Illustrative case

The parents of a 6-month-old girl with moderate plagiocephaly bring their daughter in for a well child visit. Previously, you had recommended that the parents increase “tummy time” when the baby is awake, change her position in bed, and monitor the progression of the condition. They do not feel these interventions have made a difference in the shape of their daughter’s skull, and ask about using a helmet to help correct the deformity. How would you counsel them?

Positional skull deformity (PSD) is a common problem of infancy. Approximately 45% of infants ages 7 to 12 weeks are estimated to have PSD, although three-quarters of them have mild cases.² The incidence of PSD began to increase in 1992 after the American Academy of Pediatrics (AAP) introduced its “Back to Sleep” campaign, which encouraged parents to place their infants on their back at bedtime to reduce sudden infant death syndrome.³

There are 2 common forms of PSD: plagiocephaly, and brachycephaly.¹ Plagiocephaly is unilateral occipital flattening, which may be accompanied by ipsilateral forehead prominence and asymmetrical ears. Brachycephaly is symmetric flattening of the back of the head, which can lead to prominence of the temporal areas, making the head appear wide. Children with severe plagiocephaly have a misshapen, asymmetric skull, while children with brachycephaly have a flattened skull. The cranial sutures remain open in both kinds of PSD.

Evaluating infants for PSD is part of the routine physical exam, and when the condition is noted, the exam should also differentiate PSD from other causes of skull deformity, such as craniosynostosis. Infants and preschool-aged children with PSD may score lower on developmental testing than children without skull deformity.⁴ However, these differences are small and inconsistent (2-3 points on a 100-point scale).⁴ Skull deformity persists into adolescence in only 1% to 2% of patients.⁵

Neither the AAP nor the American Academy of Family Physicians has a guideline or consensus statement on PSD. Helmets are intended to correct PSD by fitting closely to an infant’s head but allowing room for the skill to grow at the flattened area.¹ A 2011 clinical report by Laughlin et al⁶ recommended against using helmets for infants with mild to moderate deformities, but stated that there was little evidence of harm. Earlier studies have suggested that physical therapy might be effective for plagiocephaly caught early (7 and 8 weeks of age).^7,8 Biggs⁹ suggested considering helmet therapy for infants whose cranial sutures remain open and who do not respond to 4 to 8 weeks of physical therapy for PSD. van Wijk et al¹ conducted an RCT to explore the risks and benefits of helmet therapy for children with PSD.

STUDY SUMMARY: Helmets for infants: No help and some harm

This single-blind RCT of 84 infants ages 5 or 6 months with moderate or severe PSD compared helmet therapy (n=42) to no intervention (allowing natural growth, n=42). Infants were excluded if they had very severe PSD or skull deformity from another cause, such as torticollis or craniosynostosis.

Infants in the helmet therapy group received a custom-made helmet that they wore 23 hours a day until they were a year old, with regular evaluation by an orthotist and modification of the helmet as necessary to allow skull growth. The control group had usual care and no helmet.

At the end of the study, improvement in skull shape was almost the same in the helmet therapy and control groups. The primary outcome was improvement in skull shape at age 24 months as measured by the oblique diameter difference index (ODDI), a unitless measurement of plagiocephaly calculated by taking the ratio of measures of 2 dimensions of cranial diameter, and the cranioproportional index (CPI), a similar measurement of brachycephaly. Infants were considered fully recovered if they achieved an ODDI score of <104% and a CPI score of <90%. These scores indicate a normal head shape; higher scores indicate worse PSD.

At the end of the study, the reduction in ODDI and CPI scores was almost the same in both  the helmet therapy and the control groups. Ten children in the helmet group (26%) and 9 in the control group (23%) experienced complete resolution of their PSD (P=.74).

Secondary outcomes included infant motor development, infant quality of life, parental satisfaction with the shape of their infant’s head, and parental anxiety. Both groups were similar in infant motor development, infant quality of life, and parental satisfaction. Parental anxiety was assessed using the Spielberger State-Trait Anxiety Inventory (scores range from 20-80; a higher score indicates greater anxiety). There was less parental anxiety in the helmet therapy group: (-3.9; 95% confidence interval, -7.5 to -0.2; P=.04).

All parents of infants in the helmet therapy group reported at least one adverse effect from the intervention. These effects included skin irritation (96%), bad helmet odor (76%), pain associated with the helmet (33%), and feeling hindered from cuddling their child (77%).

WHAT’S NEW: RCT provides stronger evidence that helmets are not effective

This is the first RCT that assessed helmet therapy for PSD in children.¹ Before this, the evidence on helmets for PSD had been obtained mainly from observational or poorly designed studies with significant flaws.⁶ This study by van Wijk et al¹ included objective measurement of skull deformity, along with clinically meaningful outcomes of parental satisfaction, motor development, and parental anxiety. It also found that helmet therapy was significantly more expensive than care that focused on waiting for PSD to resolve on its own ($1935 vs $196, respectively).¹

CAVEATS: Results may not apply to all infants with skull deformity

These findings do not apply to infants with very severe cases of PSD or those with skull deformity due to secondary causes, such as craniosynostosis, who were excluded from this study.¹ In addition, this is the only RCT to date that has assessed helmet use in PSD, so it is possible that future studies will find helmets are effective.

CHALLENGES TO IMPLEMENTATION: Parents may find this evidence hard to accept

To appropriately implement this recommendation, a family physician must be comfortable making the assessment of mild, moderate, severe, or very severe PSD. Referral to physical therapy might be appropriate for infants with very severe PSD.

If another physician or physical therapist recommends helmet therapy—or if a parent requests it—explaining the findings of this study may be challenging. We believe that the reduction in parental anxiety in the helmet group likely occurred because the parents believed that the helmet would accelerate the normal reshaping of the skull shape that occurs spontaneously in almost all infants with PSD. Since this study shows that helmets don’t help correct skull deformities, parents can be assured that a helmet is unnecessary, costly, and causes adverse effects.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative case

The parents of a 6-month-old girl with moderate plagiocephaly bring their daughter in for a well child visit. Previously, you had recommended that the parents increase “tummy time” when the baby is awake, change her position in bed, and monitor the progression of the condition. They do not feel these interventions have made a difference in the shape of their daughter’s skull, and ask about using a helmet to help correct the deformity. How would you counsel them?

Positional skull deformity (PSD) is a common problem of infancy. Approximately 45% of infants ages 7 to 12 weeks are estimated to have PSD, although three-quarters of them have mild cases.² The incidence of PSD began to increase in 1992 after the American Academy of Pediatrics (AAP) introduced its “Back to Sleep” campaign, which encouraged parents to place their infants on their back at bedtime to reduce sudden infant death syndrome.³

There are 2 common forms of PSD: plagiocephaly, and brachycephaly.¹ Plagiocephaly is unilateral occipital flattening, which may be accompanied by ipsilateral forehead prominence and asymmetrical ears. Brachycephaly is symmetric flattening of the back of the head, which can lead to prominence of the temporal areas, making the head appear wide. Children with severe plagiocephaly have a misshapen, asymmetric skull, while children with brachycephaly have a flattened skull. The cranial sutures remain open in both kinds of PSD.

