information you’ve provided.

Offer emotional support and recommend additional resources¹⁸ (TABLE 2).

Given the progressive cognitive decline that characterizes AD, it is important to address the primary caregiver’s understanding of, and ability to cope with, the disease. It is also important to explore beliefs and attitudes regarding AD. Keep in mind that different cultural groups tend to differ in their beliefs about the nature, cause, and appropriate management of AD, as well as the role of spirituality, help-seeking, and stigma.^19,20

When communicating an Alzheimer's disease diagnosis, prioritize information and offer emotional support. The progressive and ultimately fatal nature of AD also makes planning for the future a priority. Ideally, patients should be engaged in discussions regarding end-of-life care as early as possible, while they are still able to make informed decisions and express their preferences. Discussing end-of-life care can be overwhelming for newly diagnosed patients and their families, however, so it is important that you address issues—medical, financial, and legal planning, for example—that families should be considering.

TABLE 2

Drugs address cognitive and behavioral function

No current treatments
 can cure 
or significantly alter the progression of AD, but 2 classes of medications are used to improve cognitive function. No currently available treatments can cure or significantly alter the progression of AD, but 2 classes of medications are used in an attempt to improve cognitive function. One is cholinesterase inhibitors (ChEIs), which potentiate acetylcholine synaptic transmission. The other is N-methyl-D-aspartate (NMDA) glutamate receptor blockers. Other classes of drugs are sometimes used to treat behavioral symptoms of dementia, such as agitation, aggression, mood disorders, and psychosis (eg, delusions and hallucinations).

Cognitive function. Results from studies of pharmacologic management of MCI vary widely, but recent reviews have found no convincing evidence that either ChEIs or NMDA receptor blockers have an effect on progression from MCI to dementia.^21,22 Neither class is FDA-approved for treating MCI.

In patients with dementia, the effects of ChEIs and NMDA receptor blockers on cognition are statistically significant but modest, and often of questionable clinical relevance.²³ Nonetheless, among ChEIs, donepezil is approved by the US Food and Drug Administration (FDA) for mild, moderate, and severe dementia and galantamine and rivastigmine are approved for mild and moderate dementia. There is no evidence that any one ChEI is more effective than any other,²⁴ and the choice of drugs is often guided by cost, adverse effects, and health plan formularies. Memantine, the only FDA-approved NMDA receptor blocker, is approved for moderate to severe dementia and can be used alone or in combination with a ChEI.

In patients with dementia, the effects of ChEIs and NMDA receptor blockers on cognition are statistically significant but modest, and are often of questionable clinical relevance. If these drugs are used in an attempt to improve cognition in AD, guidelines recommend the following approach for initial therapy: Prescribe a ChEI for the mild stage, a ChEI plus memantine for the moderate stage, and memantine (with or without a ChEI) for the severe stage.²⁵ The recommendations also include monitoring every 6 months.

There is no consensus about when to discontinue medication. Various published recommendations call for continuing treatment until the patient has “lost all cognitive and functional abilities;”²² until the patient’s MMSE score falls below 10 and there is no indication that the drug is having a “worthwhile effect;”²¹ or until he or she has reached stage 7 on the Reisberg Functional Assessment Staging scale, indicating nonambulatory status with speech limited to one to 5 words a day.¹⁰

Behavioral function. A variety of drugs are used to treat behavioral symptoms in AD. While not FDA-approved for this use, the most widely prescribed agents are second-generation antipsychotics (aripiprazole, olanzapine, quetiapine, and risperidone). The main effect of these drugs is often nothing more than sedation, and one large multi­site clinical trial concluded that the adverse effects offset the benefits for patients with AD.²⁶ Indeed, the FDA has issued an advisory on the use of second-generation antipsychotics in AD patients, stating that they are associated with an increased risk of death.²⁷ The recently updated Beers Criteria strongly recommend avoiding these drugs for treating behavioral disturbances in AD unless nonpharmacologic options have failed and the patient is a threat to self or others.²⁸

The FDA has issued an advisory on the use of second-generation antipsychotics in Alzheimer’s patients, stating that they are associated with an increased risk of death. Because of the black-box warning that antipsychotics increase the risk of death, some physicians have advocated obtaining informed consent prior to prescribing such medications.²⁹ At the very least, when family or guardians are involved, a conversation about risks vs benefits should take place and be documented in the medical record.

Other drug classes are also sometimes used in an attempt to improve behavioral function, including anti-seizure medications (valproic acid, carbamazepine), antidepressants (trazodone and selective serotonin reuptake inhibitors), and anxiolytics (benzodiazepines and buspirone). Other than their sedating effects, there is no strong evidence that these drugs are effective for treating dementia-related behavioral disorders. If used, caution is required due to potential adverse effects.

Nonpharmacologic management is “promising”

A recent systematic review of nonpharmacologic interventions for MCI evaluated exercise, training in compensatory strategies, and engagement in cognitively stimulating activities and found “promising but inconclusive” results. The researchers found that studies show mostly positive effects on cognition but have significant methodologic limitations.³⁰ Importantly, there is no evidence of delayed or reduced conversion to dementia.

For patients who already have mild-to-moderate dementia, cognitive stimulation seems to help in the short term.³¹ There is also some evidence that exercise and occupational therapy may slow functional decline,³² but the effects are small to modest and their actual clinical significance (eg, the ability to delay institutionalization) is unclear. There is promising but preliminary evidence that cognitive rehabilitation (helping patients devise strategies to complete daily activities) may improve functioning in everyday life.³³

While behavioral symptoms are often due to the dementia itself, it is important to identify and treat medical and environmental causes that may be contributing, such as infection, pain, and loud or unsafe environments.Interventions such as massage therapy, aromatherapy, exercise, and music therapy may be effective in the short term for agitated behavior. As noted before, nonpharmacologic treatments are generally preferred for behavioral problems and should be considered prior to drug therapy. Approaches that identify and modify both the antecedents and consequences of problem behaviors and increase pleasant events have empirical support for the management of behavioral symptoms.³⁴ Interventions including massage therapy, aromatherapy, exercise, and music therapy may also be effective in the short term for agitated behavior.³⁵

Caregivers should be encouraged to receive training in these strategies through organizations like AA. Caregiver education and support can reduce caregivers’ distress and increase their self-efficacy and coping skills.³⁶

End-of-life care must be addressed

Perhaps the most important aspect of end-of-life care in AD is assuring that families (or health care proxies) understand that AD is a fatal illness, with most patients dying within 4 to 8 years of diagnosis.¹ Evidence indicates that patients whose proxies have a clear recognition of this are less likely to experience “burdensome” interventions such as parenteral therapy, emergency department visits, hospital admissions, and tube feedings in their last 3 months of life.³⁷

Overall, decisions regarding discontinuing medical treatments in advanced AD should be made by balancing the likelihood of benefit with the potential for adverse effects.³⁸The progressive and ultimately fatal nature of Alzheimer's disease makes planning for the future a priority. For example, the American Geriatrics Society recently recommended against feeding tubes because they often result in discomfort due to agitation, use of restraints, and worsening pressure ulcers.³⁹

Unfortunately, only a minority of families receives straightforward information on the course and prognosis of AD, including the fact that patients eventually stop eating and that the natural cause of death is often an acute infection. Studies also show that patients with dementia are at risk for inadequate treatment of pain.⁴⁰ Assuring adequate pain control is an essential component of end-of-life care.

Hospice. End-of-life care can often be improved with hospice care. This service is underused by patients with dementia, even though hospice care is available at no cost through Medicare. Hospice eligibility criteria for patients with AD are shown in
TABLE 3.^41,42

Finally, a word about prevention

Numerous risk factors have been associated with an increased risk of AD (TABLE 4)^2,3. Some, like age and genetics, are nonmodifiable, while others—particularly cardiovascular risk factors—can be modified.¹ There are also factors associated with decreased risk, most notably, physical exercise and participating in cognitively stimulating activities.³ Identification of these factors has led to the hope that addressing them can prevent AD.

But association does not equal causation. In 2010, a report from the National Institutes of Health concluded that, although there are modifiable factors associated with AD, there is insufficient evidence that addressing any of them will actually prevent AD.⁴³ In fact, there is good evidence that some of these factors (eg, statin therapy) are not effective in reducing the incidence of dementia, and that others (eg, vitamin E and estrogen therapy) are potentially harmful.⁴⁴

The absence of empirically supported preventive interventions does not mean, however, that we should disregard these risks and protective factors. Encouraging social engagement, for example, may improve both emotional health and quality of life. Addressing cardiovascular risk factors can reduce the rate of coronary and cerebrovascular disease, potentially including vascular dementia, even if it does not reduce the rate of AD.

Studies are evaluating the use of monoclonal antibodies with anti-amyloid properties for preventing AD in individuals who have APOE ε4 genotypes or high amyloid loads on neuroimaging.⁴⁵ It will be several years before results are available, however, and the outcome of these studies is uncertain as the use of anti-amyloid agents for treating established dementia has not been effective.^46,47

CORRESPONDENCE
Marisa Menchola, PhD, Department of Psychiatry, University of Arizona College of Medicine, 1501 N. Campbell Ave., 7OPC. Tucson, AZ 85724; marisam@psychiatry.arizona.edu

Alzheimer’s disease (AD), the most common form of dementia, affects more than 5 million Americans.¹ Estimates suggest that by 2050, the prevalence could triple, reaching 13 to 16 million.¹ To effectively care for patients with AD and their families, family physicians need to be familiar with the latest evidence on all facets of care, from initial detection to patient management and end-of-life care.