Evaluating infants for PSD is part of the routine physical exam, and when the condition is noted, the exam should also differentiate PSD from other causes of skull deformity, such as craniosynostosis. Infants and preschool-aged children with PSD may score lower on developmental testing than children without skull deformity.⁴ However, these differences are small and inconsistent (2-3 points on a 100-point scale).⁴ Skull deformity persists into adolescence in only 1% to 2% of patients.⁵

Neither the AAP nor the American Academy of Family Physicians has a guideline or consensus statement on PSD. Helmets are intended to correct PSD by fitting closely to an infant’s head but allowing room for the skill to grow at the flattened area.¹ A 2011 clinical report by Laughlin et al⁶ recommended against using helmets for infants with mild to moderate deformities, but stated that there was little evidence of harm. Earlier studies have suggested that physical therapy might be effective for plagiocephaly caught early (7 and 8 weeks of age).^7,8 Biggs⁹ suggested considering helmet therapy for infants whose cranial sutures remain open and who do not respond to 4 to 8 weeks of physical therapy for PSD. van Wijk et al¹ conducted an RCT to explore the risks and benefits of helmet therapy for children with PSD.

STUDY SUMMARY: Helmets for infants: No help and some harm

This single-blind RCT of 84 infants ages 5 or 6 months with moderate or severe PSD compared helmet therapy (n=42) to no intervention (allowing natural growth, n=42). Infants were excluded if they had very severe PSD or skull deformity from another cause, such as torticollis or craniosynostosis.

Infants in the helmet therapy group received a custom-made helmet that they wore 23 hours a day until they were a year old, with regular evaluation by an orthotist and modification of the helmet as necessary to allow skull growth. The control group had usual care and no helmet.

At the end of the study, improvement in skull shape was almost the same in the helmet therapy and control groups. The primary outcome was improvement in skull shape at age 24 months as measured by the oblique diameter difference index (ODDI), a unitless measurement of plagiocephaly calculated by taking the ratio of measures of 2 dimensions of cranial diameter, and the cranioproportional index (CPI), a similar measurement of brachycephaly. Infants were considered fully recovered if they achieved an ODDI score of <104% and a CPI score of <90%. These scores indicate a normal head shape; higher scores indicate worse PSD.

At the end of the study, the reduction in ODDI and CPI scores was almost the same in both  the helmet therapy and the control groups. Ten children in the helmet group (26%) and 9 in the control group (23%) experienced complete resolution of their PSD (P=.74).

Secondary outcomes included infant motor development, infant quality of life, parental satisfaction with the shape of their infant’s head, and parental anxiety. Both groups were similar in infant motor development, infant quality of life, and parental satisfaction. Parental anxiety was assessed using the Spielberger State-Trait Anxiety Inventory (scores range from 20-80; a higher score indicates greater anxiety). There was less parental anxiety in the helmet therapy group: (-3.9; 95% confidence interval, -7.5 to -0.2; P=.04).

All parents of infants in the helmet therapy group reported at least one adverse effect from the intervention. These effects included skin irritation (96%), bad helmet odor (76%), pain associated with the helmet (33%), and feeling hindered from cuddling their child (77%).

WHAT’S NEW: RCT provides stronger evidence that helmets are not effective

This is the first RCT that assessed helmet therapy for PSD in children.¹ Before this, the evidence on helmets for PSD had been obtained mainly from observational or poorly designed studies with significant flaws.⁶ This study by van Wijk et al¹ included objective measurement of skull deformity, along with clinically meaningful outcomes of parental satisfaction, motor development, and parental anxiety. It also found that helmet therapy was significantly more expensive than care that focused on waiting for PSD to resolve on its own ($1935 vs $196, respectively).¹

CAVEATS: Results may not apply to all infants with skull deformity

These findings do not apply to infants with very severe cases of PSD or those with skull deformity due to secondary causes, such as craniosynostosis, who were excluded from this study.¹ In addition, this is the only RCT to date that has assessed helmet use in PSD, so it is possible that future studies will find helmets are effective.

CHALLENGES TO IMPLEMENTATION: Parents may find this evidence hard to accept

To appropriately implement this recommendation, a family physician must be comfortable making the assessment of mild, moderate, severe, or very severe PSD. Referral to physical therapy might be appropriate for infants with very severe PSD.

If another physician or physical therapist recommends helmet therapy—or if a parent requests it—explaining the findings of this study may be challenging. We believe that the reduction in parental anxiety in the helmet group likely occurred because the parents believed that the helmet would accelerate the normal reshaping of the skull shape that occurs spontaneously in almost all infants with PSD. Since this study shows that helmets don’t help correct skull deformities, parents can be assured that a helmet is unnecessary, costly, and causes adverse effects.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative case

The parents of a 6-month-old girl with moderate plagiocephaly bring their daughter in for a well child visit. Previously, you had recommended that the parents increase “tummy time” when the baby is awake, change her position in bed, and monitor the progression of the condition. They do not feel these interventions have made a difference in the shape of their daughter’s skull, and ask about using a helmet to help correct the deformity. How would you counsel them?

Positional skull deformity (PSD) is a common problem of infancy. Approximately 45% of infants ages 7 to 12 weeks are estimated to have PSD, although three-quarters of them have mild cases.² The incidence of PSD began to increase in 1992 after the American Academy of Pediatrics (AAP) introduced its “Back to Sleep” campaign, which encouraged parents to place their infants on their back at bedtime to reduce sudden infant death syndrome.³

There are 2 common forms of PSD: plagiocephaly, and brachycephaly.¹ Plagiocephaly is unilateral occipital flattening, which may be accompanied by ipsilateral forehead prominence and asymmetrical ears. Brachycephaly is symmetric flattening of the back of the head, which can lead to prominence of the temporal areas, making the head appear wide. Children with severe plagiocephaly have a misshapen, asymmetric skull, while children with brachycephaly have a flattened skull. The cranial sutures remain open in both kinds of PSD.

Evaluating infants for PSD is part of the routine physical exam, and when the condition is noted, the exam should also differentiate PSD from other causes of skull deformity, such as craniosynostosis. Infants and preschool-aged children with PSD may score lower on developmental testing than children without skull deformity.⁴ However, these differences are small and inconsistent (2-3 points on a 100-point scale).⁴ Skull deformity persists into adolescence in only 1% to 2% of patients.⁵

Neither the AAP nor the American Academy of Family Physicians has a guideline or consensus statement on PSD. Helmets are intended to correct PSD by fitting closely to an infant’s head but allowing room for the skill to grow at the flattened area.¹ A 2011 clinical report by Laughlin et al⁶ recommended against using helmets for infants with mild to moderate deformities, but stated that there was little evidence of harm. Earlier studies have suggested that physical therapy might be effective for plagiocephaly caught early (7 and 8 weeks of age).^7,8 Biggs⁹ suggested considering helmet therapy for infants whose cranial sutures remain open and who do not respond to 4 to 8 weeks of physical therapy for PSD. van Wijk et al¹ conducted an RCT to explore the risks and benefits of helmet therapy for children with PSD.

STUDY SUMMARY: Helmets for infants: No help and some harm

This single-blind RCT of 84 infants ages 5 or 6 months with moderate or severe PSD compared helmet therapy (n=42) to no intervention (allowing natural growth, n=42). Infants were excluded if they had very severe PSD or skull deformity from another cause, such as torticollis or craniosynostosis.

Infants in the helmet therapy group received a custom-made helmet that they wore 23 hours a day until they were a year old, with regular evaluation by an orthotist and modification of the helmet as necessary to allow skull growth. The control group had usual care and no helmet.

At the end of the study, improvement in skull shape was almost the same in the helmet therapy and control groups. The primary outcome was improvement in skull shape at age 24 months as measured by the oblique diameter difference index (ODDI), a unitless measurement of plagiocephaly calculated by taking the ratio of measures of 2 dimensions of cranial diameter, and the cranioproportional index (CPI), a similar measurement of brachycephaly. Infants were considered fully recovered if they achieved an ODDI score of <104% and a CPI score of <90%. These scores indicate a normal head shape; higher scores indicate worse PSD.

At the end of the study, the reduction in ODDI and CPI scores was almost the same in both  the helmet therapy and the control groups. Ten children in the helmet group (26%) and 9 in the control group (23%) experienced complete resolution of their PSD (P=.74).

Secondary outcomes included infant motor development, infant quality of life, parental satisfaction with the shape of their infant’s head, and parental anxiety. Both groups were similar in infant motor development, infant quality of life, and parental satisfaction. Parental anxiety was assessed using the Spielberger State-Trait Anxiety Inventory (scores range from 20-80; a higher score indicates greater anxiety). There was less parental anxiety in the helmet therapy group: (-3.9; 95% confidence interval, -7.5 to -0.2; P=.04).

All parents of infants in the helmet therapy group reported at least one adverse effect from the intervention. These effects included skin irritation (96%), bad helmet odor (76%), pain associated with the helmet (33%), and feeling hindered from cuddling their child (77%).

WHAT’S NEW: RCT provides stronger evidence that helmets are not effective

This is the first RCT that assessed helmet therapy for PSD in children.¹ Before this, the evidence on helmets for PSD had been obtained mainly from observational or poorly designed studies with significant flaws.⁶ This study by van Wijk et al¹ included objective measurement of skull deformity, along with clinically meaningful outcomes of parental satisfaction, motor development, and parental anxiety. It also found that helmet therapy was significantly more expensive than care that focused on waiting for PSD to resolve on its own ($1935 vs $196, respectively).¹

CAVEATS: Results may not apply to all infants with skull deformity

These findings do not apply to infants with very severe cases of PSD or those with skull deformity due to secondary causes, such as craniosynostosis, who were excluded from this study.¹ In addition, this is the only RCT to date that has assessed helmet use in PSD, so it is possible that future studies will find helmets are effective.

CHALLENGES TO IMPLEMENTATION: Parents may find this evidence hard to accept

To appropriately implement this recommendation, a family physician must be comfortable making the assessment of mild, moderate, severe, or very severe PSD. Referral to physical therapy might be appropriate for infants with very severe PSD.

If another physician or physical therapist recommends helmet therapy—or if a parent requests it—explaining the findings of this study may be challenging. We believe that the reduction in parental anxiety in the helmet group likely occurred because the parents believed that the helmet would accelerate the normal reshaping of the skull shape that occurs spontaneously in almost all infants with PSD. Since this study shows that helmets don’t help correct skull deformities, parents can be assured that a helmet is unnecessary, costly, and causes adverse effects.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

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; [email protected]

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; [email protected]

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; [email protected]

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).

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 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).

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 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).

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 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; [email protected]

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; [email protected]

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; [email protected]

ANSWER: D

Critique

The presentation is one of intermittent solid food dysphagia in the setting of frequent heartburn in a young white male. The differential diagnosis includes reflux esophagitis and peptic stricture, as well as eosinophilic esophagitis. Sometimes, the two conditions overlap. Empiric proton pump inhibitor therapy is of value in clarifying the diagnosis of gastroesophageal reflux disease in patients with typical symptoms of heartburn and regurgitation. This is because the likelihood of gastroesophageal reflux disease is very high in patients with typical reflux symptoms. However, in this setting eosinophilic esophagitis needs to be excluded. So the optimal approach is to initiate proton pump inhibitor therapy, and then inspect and biopsy the esophagus. Treatments specific for eosinophilic esophagitis (topical fluticasone, montelukast) will only be indicated if the diagnosis of eosinophilic esophagitis is confirmed.

Prednisone is not utilized often orally for the management of eosinophilic esophagitis. Baclofen, a GABA-B receptor agonist, has been demonstrated to reduce the frequency of transient lower esophageal sphincter relaxations and improve residual symptoms in patients on PPI therapy.

ANSWER: D

Critique

The presentation is one of intermittent solid food dysphagia in the setting of frequent heartburn in a young white male. The differential diagnosis includes reflux esophagitis and peptic stricture, as well as eosinophilic esophagitis. Sometimes, the two conditions overlap. Empiric proton pump inhibitor therapy is of value in clarifying the diagnosis of gastroesophageal reflux disease in patients with typical symptoms of heartburn and regurgitation. This is because the likelihood of gastroesophageal reflux disease is very high in patients with typical reflux symptoms. However, in this setting eosinophilic esophagitis needs to be excluded. So the optimal approach is to initiate proton pump inhibitor therapy, and then inspect and biopsy the esophagus. Treatments specific for eosinophilic esophagitis (topical fluticasone, montelukast) will only be indicated if the diagnosis of eosinophilic esophagitis is confirmed.

Prednisone is not utilized often orally for the management of eosinophilic esophagitis. Baclofen, a GABA-B receptor agonist, has been demonstrated to reduce the frequency of transient lower esophageal sphincter relaxations and improve residual symptoms in patients on PPI therapy.

ANSWER: D

Critique

The presentation is one of intermittent solid food dysphagia in the setting of frequent heartburn in a young white male. The differential diagnosis includes reflux esophagitis and peptic stricture, as well as eosinophilic esophagitis. Sometimes, the two conditions overlap. Empiric proton pump inhibitor therapy is of value in clarifying the diagnosis of gastroesophageal reflux disease in patients with typical symptoms of heartburn and regurgitation. This is because the likelihood of gastroesophageal reflux disease is very high in patients with typical reflux symptoms. However, in this setting eosinophilic esophagitis needs to be excluded. So the optimal approach is to initiate proton pump inhibitor therapy, and then inspect and biopsy the esophagus. Treatments specific for eosinophilic esophagitis (topical fluticasone, montelukast) will only be indicated if the diagnosis of eosinophilic esophagitis is confirmed.