This evidence-based review will help you toward that end by answering common questions regarding Alzheimer’s care, including whether routine screening is advisable, what tests should be ordered, which interventions (including nonpharmacologic options) are worth considering, and how best to counsel patients and families about end-of-life care.

Routine screening? Still subject to debate

In considering routine dementia screening in primary care, the key question is whether screening improves outcomes. Advocates note that individuals with dementia may appear unimpaired during office visits and may not report symptoms due to lack of insight; they point out, too, that waiting for an event that makes cognitive impairment obvious, such as a driving mishap, is risky.² Those who advocate routine screening also note that only about half of those who have dementia are ever diagnosed.³

Others, including the US Preventive Services Task Force (USPSTF), disagree. In its 2014 evidence review, the USPSTF indicated that there is “insufficient evidence to assess the balance of benefits and harms of screening for cognitive impairment in older adults.”⁴

Mixed messages

The dearth of evidence is also reflected in the conflicting recommendations of the Affordable Care Act (ACA) and the Centers for Medicare and Medicaid Services (CMS). The ACA requires physicians to assess the cognitive function of Medicare patients during their annual wellness visits. CMS, however, instructs providers to screen for dementia only if observation or concerns raised by the patient or family suggest the possibility of impairment, and does not recommend any particular test.⁵

Cost-effectiveness analyses raise questions about the value of routine screening, as well. Evidence suggests that if a primary care physician screens 300 older patients, 39 will have a positive screen. But only about half of those 39 will agree to a diagnostic evaluation, and no more than 9 will ultimately be diagnosed with dementia. The estimated cost of identifying 9 cases is nearly $40,000—all in the absence of a treatment to cure or stop the progression of the disorder.⁶

The bottom line: Evidence does not support routine dementia screening of older adults. When cognitive impairment is suspected, however, physicians should conduct a diagnostic evaluation—and consider educating patients and families about the Alzheimer’s Association (AA)’s 10 warning signs of AD.⁷ (See “Is it Alzheimer’s? 10 warning signs”⁷ below.) A longer version, available at http://www.alz.org/national/documents/checklist_10signs.pdf, outlines the cognitive changes that are characteristic of healthy aging and compares them to changes suggestive of early dementia.⁷

How to proceed when you suspect AD

Step 1: Screening instrument. The first step in the diagnostic evaluation of a patient with suspected AD is to determine if, in fact, cognitive impairment is present. This can be done by screening with in-office screening instruments, such as the Mini-Cog (available at alz.org/documents_custom/minicog.pdf) or Mini-Mental State Examination (MMSE; health.gov.bc.ca/pharmacare/adti/clinician/pdf/ADTI%20SMMSE-GDS%20Reference%20Card.pdf), among others.⁸

Step 2: Clinical evaluation. If observation and test results suggest cognitive impairment, the next step is to determine whether clinical findings are consistent with the diagnostic criteria for AD (TABLE 1)⁹ developed by workgroups from the National Institute on Aging (NIA)/AA in 2011. A work-up is necessary to identify conditions that can mimic dementia (eg, depression) and behaviors that suggest another type of dementia, such as frontotemporal or Lewy body dementia.¹⁰ Lab testing should be included to rule out potentially reversible causes of cognitive dysfunction (eg, hypothyroidism, vitamin D deficiency).

Step 3: Neuropsychological evaluation. The NIA/AA recommends neuropsychological testing when the brief cognitive tests, history, and clinical work-up are not sufficient for a definitive diagnosis of dementia.⁹When brief cognitive tests, history, and clinical work-up are inconclusive, refer patients for neuropsychological testing.This generally involves a referral to a neuropsychologist, who conducts a battery of standardized tests to evaluate attention, memory, language, visual-spatial abilities, and executive functions, among others. Neuropsychological testing can confirm the presence of cognitive impairment and aid in the differential diagnosis by comparing the patient’s performance in these domains with characteristic features of different dementia syndromes.

Step 4: Brain imaging with either computed tomography or magnetic resonance imaging can be included in the work-up for patients with suspected AD to rule out abnormalities—eg, metastatic cancer, hydrocephalus, or occult chronic subdural hematoma—that could be causing cognitive impairment.^9,10 Clinical features that generally warrant brain imaging include onset of cognitive impairment before age 60; unexplained focal neurologic signs or symptoms; abrupt onset or rapid decline; and/or predisposing conditions, such as cancer or anticoagulant treatment.¹⁰

The role of biomarkers and advanced brain imaging

Biomarkers that might provide confirmation of AD in patients who exhibit early symptoms of dementia have been studied extensively.¹¹ The NIA/AA identified 2 categories of AD biomarkers:

• tests for β-amyloid deposition in the brain, including spinal fluid assays for β-amyloid (Aβ₄₂) and positron emission tomography (PET) scans after intravenous injection of florbetapir or flutemetamol, which bind to amyloid in the brain; and
• tests for neuronal degeneration, which would include spinal fluid assays for tau protein and PET scans after injection of fluorodeoxyglucose (FDG), which shows decreased uptake in patients with AD.⁹

Research reveals the promise of these biomarkers as diagnostic tools, particularly in patients with an atypical presentation of dementia or mild cognitive impairment (MCI) that may be associated with early AD.¹² (More on MCI in a moment.) However, the NIA/AA concluded that additional research is needed to validate these tests for routine diagnostic purposes. Medicare covers PET scans with FDG only for the differential diagnosis of AD vs frontotemporal dementia.¹³

Mild cognitive impairment: How likely that it will progress?

Along with diagnostic criteria for AD, the NIA/AA developed criteria for a symptomatic predementia phase of AD—often referred to as MCI.¹⁴ According to the workgroup, MCI is diagnosed when:

Progression: Less likely than you might think

Patients with MCI are at risk for progression to overt dementia, with an overall annual conversion rate from MCI to dementia estimated at 10% to 15%.^15,16 This estimate must be interpreted with caution, however, because most studies were conducted prior to the 2011 guidelines, when different diagnostic criteria were used. Observers have noted, too, that the numbers largely reflect data collected in specialty clinics and that community-based studies reveal substantially lower conversion rates (3%-6% per year).¹⁶ In addition, evidence suggests that many patients with MCI demonstrate long-term stability or even reversal of deficits.¹⁷

While there is some consideration of the use of biomarkers and amyloid imaging tests to help determine which patients with MCI will progress to AD, practice guidelines do not currently recommend such testing and it is not covered by Medicare.

When evidence indicates an AD diagnosis

When faced with the need to communicate an AD diagnosis, follow the general recommendations for delivering any bad news or discouraging prognosis:

Prioritize and limit the information you provide, determining not only what the patient and family want to hear, but also how much they are able to comprehend.

Confirm that the patient and family understand the information you’ve provided.

Offer emotional support and recommend additional resources¹⁸ (TABLE 2).

Given the progressive cognitive decline that characterizes AD, it is important to address the primary caregiver’s understanding of, and ability to cope with, the disease. It is also important to explore beliefs and attitudes regarding AD. Keep in mind that different cultural groups tend to differ in their beliefs about the nature, cause, and appropriate management of AD, as well as the role of spirituality, help-seeking, and stigma.^19,20

When communicating an Alzheimer's disease diagnosis, prioritize information and offer emotional support. The progressive and ultimately fatal nature of AD also makes planning for the future a priority. Ideally, patients should be engaged in discussions regarding end-of-life care as early as possible, while they are still able to make informed decisions and express their preferences. Discussing end-of-life care can be overwhelming for newly diagnosed patients and their families, however, so it is important that you address issues—medical, financial, and legal planning, for example—that families should be considering.

TABLE 2

Drugs address cognitive and behavioral function

No current treatments
 can cure 
or significantly alter the progression of AD, but 2 classes of medications are used to improve cognitive function. No currently available treatments can cure or significantly alter the progression of AD, but 2 classes of medications are used in an attempt to improve cognitive function. One is cholinesterase inhibitors (ChEIs), which potentiate acetylcholine synaptic transmission. The other is N-methyl-D-aspartate (NMDA) glutamate receptor blockers. Other classes of drugs are sometimes used to treat behavioral symptoms of dementia, such as agitation, aggression, mood disorders, and psychosis (eg, delusions and hallucinations).

Cognitive function. Results from studies of pharmacologic management of MCI vary widely, but recent reviews have found no convincing evidence that either ChEIs or NMDA receptor blockers have an effect on progression from MCI to dementia.^21,22 Neither class is FDA-approved for treating MCI.

In patients with dementia, the effects of ChEIs and NMDA receptor blockers on cognition are statistically significant but modest, and often of questionable clinical relevance.²³ Nonetheless, among ChEIs, donepezil is approved by the US Food and Drug Administration (FDA) for mild, moderate, and severe dementia and galantamine and rivastigmine are approved for mild and moderate dementia. There is no evidence that any one ChEI is more effective than any other,²⁴ and the choice of drugs is often guided by cost, adverse effects, and health plan formularies. Memantine, the only FDA-approved NMDA receptor blocker, is approved for moderate to severe dementia and can be used alone or in combination with a ChEI.

In patients with dementia, the effects of ChEIs and NMDA receptor blockers on cognition are statistically significant but modest, and are often of questionable clinical relevance. If these drugs are used in an attempt to improve cognition in AD, guidelines recommend the following approach for initial therapy: Prescribe a ChEI for the mild stage, a ChEI plus memantine for the moderate stage, and memantine (with or without a ChEI) for the severe stage.²⁵ The recommendations also include monitoring every 6 months.