Prednisone is not utilized often orally for the management of eosinophilic esophagitis. Baclofen, a GABA-B receptor agonist, has been demonstrated to reduce the frequency of transient lower esophageal sphincter relaxations and improve residual symptoms in patients on PPI therapy.

ANSWER: D

Critique

Villous blunting is not specific to celiac disease. In this case, the patient’s history supports a diagnosis of common variable immunodeficiency (CVID), which is characterized by low levels of two Ig classes and recurrent infections. The infections most commonly involve the upper and lower respiratory tract.

Chronic diarrhea is seen in 40%-60% of patients and may lead to malabsorption. Diarrhea can be the result of infections (most commonly Salmonella, Campylobacter, Clostridium difficile, and Giardia lamblia), inflammatory disorders, or malignancy. Biopsies reveal villous blunting similar to that seen in celiac disease. Unlike celiac disease, however, the biopsies lack plasma cells. These patients also differ from those with celiac disease in that their celiac serologies are negative.

ANSWER: D

Critique

Villous blunting is not specific to celiac disease. In this case, the patient’s history supports a diagnosis of common variable immunodeficiency (CVID), which is characterized by low levels of two Ig classes and recurrent infections. The infections most commonly involve the upper and lower respiratory tract.

Chronic diarrhea is seen in 40%-60% of patients and may lead to malabsorption. Diarrhea can be the result of infections (most commonly Salmonella, Campylobacter, Clostridium difficile, and Giardia lamblia), inflammatory disorders, or malignancy. Biopsies reveal villous blunting similar to that seen in celiac disease. Unlike celiac disease, however, the biopsies lack plasma cells. These patients also differ from those with celiac disease in that their celiac serologies are negative.

ANSWER: D

Critique

Villous blunting is not specific to celiac disease. In this case, the patient’s history supports a diagnosis of common variable immunodeficiency (CVID), which is characterized by low levels of two Ig classes and recurrent infections. The infections most commonly involve the upper and lower respiratory tract.

Chronic diarrhea is seen in 40%-60% of patients and may lead to malabsorption. Diarrhea can be the result of infections (most commonly Salmonella, Campylobacter, Clostridium difficile, and Giardia lamblia), inflammatory disorders, or malignancy. Biopsies reveal villous blunting similar to that seen in celiac disease. Unlike celiac disease, however, the biopsies lack plasma cells. These patients also differ from those with celiac disease in that their celiac serologies are negative.

THE CASE

A 6-year-old girl was brought to the emergency department (ED) by her mother after the child had bumped her head while playing. While the physician examined the child’s head, the mother remarked that her daughter had recently developed bruises that appeared suddenly and only after minor, if any, known trauma. The ED physician determined that the child’s bump to the head was nothing to worry about, attributed the bruising to the child being a “healthy, active 6-year-old,” and sent her home.

Two days later the child was brought to our office because the mother was still concerned about her daughter’s easy bruising. The mother pointed out ecchymosis scattered across her daughter’s extremities and torso. The child denied any pain or other complaints, including any active or recurrent bleeding. Upon further questioning, the mother mentioned that her daughter had recovered from a cold-like illness several weeks earlier.

THE DIAGNOSIS

We ordered a complete blood count (CBC) and peripheral smear, which were normal except for the platelet count, which was 7000/mcL (normal, 150,000-450,000/mcL). Based on the child’s easy bruising and isolated thrombocytopenia, we diagnosed immune thrombocytopenia, which is also known as idiopathic thrombocytopenic purpura (ITP).

DISCUSSION

In ITP, autoantibodies are directed against platelets, leading to their sequestration and destruction in the spleen and a resultant drop in platelet count.¹ Children with ITP typically present between the ages of 2 and 10 years, with a peak incidence between 2 and 5 years.² The incidence is estimated to be as high as 8 per 100,000 children.³ However, this estimate primarily reflects symptomatic children, and the true incidence of childhood ITP may be much higher because asymptomatic children may not be brought in to see a doctor. For the majority of patients, ITP resolves within 3 months. However, for 20% to 30% of patients, thrombocytopenia will last beyond 6 months, with or without treatment.⁴ In 1% of cases, patients will have a recurrence of ITP.³

In addition to easy bruising, nearly all patients who present with possible ITP will complain of cutaneous bleeding, typically a nose bleed or bleeding in the oral cavity.² Upon questioning, 60% of patients will report a history of recent infection.⁴ Not surprisingly, bleeding severity correlates inversely with platelet count; severe bleeding is seen in patients with a platelet count <10,000/mcL.

While rare, the more worrisome complications include intracranial hemorrhage, with an incidence of 0.1% to 0.8%, and other serious hemorrhages that would require transfusion, with an estimated incidence of 2.9%.²

Vast differential seen in child bruising

When a child presents with bruising, perform a thorough history, including birth and prenatal course, as well as a physical to exclude other potential causes, such as physical abuse, use of herbal remedies or other natural supplements that may not be disclosed as medication, or even environmental exposure. When bruising is present in a child who has isolated thrombocytopenia, the diagnosis of ITP may be straightforward. However, many conditions may share thrombocytopenia in their disease process and should be considered in the differential diagnosis of a child who you suspect may have ITP.

Suspect physical abuse in a bruised child who does not have thrombocytopenia, whose mood is flat or depressed, or who has experienced recurrent injuries or bruising.

Leukemia, particularly acute lymphoblastic leukemia (ALL), the predominant leukemia found in children, should be ruled out, as well. Symptoms that may distinguish a child with ALL from one with ITP include fever, weight loss, and joint pain, as well as signs such as lymphadenopathy, hepatosplenomegaly, anemia, and leukocytosis. A peripheral smear may be ordered to help confirm or exclude a diagnosis of ALL should any of the above be present in a child with thrombocytopenia.⁵ It may show lymphoblasts and/or atypical cells in a patient with ALL.⁵

Infections should also be included in a differential when a patient is suspected of having ITP, particularly if he or she has systemic symptoms. Viral infections that may cause thrombocytopenia include mononucleosis, dengue virus, human herpesvirus-6, and human immunodeficiency virus.^6,7

The incidence of ITP may be higher during the winter months, when infections are more common. ITP often follows an infection, and the incidence of ITP may be higher during winter months, when infections are more common. However, infection may not always be the cause of ITP. Sepsis may also lead to thrombocytopenia, but a child with sepsis would present very differently from a child who has only ITP. A septic child would present acutely ill with signs and symptoms of severe systemic illness, such as high fever, altered mental status, tachycardia, pallor, diaphoresis, and hypotension.

Drug-induced thrombocytopenia (DIT) should be considered in any child who is taking or recently took a medication that may cause thrombocytopenia. Medications that can cause thrombocytopenia include heparin, quinine, vancomycin, trimethoprim-sulfamethoxazole, rifampin, carbamazepine, phenytoin, piperacillin, linezolid, and valproic acid.⁸ The measles, mumps, and rubella vaccine also can cause thrombocytopenia.⁸ A careful medication history may determine if the child is at risk for DIT.

To narrow the differential, obtain a CBC and peripheral smear when evaluating a patient you suspect may have ITP⁵ (strength of recommendation [SOR]: A). A CBC will determine the patient’s platelet count and a peripheral smear should be obtained to exclude other possible diagnoses.⁵

If there are any questions regarding the results of a peripheral smear, it may be necessary to perform a bone marrow aspiration. This, however, is not usually necessary in an otherwise typical case of ITP.⁹ Bone marrow aspiration may, however, be necessary to reevaluate the initial diagnosis for a child who does not respond to treatment for ITP.

Corticosteroids, IVIg are usually effective

To start ITP treatment, limit the patient’s risk of further injury or bleeding by stopping NSAIDs and ending participation in contact sports. The first step in treating a patient with ITP is to limit the risk of further injury or bleeding, by stopping nonsteroidal anti-inflammatory drugs or ending participation in contact sports^2,9 (SOR: C). The next step is to determine if pharmacologic therapy is warranted.

Medication, if necessary, is the mainstay of treatment for patients with ITP, particularly those experiencing significant bleeding.² Corticosteroids, intravenous (IV) immunoglobulin (IVIg), and IV Rh_o(D) immune globulin (also known as anti-D) are the medications typically used to treat a child with ITP, depending on availability of the drugs, bleeding or bleeding risk, as well as convenience of dosing. For example, corticosteroids can be used orally or IV, whereas IVIg and IV Rh_o(D) may not be readily available in some treatment settings.

Corticosteroids have been shown to more rapidly increase platelet count compared to placebo and appear to have a dose-related effect.^10,11 Oral prednisone can be dosed at 1 to 2 mg/kg/d for 14 days and then tapered over the course of one week^10,11 or one may prescribe 4 mg/kg/d for 4 days.^10,11 IV methylprednisolone typically is given at 30 mg/kg/d for 3 to 4 days.⁹

IVIg may have greater efficacy than corticosteroids in treating ITP, but it may also cause adverse effects, including nausea, headache, and fever. IVIg can be administered as a single 800 to 1000 mg/kg dose, or as a daily 400 mg/kg dose for 5 days; higher doses should be reserved for patients with severe bleeding.¹²

If ITP persists despite the use of corticosteroids or IVIg, IV Rh_o(D) Ig may be used in patients with Rh_o(D)-positive blood at a single dose of 25 to 50 mcg/kg, with additional doses administered on separate days as required to elevate platelet count. However, only Rh_o(D)-positive patients are eligible for anti-D treatment.

The response rates/times and adverse effects of common treatments for ITP are summarized in the TABLE.⁹ A small randomized study found that oral methylprednisolone 30 mg/kg/d for 3 days followed by 20 mg/kg/d for an additional 4 days was comparable to IVIg 0.4 g/kg/d for 5 days.¹¹ A different study that compared oral methylprednisolone (30 mg/kg/d or 50 mg/kg/d for 7 days) and IVIg (0.5 g/kg/d for 5 days) found no difference in outcomes among the 3 treatments.¹³ One advantage, though, of IVIg is that it can be administered as a single IV dose, rather than multiple doses over several weeks, as is the case with oral prednisone.^9,11-13

Follow platelet counts closely. Patients with ITP should have their platelet counts monitored at least once weekly and as often as twice weekly. The frequency of monitoring may be tapered depending on an individual patient’s response to treatment and the severity of the thrombocytopenia.¹⁴

We referred our patient to a nearby children’s hospital, where a repeat CBC showed her platelets had decreased to 3000/mcL. She received a 6-hour infusion of IVIg and was discharged with instructions to have her CBC closely monitored. Her platelets remained stable until 4 weeks later, when they decreased from 102,000/mcL to 71,000/mcL. She received a second infusion of IVIg as an outpatient.

Soon after, she went to our ED with a headache, nausea, and fever of 102°F. A computed tomography scan of her head was normal; a repeat CBC showed no elevation in white blood cells but her hemoglobin had decreased from 11.9 g/dL to 9.7 g/dL. (Her platelets were 254,000/mcL.) The patient’s complaints were likely adverse effects of the IVIg. The CBC abnormalities, fever, headache, and malaise resolved shortly thereafter and the patient remains asymptomatic with no recurrence of ITP.

THE TAKEAWAY

Patients with ITP should have their platelet count monitored at least once a week until platelets have increased to 150,000/mcL or higher. Suspect ITP in a child who bruises easily and who also has thrombocytopenia. Order a CBC and peripheral blood smear to rule out other potential illnesses. Pharmacotherapy, if needed, typically consists of an oral or IV corticosteroid or IVIg; IV Rh_o(D) Ig may be used in patients who are Rh_o(D)-positive who don’t respond to other treatments. Patients with ITP should have their platelet count monitored at least once weekly until platelets have increased to 150,000/mcL or higher. Frequency of monitoring may be reduced as the clinical picture improves and the patient remains stable. More frequent monitoring may be necessary based on severity, complications, and response to treatment.

Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

THE CASE

A 6-year-old girl was brought to the emergency department (ED) by her mother after the child had bumped her head while playing. While the physician examined the child’s head, the mother remarked that her daughter had recently developed bruises that appeared suddenly and only after minor, if any, known trauma. The ED physician determined that the child’s bump to the head was nothing to worry about, attributed the bruising to the child being a “healthy, active 6-year-old,” and sent her home.

Two days later the child was brought to our office because the mother was still concerned about her daughter’s easy bruising. The mother pointed out ecchymosis scattered across her daughter’s extremities and torso. The child denied any pain or other complaints, including any active or recurrent bleeding. Upon further questioning, the mother mentioned that her daughter had recovered from a cold-like illness several weeks earlier.

THE DIAGNOSIS

We ordered a complete blood count (CBC) and peripheral smear, which were normal except for the platelet count, which was 7000/mcL (normal, 150,000-450,000/mcL). Based on the child’s easy bruising and isolated thrombocytopenia, we diagnosed immune thrombocytopenia, which is also known as idiopathic thrombocytopenic purpura (ITP).