There is no consensus about when to discontinue medication. Various published recommendations call for continuing treatment until the patient has “lost all cognitive and functional abilities;”²² until the patient’s MMSE score falls below 10 and there is no indication that the drug is having a “worthwhile effect;”²¹ or until he or she has reached stage 7 on the Reisberg Functional Assessment Staging scale, indicating nonambulatory status with speech limited to one to 5 words a day.¹⁰

Behavioral function. A variety of drugs are used to treat behavioral symptoms in AD. While not FDA-approved for this use, the most widely prescribed agents are second-generation antipsychotics (aripiprazole, olanzapine, quetiapine, and risperidone). The main effect of these drugs is often nothing more than sedation, and one large multi­site clinical trial concluded that the adverse effects offset the benefits for patients with AD.²⁶ Indeed, the FDA has issued an advisory on the use of second-generation antipsychotics in AD patients, stating that they are associated with an increased risk of death.²⁷ The recently updated Beers Criteria strongly recommend avoiding these drugs for treating behavioral disturbances in AD unless nonpharmacologic options have failed and the patient is a threat to self or others.²⁸

The FDA has issued an advisory on the use of second-generation antipsychotics in Alzheimer’s patients, stating that they are associated with an increased risk of death. Because of the black-box warning that antipsychotics increase the risk of death, some physicians have advocated obtaining informed consent prior to prescribing such medications.²⁹ At the very least, when family or guardians are involved, a conversation about risks vs benefits should take place and be documented in the medical record.

Other drug classes are also sometimes used in an attempt to improve behavioral function, including anti-seizure medications (valproic acid, carbamazepine), antidepressants (trazodone and selective serotonin reuptake inhibitors), and anxiolytics (benzodiazepines and buspirone). Other than their sedating effects, there is no strong evidence that these drugs are effective for treating dementia-related behavioral disorders. If used, caution is required due to potential adverse effects.

Nonpharmacologic management is “promising”

A recent systematic review of nonpharmacologic interventions for MCI evaluated exercise, training in compensatory strategies, and engagement in cognitively stimulating activities and found “promising but inconclusive” results. The researchers found that studies show mostly positive effects on cognition but have significant methodologic limitations.³⁰ Importantly, there is no evidence of delayed or reduced conversion to dementia.

For patients who already have mild-to-moderate dementia, cognitive stimulation seems to help in the short term.³¹ There is also some evidence that exercise and occupational therapy may slow functional decline,³² but the effects are small to modest and their actual clinical significance (eg, the ability to delay institutionalization) is unclear. There is promising but preliminary evidence that cognitive rehabilitation (helping patients devise strategies to complete daily activities) may improve functioning in everyday life.³³

While behavioral symptoms are often due to the dementia itself, it is important to identify and treat medical and environmental causes that may be contributing, such as infection, pain, and loud or unsafe environments.Interventions such as massage therapy, aromatherapy, exercise, and music therapy may be effective in the short term for agitated behavior. As noted before, nonpharmacologic treatments are generally preferred for behavioral problems and should be considered prior to drug therapy. Approaches that identify and modify both the antecedents and consequences of problem behaviors and increase pleasant events have empirical support for the management of behavioral symptoms.³⁴ Interventions including massage therapy, aromatherapy, exercise, and music therapy may also be effective in the short term for agitated behavior.³⁵

Caregivers should be encouraged to receive training in these strategies through organizations like AA. Caregiver education and support can reduce caregivers’ distress and increase their self-efficacy and coping skills.³⁶

End-of-life care must be addressed

Perhaps the most important aspect of end-of-life care in AD is assuring that families (or health care proxies) understand that AD is a fatal illness, with most patients dying within 4 to 8 years of diagnosis.¹ Evidence indicates that patients whose proxies have a clear recognition of this are less likely to experience “burdensome” interventions such as parenteral therapy, emergency department visits, hospital admissions, and tube feedings in their last 3 months of life.³⁷

Overall, decisions regarding discontinuing medical treatments in advanced AD should be made by balancing the likelihood of benefit with the potential for adverse effects.³⁸The progressive and ultimately fatal nature of Alzheimer's disease makes planning for the future a priority. For example, the American Geriatrics Society recently recommended against feeding tubes because they often result in discomfort due to agitation, use of restraints, and worsening pressure ulcers.³⁹

Unfortunately, only a minority of families receives straightforward information on the course and prognosis of AD, including the fact that patients eventually stop eating and that the natural cause of death is often an acute infection. Studies also show that patients with dementia are at risk for inadequate treatment of pain.⁴⁰ Assuring adequate pain control is an essential component of end-of-life care.

Hospice. End-of-life care can often be improved with hospice care. This service is underused by patients with dementia, even though hospice care is available at no cost through Medicare. Hospice eligibility criteria for patients with AD are shown in
TABLE 3.^41,42

Finally, a word about prevention

Numerous risk factors have been associated with an increased risk of AD (TABLE 4)^2,3. Some, like age and genetics, are nonmodifiable, while others—particularly cardiovascular risk factors—can be modified.¹ There are also factors associated with decreased risk, most notably, physical exercise and participating in cognitively stimulating activities.³ Identification of these factors has led to the hope that addressing them can prevent AD.

But association does not equal causation. In 2010, a report from the National Institutes of Health concluded that, although there are modifiable factors associated with AD, there is insufficient evidence that addressing any of them will actually prevent AD.⁴³ In fact, there is good evidence that some of these factors (eg, statin therapy) are not effective in reducing the incidence of dementia, and that others (eg, vitamin E and estrogen therapy) are potentially harmful.⁴⁴

The absence of empirically supported preventive interventions does not mean, however, that we should disregard these risks and protective factors. Encouraging social engagement, for example, may improve both emotional health and quality of life. Addressing cardiovascular risk factors can reduce the rate of coronary and cerebrovascular disease, potentially including vascular dementia, even if it does not reduce the rate of AD.

Studies are evaluating the use of monoclonal antibodies with anti-amyloid properties for preventing AD in individuals who have APOE ε4 genotypes or high amyloid loads on neuroimaging.⁴⁵ It will be several years before results are available, however, and the outcome of these studies is uncertain as the use of anti-amyloid agents for treating established dementia has not been effective.^46,47

CORRESPONDENCE
Marisa Menchola, PhD, Department of Psychiatry, University of Arizona College of Medicine, 1501 N. Campbell Ave., 7OPC. Tucson, AZ 85724; marisam@psychiatry.arizona.edu

EVIDENCE SUMMARY

A systematic review and meta-analysis included 29 studies that compared the sensitivity and specificity of nucleic acid amplification tests on specimens collected invasively from the cervix or urethra with noninvasively collected urine specimens.¹ Studies included both asymptomatic and symptomatic patients. Reference standards varied and included cervical culture, enzyme immunoassay, direct fluorescent antibody, ligase chain reaction, and positive results on 2 of 3 nucleic acid amplification assays.

The sensitivity and specificity of chlamydia and gonorrhea detection didn’t differ between urine and cervical specimens. The pooled sensitivity and specificity for polymerase chain reaction urine samples were 83.3% (95% confidence interval [CI], 77.7%-88.9%) and 99.5% (CI, 99.3%-99.8%), respectively, and for cervical samples 85.5% (CI, 80.3%-90.6%) and 99.6% (CI, 99.4%-99.8%), respectively.¹

Pelvic exams detect adnexal masses, but not reliably

A prospective cohort of 127 women undergoing pelvic surgery had preoperative bimanual exams under anesthesia to detect an adnexal mass.² The gold standard for detection was findings at surgery. The woman had a high prevalence (20%) of ovarian masses. Indications for surgery included diagnosis, sterilization, and suspected malignancy.

When the preoperative bimanual examination detected a left adnexal mass, the odds of finding one at surgery increased 2.8 times, whereas when the exam was normal the odds decreased by 0.8 (positive predictive value [PPV]=0.64; 95% CI, 0.45-0.83). Conversely, the preoperative examination failed to correctly predict a right adnexal mass regardless of the result; the likelihood ratio for both normal and abnormal right adnexal examinations was 1 (PPV=0.26; 95% CI, 0.12-0.47).

 

 

What about pelvic exams with ultrasound?

An investigation of transvaginal ultrasonography (TVUS) from November 1987 to January 1991 screened a cohort of 1300 asymptomatic postmenopausal women for an ovarian tumor.³ To be eligible for the study, subjects had to have been without menses for at least 6 months and have no history of a pelvic tumor. Each woman underwent both a pelvic exam and TVUS.

TVUS found that 33 of the women had abnormal ovarian size and morphology when compared with normal standards. Twenty-seven of the 33, who had abnormalities that persisted longer than 1 month, underwent exploratory laparotomy. Ovarian enlargement also was apparent on clinical examination in 10 patients.

Of the 27 patients who underwent surgery, 2 had primary ovarian carcinomas. Significantly, both women had documented normal pelvic examinations on screening.

Another cohort trial conducted between October 1984 and July 1987 studied 801 women ages 40 to 70 years who were at high risk for ovarian cancer.⁴ Risk factors included nulliparity; symptoms such as abdominal pain, urinary frequency, or irregular bleeding; a personal history of cancer; and a family history of ovarian, breast, or endometrial cancer.

The women underwent both pelvic examination and abdominal ultrasound scanning. Fifty-one patients had abnormal pelvic examinations but normal sonograms. None of the 51 patients, who were followed to the end of the study, developed evidence of ovarian carcinoma. Abnormal abdominal ultrasound scans in 163 patients resulted in 3 diagnoses of malignancy. The 3 patients had normal pelvic examinations.  

A pelvic exam isn’t needed before prescribing hormonal contraception

A 2001 JAMA literature review addressed pelvic exams as a prerequisite for administering hormonal contraceptives.⁵ Investigators identified consensus statements, policy statements, and reviews on the subject and contacted major health associations such as the World Health Organization for their recommendations.

Despite a lack of evidence, these expert sources concluded that a pelvic exam isn’t necessary to identify conditions in which OCPs are contraindicated (pregnancy, breast cancer, hypertension, and thromboembolic disease). Medical history and blood pressure measurement provide adequate screening.

 

 

Vulvar cancer is rare and usually symptomatic

Vulvar disease is uncommon and almost always symptomatic. The United Kingdom national cancer registry found an incidence of 3.7 per 100,000.⁶ A prospective study of 102 women presenting with squamous cell carcinoma of the vulva showed that 94% reported a history of symptomatic vulvar irritation.⁷ Eighty-eight percent had had symptoms for longer than 6 months.

RECOMMENDATIONS

Regarding screening for gonorrhea and chlamydia, the United States Preventive Services Task Force (USPSTF) states that newer tests, including nucleic acid amplification tests of urine, have improved sensitivity and comparable specificity when compared with cervical culture.^8,9

An ACOG committee recommends annual exams, even though it found no evidence to support an annual pelvic exam for asymptomatic, low-risk patients. The USPSTF recommends against screening for ovarian cancer in general, (Grade D recommendation: no net benefit or the harms outweigh the benefits). The Task Force states that the sensitivity of pelvic examination in detecting ovarian cancer is unknown based on several ultrasound studies.¹⁰

A 2012 ACOG committee opinion recommends that an annual pelvic examination remain a part of the well-woman visit even though the committee found no evidence in support of an annual exam for asymptomatic, low-risk patients.¹¹ The committee notes that patients and providers should discuss the decision to perform a pelvic exam annually.

EVIDENCE SUMMARY

A systematic review and meta-analysis included 29 studies that compared the sensitivity and specificity of nucleic acid amplification tests on specimens collected invasively from the cervix or urethra with noninvasively collected urine specimens.¹ Studies included both asymptomatic and symptomatic patients. Reference standards varied and included cervical culture, enzyme immunoassay, direct fluorescent antibody, ligase chain reaction, and positive results on 2 of 3 nucleic acid amplification assays.

The sensitivity and specificity of chlamydia and gonorrhea detection didn’t differ between urine and cervical specimens. The pooled sensitivity and specificity for polymerase chain reaction urine samples were 83.3% (95% confidence interval [CI], 77.7%-88.9%) and 99.5% (CI, 99.3%-99.8%), respectively, and for cervical samples 85.5% (CI, 80.3%-90.6%) and 99.6% (CI, 99.4%-99.8%), respectively.¹

Pelvic exams detect adnexal masses, but not reliably

A prospective cohort of 127 women undergoing pelvic surgery had preoperative bimanual exams under anesthesia to detect an adnexal mass.² The gold standard for detection was findings at surgery. The woman had a high prevalence (20%) of ovarian masses. Indications for surgery included diagnosis, sterilization, and suspected malignancy.

When the preoperative bimanual examination detected a left adnexal mass, the odds of finding one at surgery increased 2.8 times, whereas when the exam was normal the odds decreased by 0.8 (positive predictive value [PPV]=0.64; 95% CI, 0.45-0.83). Conversely, the preoperative examination failed to correctly predict a right adnexal mass regardless of the result; the likelihood ratio for both normal and abnormal right adnexal examinations was 1 (PPV=0.26; 95% CI, 0.12-0.47).

 

 

What about pelvic exams with ultrasound?

An investigation of transvaginal ultrasonography (TVUS) from November 1987 to January 1991 screened a cohort of 1300 asymptomatic postmenopausal women for an ovarian tumor.³ To be eligible for the study, subjects had to have been without menses for at least 6 months and have no history of a pelvic tumor. Each woman underwent both a pelvic exam and TVUS.

TVUS found that 33 of the women had abnormal ovarian size and morphology when compared with normal standards. Twenty-seven of the 33, who had abnormalities that persisted longer than 1 month, underwent exploratory laparotomy. Ovarian enlargement also was apparent on clinical examination in 10 patients.

Of the 27 patients who underwent surgery, 2 had primary ovarian carcinomas. Significantly, both women had documented normal pelvic examinations on screening.

Another cohort trial conducted between October 1984 and July 1987 studied 801 women ages 40 to 70 years who were at high risk for ovarian cancer.⁴ Risk factors included nulliparity; symptoms such as abdominal pain, urinary frequency, or irregular bleeding; a personal history of cancer; and a family history of ovarian, breast, or endometrial cancer.

The women underwent both pelvic examination and abdominal ultrasound scanning. Fifty-one patients had abnormal pelvic examinations but normal sonograms. None of the 51 patients, who were followed to the end of the study, developed evidence of ovarian carcinoma. Abnormal abdominal ultrasound scans in 163 patients resulted in 3 diagnoses of malignancy. The 3 patients had normal pelvic examinations.  

A pelvic exam isn’t needed before prescribing hormonal contraception

A 2001 JAMA literature review addressed pelvic exams as a prerequisite for administering hormonal contraceptives.⁵ Investigators identified consensus statements, policy statements, and reviews on the subject and contacted major health associations such as the World Health Organization for their recommendations.

Despite a lack of evidence, these expert sources concluded that a pelvic exam isn’t necessary to identify conditions in which OCPs are contraindicated (pregnancy, breast cancer, hypertension, and thromboembolic disease). Medical history and blood pressure measurement provide adequate screening.

 

 

Vulvar cancer is rare and usually symptomatic

Vulvar disease is uncommon and almost always symptomatic. The United Kingdom national cancer registry found an incidence of 3.7 per 100,000.⁶ A prospective study of 102 women presenting with squamous cell carcinoma of the vulva showed that 94% reported a history of symptomatic vulvar irritation.⁷ Eighty-eight percent had had symptoms for longer than 6 months.

RECOMMENDATIONS

Regarding screening for gonorrhea and chlamydia, the United States Preventive Services Task Force (USPSTF) states that newer tests, including nucleic acid amplification tests of urine, have improved sensitivity and comparable specificity when compared with cervical culture.^8,9

An ACOG committee recommends annual exams, even though it found no evidence to support an annual pelvic exam for asymptomatic, low-risk patients. The USPSTF recommends against screening for ovarian cancer in general, (Grade D recommendation: no net benefit or the harms outweigh the benefits). The Task Force states that the sensitivity of pelvic examination in detecting ovarian cancer is unknown based on several ultrasound studies.¹⁰

A 2012 ACOG committee opinion recommends that an annual pelvic examination remain a part of the well-woman visit even though the committee found no evidence in support of an annual exam for asymptomatic, low-risk patients.¹¹ The committee notes that patients and providers should discuss the decision to perform a pelvic exam annually.

EVIDENCE SUMMARY

A systematic review and meta-analysis included 29 studies that compared the sensitivity and specificity of nucleic acid amplification tests on specimens collected invasively from the cervix or urethra with noninvasively collected urine specimens.¹ Studies included both asymptomatic and symptomatic patients. Reference standards varied and included cervical culture, enzyme immunoassay, direct fluorescent antibody, ligase chain reaction, and positive results on 2 of 3 nucleic acid amplification assays.

The sensitivity and specificity of chlamydia and gonorrhea detection didn’t differ between urine and cervical specimens. The pooled sensitivity and specificity for polymerase chain reaction urine samples were 83.3% (95% confidence interval [CI], 77.7%-88.9%) and 99.5% (CI, 99.3%-99.8%), respectively, and for cervical samples 85.5% (CI, 80.3%-90.6%) and 99.6% (CI, 99.4%-99.8%), respectively.¹

Pelvic exams detect adnexal masses, but not reliably

A prospective cohort of 127 women undergoing pelvic surgery had preoperative bimanual exams under anesthesia to detect an adnexal mass.² The gold standard for detection was findings at surgery. The woman had a high prevalence (20%) of ovarian masses. Indications for surgery included diagnosis, sterilization, and suspected malignancy.

When the preoperative bimanual examination detected a left adnexal mass, the odds of finding one at surgery increased 2.8 times, whereas when the exam was normal the odds decreased by 0.8 (positive predictive value [PPV]=0.64; 95% CI, 0.45-0.83). Conversely, the preoperative examination failed to correctly predict a right adnexal mass regardless of the result; the likelihood ratio for both normal and abnormal right adnexal examinations was 1 (PPV=0.26; 95% CI, 0.12-0.47).

 

 

What about pelvic exams with ultrasound?

An investigation of transvaginal ultrasonography (TVUS) from November 1987 to January 1991 screened a cohort of 1300 asymptomatic postmenopausal women for an ovarian tumor.³ To be eligible for the study, subjects had to have been without menses for at least 6 months and have no history of a pelvic tumor. Each woman underwent both a pelvic exam and TVUS.

TVUS found that 33 of the women had abnormal ovarian size and morphology when compared with normal standards. Twenty-seven of the 33, who had abnormalities that persisted longer than 1 month, underwent exploratory laparotomy. Ovarian enlargement also was apparent on clinical examination in 10 patients.