DISCUSSION

In ITP, autoantibodies are directed against platelets, leading to their sequestration and destruction in the spleen and a resultant drop in platelet count.¹ Children with ITP typically present between the ages of 2 and 10 years, with a peak incidence between 2 and 5 years.² The incidence is estimated to be as high as 8 per 100,000 children.³ However, this estimate primarily reflects symptomatic children, and the true incidence of childhood ITP may be much higher because asymptomatic children may not be brought in to see a doctor. For the majority of patients, ITP resolves within 3 months. However, for 20% to 30% of patients, thrombocytopenia will last beyond 6 months, with or without treatment.⁴ In 1% of cases, patients will have a recurrence of ITP.³

In addition to easy bruising, nearly all patients who present with possible ITP will complain of cutaneous bleeding, typically a nose bleed or bleeding in the oral cavity.² Upon questioning, 60% of patients will report a history of recent infection.⁴ Not surprisingly, bleeding severity correlates inversely with platelet count; severe bleeding is seen in patients with a platelet count <10,000/mcL.

While rare, the more worrisome complications include intracranial hemorrhage, with an incidence of 0.1% to 0.8%, and other serious hemorrhages that would require transfusion, with an estimated incidence of 2.9%.²

Vast differential seen in child bruising

When a child presents with bruising, perform a thorough history, including birth and prenatal course, as well as a physical to exclude other potential causes, such as physical abuse, use of herbal remedies or other natural supplements that may not be disclosed as medication, or even environmental exposure. When bruising is present in a child who has isolated thrombocytopenia, the diagnosis of ITP may be straightforward. However, many conditions may share thrombocytopenia in their disease process and should be considered in the differential diagnosis of a child who you suspect may have ITP.

Suspect physical abuse in a bruised child who does not have thrombocytopenia, whose mood is flat or depressed, or who has experienced recurrent injuries or bruising.

Leukemia, particularly acute lymphoblastic leukemia (ALL), the predominant leukemia found in children, should be ruled out, as well. Symptoms that may distinguish a child with ALL from one with ITP include fever, weight loss, and joint pain, as well as signs such as lymphadenopathy, hepatosplenomegaly, anemia, and leukocytosis. A peripheral smear may be ordered to help confirm or exclude a diagnosis of ALL should any of the above be present in a child with thrombocytopenia.⁵ It may show lymphoblasts and/or atypical cells in a patient with ALL.⁵

Infections should also be included in a differential when a patient is suspected of having ITP, particularly if he or she has systemic symptoms. Viral infections that may cause thrombocytopenia include mononucleosis, dengue virus, human herpesvirus-6, and human immunodeficiency virus.^6,7

The incidence of ITP may be higher during the winter months, when infections are more common. ITP often follows an infection, and the incidence of ITP may be higher during winter months, when infections are more common. However, infection may not always be the cause of ITP. Sepsis may also lead to thrombocytopenia, but a child with sepsis would present very differently from a child who has only ITP. A septic child would present acutely ill with signs and symptoms of severe systemic illness, such as high fever, altered mental status, tachycardia, pallor, diaphoresis, and hypotension.

Drug-induced thrombocytopenia (DIT) should be considered in any child who is taking or recently took a medication that may cause thrombocytopenia. Medications that can cause thrombocytopenia include heparin, quinine, vancomycin, trimethoprim-sulfamethoxazole, rifampin, carbamazepine, phenytoin, piperacillin, linezolid, and valproic acid.⁸ The measles, mumps, and rubella vaccine also can cause thrombocytopenia.⁸ A careful medication history may determine if the child is at risk for DIT.

To narrow the differential, obtain a CBC and peripheral smear when evaluating a patient you suspect may have ITP⁵ (strength of recommendation [SOR]: A). A CBC will determine the patient’s platelet count and a peripheral smear should be obtained to exclude other possible diagnoses.⁵

If there are any questions regarding the results of a peripheral smear, it may be necessary to perform a bone marrow aspiration. This, however, is not usually necessary in an otherwise typical case of ITP.⁹ Bone marrow aspiration may, however, be necessary to reevaluate the initial diagnosis for a child who does not respond to treatment for ITP.

Corticosteroids, IVIg are usually effective

To start ITP treatment, limit the patient’s risk of further injury or bleeding by stopping NSAIDs and ending participation in contact sports. The first step in treating a patient with ITP is to limit the risk of further injury or bleeding, by stopping nonsteroidal anti-inflammatory drugs or ending participation in contact sports^2,9 (SOR: C). The next step is to determine if pharmacologic therapy is warranted.

Medication, if necessary, is the mainstay of treatment for patients with ITP, particularly those experiencing significant bleeding.² Corticosteroids, intravenous (IV) immunoglobulin (IVIg), and IV Rh_o(D) immune globulin (also known as anti-D) are the medications typically used to treat a child with ITP, depending on availability of the drugs, bleeding or bleeding risk, as well as convenience of dosing. For example, corticosteroids can be used orally or IV, whereas IVIg and IV Rh_o(D) may not be readily available in some treatment settings.

Corticosteroids have been shown to more rapidly increase platelet count compared to placebo and appear to have a dose-related effect.^10,11 Oral prednisone can be dosed at 1 to 2 mg/kg/d for 14 days and then tapered over the course of one week^10,11 or one may prescribe 4 mg/kg/d for 4 days.^10,11 IV methylprednisolone typically is given at 30 mg/kg/d for 3 to 4 days.⁹

IVIg may have greater efficacy than corticosteroids in treating ITP, but it may also cause adverse effects, including nausea, headache, and fever. IVIg can be administered as a single 800 to 1000 mg/kg dose, or as a daily 400 mg/kg dose for 5 days; higher doses should be reserved for patients with severe bleeding.¹²

If ITP persists despite the use of corticosteroids or IVIg, IV Rh_o(D) Ig may be used in patients with Rh_o(D)-positive blood at a single dose of 25 to 50 mcg/kg, with additional doses administered on separate days as required to elevate platelet count. However, only Rh_o(D)-positive patients are eligible for anti-D treatment.

The response rates/times and adverse effects of common treatments for ITP are summarized in the TABLE.⁹ A small randomized study found that oral methylprednisolone 30 mg/kg/d for 3 days followed by 20 mg/kg/d for an additional 4 days was comparable to IVIg 0.4 g/kg/d for 5 days.¹¹ A different study that compared oral methylprednisolone (30 mg/kg/d or 50 mg/kg/d for 7 days) and IVIg (0.5 g/kg/d for 5 days) found no difference in outcomes among the 3 treatments.¹³ One advantage, though, of IVIg is that it can be administered as a single IV dose, rather than multiple doses over several weeks, as is the case with oral prednisone.^9,11-13

Follow platelet counts closely. Patients with ITP should have their platelet counts monitored at least once weekly and as often as twice weekly. The frequency of monitoring may be tapered depending on an individual patient’s response to treatment and the severity of the thrombocytopenia.¹⁴

We referred our patient to a nearby children’s hospital, where a repeat CBC showed her platelets had decreased to 3000/mcL. She received a 6-hour infusion of IVIg and was discharged with instructions to have her CBC closely monitored. Her platelets remained stable until 4 weeks later, when they decreased from 102,000/mcL to 71,000/mcL. She received a second infusion of IVIg as an outpatient.