Of the 27 patients who underwent surgery, 2 had primary ovarian carcinomas. Significantly, both women had documented normal pelvic examinations on screening.

Another cohort trial conducted between October 1984 and July 1987 studied 801 women ages 40 to 70 years who were at high risk for ovarian cancer.⁴ Risk factors included nulliparity; symptoms such as abdominal pain, urinary frequency, or irregular bleeding; a personal history of cancer; and a family history of ovarian, breast, or endometrial cancer.

The women underwent both pelvic examination and abdominal ultrasound scanning. Fifty-one patients had abnormal pelvic examinations but normal sonograms. None of the 51 patients, who were followed to the end of the study, developed evidence of ovarian carcinoma. Abnormal abdominal ultrasound scans in 163 patients resulted in 3 diagnoses of malignancy. The 3 patients had normal pelvic examinations.  

A pelvic exam isn’t needed before prescribing hormonal contraception

A 2001 JAMA literature review addressed pelvic exams as a prerequisite for administering hormonal contraceptives.⁵ Investigators identified consensus statements, policy statements, and reviews on the subject and contacted major health associations such as the World Health Organization for their recommendations.

Despite a lack of evidence, these expert sources concluded that a pelvic exam isn’t necessary to identify conditions in which OCPs are contraindicated (pregnancy, breast cancer, hypertension, and thromboembolic disease). Medical history and blood pressure measurement provide adequate screening.

 

 

Vulvar cancer is rare and usually symptomatic

Vulvar disease is uncommon and almost always symptomatic. The United Kingdom national cancer registry found an incidence of 3.7 per 100,000.⁶ A prospective study of 102 women presenting with squamous cell carcinoma of the vulva showed that 94% reported a history of symptomatic vulvar irritation.⁷ Eighty-eight percent had had symptoms for longer than 6 months.

RECOMMENDATIONS

Regarding screening for gonorrhea and chlamydia, the United States Preventive Services Task Force (USPSTF) states that newer tests, including nucleic acid amplification tests of urine, have improved sensitivity and comparable specificity when compared with cervical culture.^8,9

An ACOG committee recommends annual exams, even though it found no evidence to support an annual pelvic exam for asymptomatic, low-risk patients. The USPSTF recommends against screening for ovarian cancer in general, (Grade D recommendation: no net benefit or the harms outweigh the benefits). The Task Force states that the sensitivity of pelvic examination in detecting ovarian cancer is unknown based on several ultrasound studies.¹⁰

A 2012 ACOG committee opinion recommends that an annual pelvic examination remain a part of the well-woman visit even though the committee found no evidence in support of an annual exam for asymptomatic, low-risk patients.¹¹ The committee notes that patients and providers should discuss the decision to perform a pelvic exam annually.

CASE  › Mitchell J, age 62, comes to see you because he’s had a cough with increasing dyspnea for a month. Mr. J has never smoked but has type 2 diabetes mellitus. He also tells you that over the past month, he’s had occasional night sweats and has lost 8 pounds, although he’s not changed his diet. During the past week, he’s noticed blood-tinged sputum. Physical examination reveals a thin, chronically ill appearing man with an oral temperature of 100.6°F and mild tachypnea. You order a complete blood count, chest x-ray, and metabolic profile, administer a tuberculin skin test (TST), and initiate levofloxacin 500 mg/d for a presumed bacterial pneumonia. His lab work reveals mild leukocytosis and hyperglycemia, and the chest x-ray shows a left upper lobe infiltrate. The TST reaction—4 mm 50 hours after placement—was negative.

Mr. J returns a week later and says he feels worse. Your examination reveals worsened tachypnea, with tachycardia and crackles over the left upper lung fields.

How would you proceed with his care?

More people die of tuberculosis (TB) each year than any other infectious disease except human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. In 2013, an estimated 9 million people worldwide developed active TB and 1.5 million died of the disease.¹ Many of these deaths could have been prevented if patients had received a diagnosis and treatment during the latent phase (when the patient was infected, but had no active disease), or as soon as the patient developed active disease. In this article we describe treatment for both latent and active TB.

Before treating latent TB infection, first rule out active TB

Patients with latent tuberculosis infection (LTBI) have a 5% to 10% lifetime risk of developing active TB disease.² Treatment of LTBI can reduce this risk to 1% to 2%.³

Assess patients with latent TB infection for signs of active TB, such as weight loss, unexplained fever, night sweats, or hemoptysis. Although not the focus of this article, diagnosis of LTBI is made by using either a TST, in which the patient receives an intradermal injection of purified protein derivative and the size of the skin induration is measured 48 to 72 hours after administration, or an interferon-gamma release assay (IGRA), which requires a blood draw. After receiving a positive test result for LTBI, the next step is to rule out active TB.⁴ This is necessary because the primary treatment regimen for LTBI involves only one drug, whereas treating active TB with one drug is strongly associated with treatment failure and future resistance to that drug.⁵

To rule out active TB, perform a brief, problem-focused history and physical, and obtain a chest x-ray.⁴ Pertinent findings that suggest active disease include:

• any history of recent weight loss, unexplained fever, night sweats, cough or hemoptysis
• fever or any unexpected lung findings on physical exam
• any parenchymal infiltrates on chest x-ray. (Granulomas and scarring may be signs of previously healed TB infection, but do not indicate active TB.)

Any of these findings should prompt a further investigation to either confirm or definitively rule out active TB disease. In the absence of these findings, the physician may proceed with treatment for LTBI.

Latent TB infection treatment: Isoniazid alone, or another regimen?

The current preferred regimen for most patients with LTBI is 9 months of isoniazid (INH) 5 mg/kg/d (10 mg/kg/d in children) up to a maximum of 300 mg/d. This regimen has been recommended by the Centers for Disease Control and Prevention (CDC), the American Thoracic Society, and the Infectious Diseases Society of America.³ However, there are 3 other CDC-recommended LTBI treatment regimens that include INH, INH plus rifapentine (RPT), or rifampin (RIF) for 6, 3, or 4 months, respectively (TABLE 1).⁶ These other regimens may be considered under certain circumstances. For example, INH and rifapentine might be used to treat an otherwise healthy patient who has had recent exposure to an individual with active, contagious TB.

If the patient is pregnant. INH is a pregnancy category C drug. Treatment for LTBI during pregnancy is generally regarded as safe and should be strongly considered if the patient has risk factors for progression to active TB, such as a recent exposure to someone with active TB.⁷ In otherwise healthy patients, treatment for LTBI may be deferred until after delivery.

Take steps to avoid complications of drug therapy

Drug-induced hepatitis is the primary adverse effect of INH treatment. Risk increases with age, previous hepatic injury, or concomitant use of other hepatotoxic medications. The risk is very small (<0.1%) for healthy children but may be over 10% for adults with multiple risk factors.⁸ Hepatitis is generally preceded by asymptomatic elevation of liver function tests (LFTs), which is much more common than clinical hepatitis.

Baseline LFTs should be obtained in patients who:

• have underlying liver disease, such as hepatitis B or C⁹
• consume ≥2 alcoholic drinks daily or >5 drinks at a time on any occasion
• take other medications with potential hepatotoxicity, such as statins
• have HIV infection¹⁰
• are pregnant or postpartum.

If a patient being considered for INH treatment has not had serologic testing for HIV, hepatitis B, or hepatitis C, these tests should be done prior to initiating INH. LFTs should be monitored every 1 to 2 months during INH therapy for patients who have ≥1 of these conditions and normal baseline LFTs. If baseline transaminases are >3 times the upper limit of normal, treatment for LTBI should probably be withheld, though might be considered in those whose LFTs return to normal after withdrawal of a modifiable risk factor, such as alcohol or a statin medication.

Patients with latent TB infection who are receiving isoniazid should be monitored regularly for signs and symptoms of hepatitis. After beginning LTBI treatment, patients should be monitored regularly for signs and symptoms of hepatitis, including anorexia, nausea, abdominal pain, icterus, and dark urine, and LFTs performed if these develop. If during treatment transaminases increase to >3 times normal in a symptomatic patient (or >5 times normal in an asymptomatic patient), INH should be stopped and generally not resumed, even after LFTs return to normal. (Such patients would be considered to have partially treated LTBI, and their physicians should be alert to signs and symptoms of active TB, such as unexplained fever, weight loss, or blood-tinged sputum, during subsequent patient encounters.)

Peripheral neuropathy is a less common adverse effect of INH. It occurs in up to 2% of patients and is caused by interference with vitamin B6 (pyridoxine) metabolism. It can be prevented by supplementation with pyridoxine 25 to 50 mg/d. Vitamin B6, however, does not prevent INH-induced hepatotoxicity.

Noncompliance is a concern with INH therapy because treatment typically requires a 9-month course of daily medication.¹¹ Patients for whom compliance is likely to be an issue might be considered for a 3-month, 12-dose course of once-weekly, directly-observed therapy (DOT) with INH and RPT administered by a public health agency. (See “Which patients with TB should receive directly observed therapy?” on page 32.^12-14) A randomized, open-label trial involving nearly 8000 patients in 4 low-risk countries found this regimen was as effective as 9 months of self-administered INH.¹⁵ The CDC has published recommendations for using this regimen.¹⁶

Suspect active TB? Don’t wait for cultures to begin Tx

Unlike LTBI, for which the results of diagnostic testing are available within a few days, active TB is diagnosed by culture, which may take as long as 6 to 8 weeks. Don’t wait to receive culture results to initiate treatment in a patient you suspect may have active TB. However, if you suspect your patient has active TB, do not delay treatment while waiting for culture results, or defer treatment for a patient who has a negative acid-fast bacilli (AFB) smear or rapid nucleic acid amplification test.¹⁷ These 2 tests, which are routinely performed during TB cultures, look for other evidence of the presence of TB bacilli; they are not as accurate as cultures, but results are available within days. Likewise, a negative TST or IGRA should not prevent empiric treatment for active TB. Treatment for active TB should be begun empirically based on risk factors and clinical presentation, and can be modified or stopped if cultures are negative, the patient fails to improve, or an alternative diagnosis is found to explain the patient’s symptoms.

Rapid testing for evidence of active TB disease—as well as resistance to medications commonly used to treat TB—can be performed using newer modalities such as MODS (Microscopic-Observation Drug-Susceptibility)^18,19 or Xpert MTB/RIF²⁰ testing. However, these tests are not available in many hospitals, and culture and drug sensitivity testing remain the gold standard.²¹

CASE › Mr. J’s clinical history and chest x-ray findings are highly suggestive of active TB. It was not unreasonable to initially treat him for a bacterial pneumonia, although fluoroquinolones should be used cautiously in this setting, because they are one of the most effective second-line drugs for TB, and using them as a single agent will often invoke drug resistance. Because he failed to respond to treatment for bacterial pneumonia and his presentation suggests TB or another serious cause of nonresponsiveness to standard treatment for community-acquired pneumonia (CAP), you admit him to the hospital.

Treatment for active TB requires multiple drugs in 2 phases

While all family physicians should suspect active TB in appropriate clinical situations and be comfortable with obtaining cultures and initiating empiric treatment, most will want to seek consultation with an infectious disease (ID) specialist especially in the scenarios listed in TABLE 2.^5,22 Delayed or inappropriate treatment of active TB remains a major public health problem and cause of multidrug-resistant TB. Inappropriate treatment has been shown to be associated with a 27-fold increase in treatment failure.²³ TB treatment guidelines are available from the CDC,²⁴ World Health Organization,²⁵ and International Union Against Tuberculosis and Lung Disease.²⁶

In the initial phase of treatment for active TB, patients should begin 4 drugs—INH, RIF, EMB, and PZA—for 2 months. Appropriate treatment requires the use of multiple medications administered in 2 phases. In the initial phase, a patient with suspected TB should begin 4 drugs—usually INH, RIF, ethambutol (EMB), and pyrazinamide (PZA)—for 2 months.^1,2,27 The daily pediatric and adult doses and common adverse effects of these medications are summarized in TABLE 3.²⁸ Although most cases of TB can be adequately treated with 2 drugs to which the organism is susceptible, 4 drugs are used initially while awaiting drug sensitivity test results because of the risk of inadequately treating a strain of drug-resistant TB. Before beginning these medications, a chest x-ray, LFTs, HIV antibody test, hepatitis B and C serologies, a serum creatinine, and complete blood count should be obtained in all patients.⁵ If EMB is prescribed, the patient should also undergo testing for red-green color discrimination, because red-green color vision disturbance is a potential adverse effect of this medication.

All 4 drugs may be administered as a single daily dose, and may be taken together.²⁹ They are ordinarily given either daily for 8 weeks, or daily for 2 weeks followed by a twice-weekly schedule for the remaining 6 weeks in higher doses, although the twice-weekly dose of RIF is the same as the daily dose. All are pregnancy category C, although for active TB, the benefit of treatment is almost always greater than the potential harm.

The continuation phase of treatment starts at 8 weeks, when the results of initial cultures and drug sensitivity tests should be available to guide therapy. A second set of cultures and AFB smears is obtained at 8 weeks to document clearing of the initial infection and guide duration of the continuation phase. If the initial culture was positive for Mycobacterium tuberculosis and the organism was sensitive to both INH and RIF, these 2 drugs should be continued for another 4 months (for a total of 6 months of treatment). PZA and EMB may be stopped at 2 months if the organism is sensitive to both INH and RIF. Thus, for most patients with active TB, the standard regimen will be 4 drugs for 2 months, then 2 drugs for 4 months.²

When should the standard treatment regimen be modified?

If a patient with active TB has persistently positive cultures and cavitary disease on an initial chest x-ray, treatment should be extended to 9 months. If the second set of cultures obtained 2 months after beginning drug treatment is positive and there was cavitary disease on the initial chest x-ray, the continuation phase should be extended by 7 months (for a total of 9 months of treatment).³⁰ If a patient has either cavitary disease or persistently positive cultures (but not both), then the length of therapy is determined on an individual basis in consultation with an ID specialist.

Should a patient’s cultures show resistance to any of the first-line drugs, obtain consultation with an ID specialist. Treatment of multidrug-resistant TB (resistant to INH and RIF) and its subset, extensively drug-resistant TB (resistant to INH and RIF, plus any fluoroquinolone, plus either an aminoglycoside or capreomycin) requires prolonged courses of therapy with multiple drugs administered by DOT.^31,32

If at any point during treatment a patient shows clinical deterioration that’s believed to be due to a resurgence of his or her TB disease, obtain a new set of cultures and, in consultation with an ID specialist, add at least 2 drugs to which the patient has not been exposed. Never add only one drug to a failing regimen; active TB always requires 2 drugs to cure, and the patient may have developed resistance to all of the drugs he or she is currently receiving.

If initial cultures are negative for Mycobacterium tuberculosis but the patient responds to treatment, he or she is considered to have “culture-negative TB,” and should generally be continued on INH and RIF for 2 more months after completion of the initial treatment phase (for a total of 4 months of INH and RIF).³³

Remember to report. In the United States, active TB must be reported to your local health department, which can be invaluable in coordinating care and administering DOT.

CASE › In the hospital, Mr. J was placed in respiratory isolation, had prompt sputum cultures for TB, and was started on empiric treatment for active TB with INH, RIF, PZA, and EMB in standard doses. A search for other causes of nonresponsiveness to CAP showed no evidence of malignancy or HIV infection. He improved steadily and was discharged from the hospital after 2 weeks to complete 2 months of 4-drug therapy, with follow-up care coordinated by the local health department, including a home health nurse experienced in administering DOT. Cultures were positive for Mycobacterium tuberculosis sensitive to all drugs tested. After his initial 2 months of 4-drug therapy, he completed 4 months of additional treatment with INH and RIF, given by DOT, and recovered completely. 

CORRESPONDENCE
Jeff Hall, MD, University of South Carolina Department of Family and Preventive Medicine, 3209 Colonial Drive, Columbia, SC 29203; jeff.hall@uscmed.sc.edu

CASE  › Mitchell J, age 62, comes to see you because he’s had a cough with increasing dyspnea for a month. Mr. J has never smoked but has type 2 diabetes mellitus. He also tells you that over the past month, he’s had occasional night sweats and has lost 8 pounds, although he’s not changed his diet. During the past week, he’s noticed blood-tinged sputum. Physical examination reveals a thin, chronically ill appearing man with an oral temperature of 100.6°F and mild tachypnea. You order a complete blood count, chest x-ray, and metabolic profile, administer a tuberculin skin test (TST), and initiate levofloxacin 500 mg/d for a presumed bacterial pneumonia. His lab work reveals mild leukocytosis and hyperglycemia, and the chest x-ray shows a left upper lobe infiltrate. The TST reaction—4 mm 50 hours after placement—was negative.

Mr. J returns a week later and says he feels worse. Your examination reveals worsened tachypnea, with tachycardia and crackles over the left upper lung fields.

How would you proceed with his care?

More people die of tuberculosis (TB) each year than any other infectious disease except human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. In 2013, an estimated 9 million people worldwide developed active TB and 1.5 million died of the disease.¹ Many of these deaths could have been prevented if patients had received a diagnosis and treatment during the latent phase (when the patient was infected, but had no active disease), or as soon as the patient developed active disease. In this article we describe treatment for both latent and active TB.

Before treating latent TB infection, first rule out active TB

Patients with latent tuberculosis infection (LTBI) have a 5% to 10% lifetime risk of developing active TB disease.² Treatment of LTBI can reduce this risk to 1% to 2%.³

Assess patients with latent TB infection for signs of active TB, such as weight loss, unexplained fever, night sweats, or hemoptysis. Although not the focus of this article, diagnosis of LTBI is made by using either a TST, in which the patient receives an intradermal injection of purified protein derivative and the size of the skin induration is measured 48 to 72 hours after administration, or an interferon-gamma release assay (IGRA), which requires a blood draw. After receiving a positive test result for LTBI, the next step is to rule out active TB.⁴ This is necessary because the primary treatment regimen for LTBI involves only one drug, whereas treating active TB with one drug is strongly associated with treatment failure and future resistance to that drug.⁵

To rule out active TB, perform a brief, problem-focused history and physical, and obtain a chest x-ray.⁴ Pertinent findings that suggest active disease include:

• any history of recent weight loss, unexplained fever, night sweats, cough or hemoptysis
• fever or any unexpected lung findings on physical exam
• any parenchymal infiltrates on chest x-ray. (Granulomas and scarring may be signs of previously healed TB infection, but do not indicate active TB.)

Any of these findings should prompt a further investigation to either confirm or definitively rule out active TB disease. In the absence of these findings, the physician may proceed with treatment for LTBI.

Latent TB infection treatment: Isoniazid alone, or another regimen?