Soon after, she went to our ED with a headache, nausea, and fever of 102°F. A computed tomography scan of her head was normal; a repeat CBC showed no elevation in white blood cells but her hemoglobin had decreased from 11.9 g/dL to 9.7 g/dL. (Her platelets were 254,000/mcL.) The patient’s complaints were likely adverse effects of the IVIg. The CBC abnormalities, fever, headache, and malaise resolved shortly thereafter and the patient remains asymptomatic with no recurrence of ITP.

THE TAKEAWAY

Patients with ITP should have their platelet count monitored at least once a week until platelets have increased to 150,000/mcL or higher. Suspect ITP in a child who bruises easily and who also has thrombocytopenia. Order a CBC and peripheral blood smear to rule out other potential illnesses. Pharmacotherapy, if needed, typically consists of an oral or IV corticosteroid or IVIg; IV Rh_o(D) Ig may be used in patients who are Rh_o(D)-positive who don’t respond to other treatments. Patients with ITP should have their platelet count monitored at least once weekly until platelets have increased to 150,000/mcL or higher. Frequency of monitoring may be reduced as the clinical picture improves and the patient remains stable. More frequent monitoring may be necessary based on severity, complications, and response to treatment.

Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

THE CASE

A 6-year-old girl was brought to the emergency department (ED) by her mother after the child had bumped her head while playing. While the physician examined the child’s head, the mother remarked that her daughter had recently developed bruises that appeared suddenly and only after minor, if any, known trauma. The ED physician determined that the child’s bump to the head was nothing to worry about, attributed the bruising to the child being a “healthy, active 6-year-old,” and sent her home.

Two days later the child was brought to our office because the mother was still concerned about her daughter’s easy bruising. The mother pointed out ecchymosis scattered across her daughter’s extremities and torso. The child denied any pain or other complaints, including any active or recurrent bleeding. Upon further questioning, the mother mentioned that her daughter had recovered from a cold-like illness several weeks earlier.

THE DIAGNOSIS

We ordered a complete blood count (CBC) and peripheral smear, which were normal except for the platelet count, which was 7000/mcL (normal, 150,000-450,000/mcL). Based on the child’s easy bruising and isolated thrombocytopenia, we diagnosed immune thrombocytopenia, which is also known as idiopathic thrombocytopenic purpura (ITP).

DISCUSSION

In ITP, autoantibodies are directed against platelets, leading to their sequestration and destruction in the spleen and a resultant drop in platelet count.¹ Children with ITP typically present between the ages of 2 and 10 years, with a peak incidence between 2 and 5 years.² The incidence is estimated to be as high as 8 per 100,000 children.³ However, this estimate primarily reflects symptomatic children, and the true incidence of childhood ITP may be much higher because asymptomatic children may not be brought in to see a doctor. For the majority of patients, ITP resolves within 3 months. However, for 20% to 30% of patients, thrombocytopenia will last beyond 6 months, with or without treatment.⁴ In 1% of cases, patients will have a recurrence of ITP.³

In addition to easy bruising, nearly all patients who present with possible ITP will complain of cutaneous bleeding, typically a nose bleed or bleeding in the oral cavity.² Upon questioning, 60% of patients will report a history of recent infection.⁴ Not surprisingly, bleeding severity correlates inversely with platelet count; severe bleeding is seen in patients with a platelet count <10,000/mcL.

While rare, the more worrisome complications include intracranial hemorrhage, with an incidence of 0.1% to 0.8%, and other serious hemorrhages that would require transfusion, with an estimated incidence of 2.9%.²

Vast differential seen in child bruising

When a child presents with bruising, perform a thorough history, including birth and prenatal course, as well as a physical to exclude other potential causes, such as physical abuse, use of herbal remedies or other natural supplements that may not be disclosed as medication, or even environmental exposure. When bruising is present in a child who has isolated thrombocytopenia, the diagnosis of ITP may be straightforward. However, many conditions may share thrombocytopenia in their disease process and should be considered in the differential diagnosis of a child who you suspect may have ITP.

Suspect physical abuse in a bruised child who does not have thrombocytopenia, whose mood is flat or depressed, or who has experienced recurrent injuries or bruising.

Leukemia, particularly acute lymphoblastic leukemia (ALL), the predominant leukemia found in children, should be ruled out, as well. Symptoms that may distinguish a child with ALL from one with ITP include fever, weight loss, and joint pain, as well as signs such as lymphadenopathy, hepatosplenomegaly, anemia, and leukocytosis. A peripheral smear may be ordered to help confirm or exclude a diagnosis of ALL should any of the above be present in a child with thrombocytopenia.⁵ It may show lymphoblasts and/or atypical cells in a patient with ALL.⁵

Infections should also be included in a differential when a patient is suspected of having ITP, particularly if he or she has systemic symptoms. Viral infections that may cause thrombocytopenia include mononucleosis, dengue virus, human herpesvirus-6, and human immunodeficiency virus.^6,7

The incidence of ITP may be higher during the winter months, when infections are more common. ITP often follows an infection, and the incidence of ITP may be higher during winter months, when infections are more common. However, infection may not always be the cause of ITP. Sepsis may also lead to thrombocytopenia, but a child with sepsis would present very differently from a child who has only ITP. A septic child would present acutely ill with signs and symptoms of severe systemic illness, such as high fever, altered mental status, tachycardia, pallor, diaphoresis, and hypotension.

Drug-induced thrombocytopenia (DIT) should be considered in any child who is taking or recently took a medication that may cause thrombocytopenia. Medications that can cause thrombocytopenia include heparin, quinine, vancomycin, trimethoprim-sulfamethoxazole, rifampin, carbamazepine, phenytoin, piperacillin, linezolid, and valproic acid.⁸ The measles, mumps, and rubella vaccine also can cause thrombocytopenia.⁸ A careful medication history may determine if the child is at risk for DIT.

To narrow the differential, obtain a CBC and peripheral smear when evaluating a patient you suspect may have ITP⁵ (strength of recommendation [SOR]: A). A CBC will determine the patient’s platelet count and a peripheral smear should be obtained to exclude other possible diagnoses.⁵

If there are any questions regarding the results of a peripheral smear, it may be necessary to perform a bone marrow aspiration. This, however, is not usually necessary in an otherwise typical case of ITP.⁹ Bone marrow aspiration may, however, be necessary to reevaluate the initial diagnosis for a child who does not respond to treatment for ITP.

Corticosteroids, IVIg are usually effective

To start ITP treatment, limit the patient’s risk of further injury or bleeding by stopping NSAIDs and ending participation in contact sports. The first step in treating a patient with ITP is to limit the risk of further injury or bleeding, by stopping nonsteroidal anti-inflammatory drugs or ending participation in contact sports^2,9 (SOR: C). The next step is to determine if pharmacologic therapy is warranted.