The current preferred regimen for most patients with LTBI is 9 months of isoniazid (INH) 5 mg/kg/d (10 mg/kg/d in children) up to a maximum of 300 mg/d. This regimen has been recommended by the Centers for Disease Control and Prevention (CDC), the American Thoracic Society, and the Infectious Diseases Society of America.³ However, there are 3 other CDC-recommended LTBI treatment regimens that include INH, INH plus rifapentine (RPT), or rifampin (RIF) for 6, 3, or 4 months, respectively (TABLE 1).⁶ These other regimens may be considered under certain circumstances. For example, INH and rifapentine might be used to treat an otherwise healthy patient who has had recent exposure to an individual with active, contagious TB.

If the patient is pregnant. INH is a pregnancy category C drug. Treatment for LTBI during pregnancy is generally regarded as safe and should be strongly considered if the patient has risk factors for progression to active TB, such as a recent exposure to someone with active TB.⁷ In otherwise healthy patients, treatment for LTBI may be deferred until after delivery.

Take steps to avoid complications of drug therapy

Drug-induced hepatitis is the primary adverse effect of INH treatment. Risk increases with age, previous hepatic injury, or concomitant use of other hepatotoxic medications. The risk is very small (<0.1%) for healthy children but may be over 10% for adults with multiple risk factors.⁸ Hepatitis is generally preceded by asymptomatic elevation of liver function tests (LFTs), which is much more common than clinical hepatitis.

Baseline LFTs should be obtained in patients who:

• have underlying liver disease, such as hepatitis B or C⁹
• consume ≥2 alcoholic drinks daily or >5 drinks at a time on any occasion
• take other medications with potential hepatotoxicity, such as statins
• have HIV infection¹⁰
• are pregnant or postpartum.

If a patient being considered for INH treatment has not had serologic testing for HIV, hepatitis B, or hepatitis C, these tests should be done prior to initiating INH. LFTs should be monitored every 1 to 2 months during INH therapy for patients who have ≥1 of these conditions and normal baseline LFTs. If baseline transaminases are >3 times the upper limit of normal, treatment for LTBI should probably be withheld, though might be considered in those whose LFTs return to normal after withdrawal of a modifiable risk factor, such as alcohol or a statin medication.

Patients with latent TB infection who are receiving isoniazid should be monitored regularly for signs and symptoms of hepatitis. After beginning LTBI treatment, patients should be monitored regularly for signs and symptoms of hepatitis, including anorexia, nausea, abdominal pain, icterus, and dark urine, and LFTs performed if these develop. If during treatment transaminases increase to >3 times normal in a symptomatic patient (or >5 times normal in an asymptomatic patient), INH should be stopped and generally not resumed, even after LFTs return to normal. (Such patients would be considered to have partially treated LTBI, and their physicians should be alert to signs and symptoms of active TB, such as unexplained fever, weight loss, or blood-tinged sputum, during subsequent patient encounters.)

Peripheral neuropathy is a less common adverse effect of INH. It occurs in up to 2% of patients and is caused by interference with vitamin B6 (pyridoxine) metabolism. It can be prevented by supplementation with pyridoxine 25 to 50 mg/d. Vitamin B6, however, does not prevent INH-induced hepatotoxicity.

Noncompliance is a concern with INH therapy because treatment typically requires a 9-month course of daily medication.¹¹ Patients for whom compliance is likely to be an issue might be considered for a 3-month, 12-dose course of once-weekly, directly-observed therapy (DOT) with INH and RPT administered by a public health agency. (See “Which patients with TB should receive directly observed therapy?” on page 32.^12-14) A randomized, open-label trial involving nearly 8000 patients in 4 low-risk countries found this regimen was as effective as 9 months of self-administered INH.¹⁵ The CDC has published recommendations for using this regimen.¹⁶

Suspect active TB? Don’t wait for cultures to begin Tx

Unlike LTBI, for which the results of diagnostic testing are available within a few days, active TB is diagnosed by culture, which may take as long as 6 to 8 weeks. Don’t wait to receive culture results to initiate treatment in a patient you suspect may have active TB. However, if you suspect your patient has active TB, do not delay treatment while waiting for culture results, or defer treatment for a patient who has a negative acid-fast bacilli (AFB) smear or rapid nucleic acid amplification test.¹⁷ These 2 tests, which are routinely performed during TB cultures, look for other evidence of the presence of TB bacilli; they are not as accurate as cultures, but results are available within days. Likewise, a negative TST or IGRA should not prevent empiric treatment for active TB. Treatment for active TB should be begun empirically based on risk factors and clinical presentation, and can be modified or stopped if cultures are negative, the patient fails to improve, or an alternative diagnosis is found to explain the patient’s symptoms.

Rapid testing for evidence of active TB disease—as well as resistance to medications commonly used to treat TB—can be performed using newer modalities such as MODS (Microscopic-Observation Drug-Susceptibility)^18,19 or Xpert MTB/RIF²⁰ testing. However, these tests are not available in many hospitals, and culture and drug sensitivity testing remain the gold standard.²¹

CASE › Mr. J’s clinical history and chest x-ray findings are highly suggestive of active TB. It was not unreasonable to initially treat him for a bacterial pneumonia, although fluoroquinolones should be used cautiously in this setting, because they are one of the most effective second-line drugs for TB, and using them as a single agent will often invoke drug resistance. Because he failed to respond to treatment for bacterial pneumonia and his presentation suggests TB or another serious cause of nonresponsiveness to standard treatment for community-acquired pneumonia (CAP), you admit him to the hospital.

Treatment for active TB requires multiple drugs in 2 phases

While all family physicians should suspect active TB in appropriate clinical situations and be comfortable with obtaining cultures and initiating empiric treatment, most will want to seek consultation with an infectious disease (ID) specialist especially in the scenarios listed in TABLE 2.^5,22 Delayed or inappropriate treatment of active TB remains a major public health problem and cause of multidrug-resistant TB. Inappropriate treatment has been shown to be associated with a 27-fold increase in treatment failure.²³ TB treatment guidelines are available from the CDC,²⁴ World Health Organization,²⁵ and International Union Against Tuberculosis and Lung Disease.²⁶

In the initial phase of treatment for active TB, patients should begin 4 drugs—INH, RIF, EMB, and PZA—for 2 months. Appropriate treatment requires the use of multiple medications administered in 2 phases. In the initial phase, a patient with suspected TB should begin 4 drugs—usually INH, RIF, ethambutol (EMB), and pyrazinamide (PZA)—for 2 months.^1,2,27 The daily pediatric and adult doses and common adverse effects of these medications are summarized in TABLE 3.²⁸ Although most cases of TB can be adequately treated with 2 drugs to which the organism is susceptible, 4 drugs are used initially while awaiting drug sensitivity test results because of the risk of inadequately treating a strain of drug-resistant TB. Before beginning these medications, a chest x-ray, LFTs, HIV antibody test, hepatitis B and C serologies, a serum creatinine, and complete blood count should be obtained in all patients.⁵ If EMB is prescribed, the patient should also undergo testing for red-green color discrimination, because red-green color vision disturbance is a potential adverse effect of this medication.

All 4 drugs may be administered as a single daily dose, and may be taken together.²⁹ They are ordinarily given either daily for 8 weeks, or daily for 2 weeks followed by a twice-weekly schedule for the remaining 6 weeks in higher doses, although the twice-weekly dose of RIF is the same as the daily dose. All are pregnancy category C, although for active TB, the benefit of treatment is almost always greater than the potential harm.

The continuation phase of treatment starts at 8 weeks, when the results of initial cultures and drug sensitivity tests should be available to guide therapy. A second set of cultures and AFB smears is obtained at 8 weeks to document clearing of the initial infection and guide duration of the continuation phase. If the initial culture was positive for Mycobacterium tuberculosis and the organism was sensitive to both INH and RIF, these 2 drugs should be continued for another 4 months (for a total of 6 months of treatment). PZA and EMB may be stopped at 2 months if the organism is sensitive to both INH and RIF. Thus, for most patients with active TB, the standard regimen will be 4 drugs for 2 months, then 2 drugs for 4 months.²

When should the standard treatment regimen be modified?

If a patient with active TB has persistently positive cultures and cavitary disease on an initial chest x-ray, treatment should be extended to 9 months. If the second set of cultures obtained 2 months after beginning drug treatment is positive and there was cavitary disease on the initial chest x-ray, the continuation phase should be extended by 7 months (for a total of 9 months of treatment).³⁰ If a patient has either cavitary disease or persistently positive cultures (but not both), then the length of therapy is determined on an individual basis in consultation with an ID specialist.

Should a patient’s cultures show resistance to any of the first-line drugs, obtain consultation with an ID specialist. Treatment of multidrug-resistant TB (resistant to INH and RIF) and its subset, extensively drug-resistant TB (resistant to INH and RIF, plus any fluoroquinolone, plus either an aminoglycoside or capreomycin) requires prolonged courses of therapy with multiple drugs administered by DOT.^31,32

If at any point during treatment a patient shows clinical deterioration that’s believed to be due to a resurgence of his or her TB disease, obtain a new set of cultures and, in consultation with an ID specialist, add at least 2 drugs to which the patient has not been exposed. Never add only one drug to a failing regimen; active TB always requires 2 drugs to cure, and the patient may have developed resistance to all of the drugs he or she is currently receiving.

If initial cultures are negative for Mycobacterium tuberculosis but the patient responds to treatment, he or she is considered to have “culture-negative TB,” and should generally be continued on INH and RIF for 2 more months after completion of the initial treatment phase (for a total of 4 months of INH and RIF).³³

Remember to report. In the United States, active TB must be reported to your local health department, which can be invaluable in coordinating care and administering DOT.

CASE › In the hospital, Mr. J was placed in respiratory isolation, had prompt sputum cultures for TB, and was started on empiric treatment for active TB with INH, RIF, PZA, and EMB in standard doses. A search for other causes of nonresponsiveness to CAP showed no evidence of malignancy or HIV infection. He improved steadily and was discharged from the hospital after 2 weeks to complete 2 months of 4-drug therapy, with follow-up care coordinated by the local health department, including a home health nurse experienced in administering DOT. Cultures were positive for Mycobacterium tuberculosis sensitive to all drugs tested. After his initial 2 months of 4-drug therapy, he completed 4 months of additional treatment with INH and RIF, given by DOT, and recovered completely. 

CORRESPONDENCE
Jeff Hall, MD, University of South Carolina Department of Family and Preventive Medicine, 3209 Colonial Drive, Columbia, SC 29203; jeff.hall@uscmed.sc.edu

CASE  › Mitchell J, age 62, comes to see you because he’s had a cough with increasing dyspnea for a month. Mr. J has never smoked but has type 2 diabetes mellitus. He also tells you that over the past month, he’s had occasional night sweats and has lost 8 pounds, although he’s not changed his diet. During the past week, he’s noticed blood-tinged sputum. Physical examination reveals a thin, chronically ill appearing man with an oral temperature of 100.6°F and mild tachypnea. You order a complete blood count, chest x-ray, and metabolic profile, administer a tuberculin skin test (TST), and initiate levofloxacin 500 mg/d for a presumed bacterial pneumonia. His lab work reveals mild leukocytosis and hyperglycemia, and the chest x-ray shows a left upper lobe infiltrate. The TST reaction—4 mm 50 hours after placement—was negative.

Mr. J returns a week later and says he feels worse. Your examination reveals worsened tachypnea, with tachycardia and crackles over the left upper lung fields.

How would you proceed with his care?

More people die of tuberculosis (TB) each year than any other infectious disease except human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. In 2013, an estimated 9 million people worldwide developed active TB and 1.5 million died of the disease.¹ Many of these deaths could have been prevented if patients had received a diagnosis and treatment during the latent phase (when the patient was infected, but had no active disease), or as soon as the patient developed active disease. In this article we describe treatment for both latent and active TB.

Before treating latent TB infection, first rule out active TB

Patients with latent tuberculosis infection (LTBI) have a 5% to 10% lifetime risk of developing active TB disease.² Treatment of LTBI can reduce this risk to 1% to 2%.³

Assess patients with latent TB infection for signs of active TB, such as weight loss, unexplained fever, night sweats, or hemoptysis. Although not the focus of this article, diagnosis of LTBI is made by using either a TST, in which the patient receives an intradermal injection of purified protein derivative and the size of the skin induration is measured 48 to 72 hours after administration, or an interferon-gamma release assay (IGRA), which requires a blood draw. After receiving a positive test result for LTBI, the next step is to rule out active TB.⁴ This is necessary because the primary treatment regimen for LTBI involves only one drug, whereas treating active TB with one drug is strongly associated with treatment failure and future resistance to that drug.⁵

To rule out active TB, perform a brief, problem-focused history and physical, and obtain a chest x-ray.⁴ Pertinent findings that suggest active disease include:

• any history of recent weight loss, unexplained fever, night sweats, cough or hemoptysis
• fever or any unexpected lung findings on physical exam
• any parenchymal infiltrates on chest x-ray. (Granulomas and scarring may be signs of previously healed TB infection, but do not indicate active TB.)

Any of these findings should prompt a further investigation to either confirm or definitively rule out active TB disease. In the absence of these findings, the physician may proceed with treatment for LTBI.

Latent TB infection treatment: Isoniazid alone, or another regimen?

The current preferred regimen for most patients with LTBI is 9 months of isoniazid (INH) 5 mg/kg/d (10 mg/kg/d in children) up to a maximum of 300 mg/d. This regimen has been recommended by the Centers for Disease Control and Prevention (CDC), the American Thoracic Society, and the Infectious Diseases Society of America.³ However, there are 3 other CDC-recommended LTBI treatment regimens that include INH, INH plus rifapentine (RPT), or rifampin (RIF) for 6, 3, or 4 months, respectively (TABLE 1).⁶ These other regimens may be considered under certain circumstances. For example, INH and rifapentine might be used to treat an otherwise healthy patient who has had recent exposure to an individual with active, contagious TB.

If the patient is pregnant. INH is a pregnancy category C drug. Treatment for LTBI during pregnancy is generally regarded as safe and should be strongly considered if the patient has risk factors for progression to active TB, such as a recent exposure to someone with active TB.⁷ In otherwise healthy patients, treatment for LTBI may be deferred until after delivery.

Take steps to avoid complications of drug therapy

Drug-induced hepatitis is the primary adverse effect of INH treatment. Risk increases with age, previous hepatic injury, or concomitant use of other hepatotoxic medications. The risk is very small (<0.1%) for healthy children but may be over 10% for adults with multiple risk factors.⁸ Hepatitis is generally preceded by asymptomatic elevation of liver function tests (LFTs), which is much more common than clinical hepatitis.

Baseline LFTs should be obtained in patients who:

• have underlying liver disease, such as hepatitis B or C⁹
• consume ≥2 alcoholic drinks daily or >5 drinks at a time on any occasion
• take other medications with potential hepatotoxicity, such as statins
• have HIV infection¹⁰
• are pregnant or postpartum.

If a patient being considered for INH treatment has not had serologic testing for HIV, hepatitis B, or hepatitis C, these tests should be done prior to initiating INH. LFTs should be monitored every 1 to 2 months during INH therapy for patients who have ≥1 of these conditions and normal baseline LFTs. If baseline transaminases are >3 times the upper limit of normal, treatment for LTBI should probably be withheld, though might be considered in those whose LFTs return to normal after withdrawal of a modifiable risk factor, such as alcohol or a statin medication.

Patients with latent TB infection who are receiving isoniazid should be monitored regularly for signs and symptoms of hepatitis. After beginning LTBI treatment, patients should be monitored regularly for signs and symptoms of hepatitis, including anorexia, nausea, abdominal pain, icterus, and dark urine, and LFTs performed if these develop. If during treatment transaminases increase to >3 times normal in a symptomatic patient (or >5 times normal in an asymptomatic patient), INH should be stopped and generally not resumed, even after LFTs return to normal. (Such patients would be considered to have partially treated LTBI, and their physicians should be alert to signs and symptoms of active TB, such as unexplained fever, weight loss, or blood-tinged sputum, during subsequent patient encounters.)

Peripheral neuropathy is a less common adverse effect of INH. It occurs in up to 2% of patients and is caused by interference with vitamin B6 (pyridoxine) metabolism. It can be prevented by supplementation with pyridoxine 25 to 50 mg/d. Vitamin B6, however, does not prevent INH-induced hepatotoxicity.

Noncompliance is a concern with INH therapy because treatment typically requires a 9-month course of daily medication.¹¹ Patients for whom compliance is likely to be an issue might be considered for a 3-month, 12-dose course of once-weekly, directly-observed therapy (DOT) with INH and RPT administered by a public health agency. (See “Which patients with TB should receive directly observed therapy?” on page 32.^12-14) A randomized, open-label trial involving nearly 8000 patients in 4 low-risk countries found this regimen was as effective as 9 months of self-administered INH.¹⁵ The CDC has published recommendations for using this regimen.¹⁶

Suspect active TB? Don’t wait for cultures to begin Tx

Unlike LTBI, for which the results of diagnostic testing are available within a few days, active TB is diagnosed by culture, which may take as long as 6 to 8 weeks. Don’t wait to receive culture results to initiate treatment in a patient you suspect may have active TB. However, if you suspect your patient has active TB, do not delay treatment while waiting for culture results, or defer treatment for a patient who has a negative acid-fast bacilli (AFB) smear or rapid nucleic acid amplification test.¹⁷ These 2 tests, which are routinely performed during TB cultures, look for other evidence of the presence of TB bacilli; they are not as accurate as cultures, but results are available within days. Likewise, a negative TST or IGRA should not prevent empiric treatment for active TB. Treatment for active TB should be begun empirically based on risk factors and clinical presentation, and can be modified or stopped if cultures are negative, the patient fails to improve, or an alternative diagnosis is found to explain the patient’s symptoms.

Rapid testing for evidence of active TB disease—as well as resistance to medications commonly used to treat TB—can be performed using newer modalities such as MODS (Microscopic-Observation Drug-Susceptibility)^18,19 or Xpert MTB/RIF²⁰ testing. However, these tests are not available in many hospitals, and culture and drug sensitivity testing remain the gold standard.²¹

CASE › Mr. J’s clinical history and chest x-ray findings are highly suggestive of active TB. It was not unreasonable to initially treat him for a bacterial pneumonia, although fluoroquinolones should be used cautiously in this setting, because they are one of the most effective second-line drugs for TB, and using them as a single agent will often invoke drug resistance. Because he failed to respond to treatment for bacterial pneumonia and his presentation suggests TB or another serious cause of nonresponsiveness to standard treatment for community-acquired pneumonia (CAP), you admit him to the hospital.

Treatment for active TB requires multiple drugs in 2 phases