Medication, if necessary, is the mainstay of treatment for patients with ITP, particularly those experiencing significant bleeding.² Corticosteroids, intravenous (IV) immunoglobulin (IVIg), and IV Rh_o(D) immune globulin (also known as anti-D) are the medications typically used to treat a child with ITP, depending on availability of the drugs, bleeding or bleeding risk, as well as convenience of dosing. For example, corticosteroids can be used orally or IV, whereas IVIg and IV Rh_o(D) may not be readily available in some treatment settings.

Corticosteroids have been shown to more rapidly increase platelet count compared to placebo and appear to have a dose-related effect.^10,11 Oral prednisone can be dosed at 1 to 2 mg/kg/d for 14 days and then tapered over the course of one week^10,11 or one may prescribe 4 mg/kg/d for 4 days.^10,11 IV methylprednisolone typically is given at 30 mg/kg/d for 3 to 4 days.⁹

IVIg may have greater efficacy than corticosteroids in treating ITP, but it may also cause adverse effects, including nausea, headache, and fever. IVIg can be administered as a single 800 to 1000 mg/kg dose, or as a daily 400 mg/kg dose for 5 days; higher doses should be reserved for patients with severe bleeding.¹²

If ITP persists despite the use of corticosteroids or IVIg, IV Rh_o(D) Ig may be used in patients with Rh_o(D)-positive blood at a single dose of 25 to 50 mcg/kg, with additional doses administered on separate days as required to elevate platelet count. However, only Rh_o(D)-positive patients are eligible for anti-D treatment.

The response rates/times and adverse effects of common treatments for ITP are summarized in the TABLE.⁹ A small randomized study found that oral methylprednisolone 30 mg/kg/d for 3 days followed by 20 mg/kg/d for an additional 4 days was comparable to IVIg 0.4 g/kg/d for 5 days.¹¹ A different study that compared oral methylprednisolone (30 mg/kg/d or 50 mg/kg/d for 7 days) and IVIg (0.5 g/kg/d for 5 days) found no difference in outcomes among the 3 treatments.¹³ One advantage, though, of IVIg is that it can be administered as a single IV dose, rather than multiple doses over several weeks, as is the case with oral prednisone.^9,11-13

Follow platelet counts closely. Patients with ITP should have their platelet counts monitored at least once weekly and as often as twice weekly. The frequency of monitoring may be tapered depending on an individual patient’s response to treatment and the severity of the thrombocytopenia.¹⁴

We referred our patient to a nearby children’s hospital, where a repeat CBC showed her platelets had decreased to 3000/mcL. She received a 6-hour infusion of IVIg and was discharged with instructions to have her CBC closely monitored. Her platelets remained stable until 4 weeks later, when they decreased from 102,000/mcL to 71,000/mcL. She received a second infusion of IVIg as an outpatient.

Soon after, she went to our ED with a headache, nausea, and fever of 102°F. A computed tomography scan of her head was normal; a repeat CBC showed no elevation in white blood cells but her hemoglobin had decreased from 11.9 g/dL to 9.7 g/dL. (Her platelets were 254,000/mcL.) The patient’s complaints were likely adverse effects of the IVIg. The CBC abnormalities, fever, headache, and malaise resolved shortly thereafter and the patient remains asymptomatic with no recurrence of ITP.

THE TAKEAWAY

Patients with ITP should have their platelet count monitored at least once a week until platelets have increased to 150,000/mcL or higher. Suspect ITP in a child who bruises easily and who also has thrombocytopenia. Order a CBC and peripheral blood smear to rule out other potential illnesses. Pharmacotherapy, if needed, typically consists of an oral or IV corticosteroid or IVIg; IV Rh_o(D) Ig may be used in patients who are Rh_o(D)-positive who don’t respond to other treatments. Patients with ITP should have their platelet count monitored at least once weekly until platelets have increased to 150,000/mcL or higher. Frequency of monitoring may be reduced as the clinical picture improves and the patient remains stable. More frequent monitoring may be necessary based on severity, complications, and response to treatment.

Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

THE CASE

A 26-year-old Hispanic woman presented to the emergency department (ED) with myalgia and weakness. The work-up revealed profound hyperthyroidism, with a thyroid-stimulating hormone (TSH) <0.01 mIU/mL (normal, 0.4-4.2 mIU/L), potassium 2.4 mEq/L (normal, 3.7-5.2 mEq/L), hypophosphatemia, and low urinary potassium. There were no prior symptoms and family history was negative for endocrinopathies. She was admitted and started on methimazole 10 mg twice a day for thyroid suppression and given propranolol 10 mg twice a day for anticipated hyperadrenergic adverse effects. The remainder of her hospital stay was uneventful and she was discharged 6 days after admission. Soon after, an outpatient thyroid scan ordered by her primary care physician confirmed that the patient had Graves’ disease.

Eight months later, the patient returned to the ED with myalgia and rapidly progressing paralysis from the neck down; she was immediately intubated. Her potassium level was 1.2 mEq/L. An electrocardiogram (EKG) revealed conduction abnormalities consistent with hypokalemia.

THE DIAGNOSIS

Based on our patient’s paralysis, hyperthyroidism, and hypokalemia, we diagnosed thyrotoxic hypokalemic periodic paralysis (THPP), a rare endocrinopathy that causes electrolyte disturbances that can result in paralysis and lethal tachyarrhythmias.^1-6

Patients with THPP typically have a history of myalgia, cramping, and stiffness followed by weakness or paralysis that tends to develop rapidly, most commonly in the late evening or early morning^1-4,6,7 (TABLE^1-9). Proximal muscles are predominantly affected symmetrically and the attacks usually resolve in a period of hours to several days. Ocular, bulbar, and respiratory muscles are usually spared, but these can be affected by the hypokalemia.¹

DISCUSSION

Traditionally THPP has been seen primarily in Asia, with an incidence as high as 2%.^1-6 The incidence in the United States is lower (0.1%-0.2%) and THPP occurs primarily in Asian, African, Hispanic, and Native American populations.^1,4,6

Although thyrotoxicosis is more common in women, THPP has a predilection for men (20:1).^1,3-6 THPP occurs in patients with hyperthyroidism, most commonly from Graves’ disease,^1,6 who are exposed to certain precipitating factors, such as exercise, carbohydrate loading, high-salt diet, excessive alcohol consumption, trauma, cold exposure, infection, menstruation, or emotional stress.^1,6 THPP can also occur in people taking medications such as corticosteroids, β₂-adrenergic bronchodilators, epinephrine, acetazolamide, insulin, nonsteroidal anti-inflammatory drugs, thyroxine, amiodarone, and tiratricol.^1,5,6 THPP is more common in the summer.¹

A genetic basis for THPP. A Kir2.6 mutation results in a thyroid hormone-sensitive channelopathy involving the sodium-potassium-adenosine triphosphate (Na⁺,K⁺-ATPase) pump, which appears to be responsible for THPP.^1-6,8,9 This mutation should not be confused with the pathogenesis of familial periodic paralysis (FPP)—a hereditary disorder resulting in abnormalities in calcium, sodium, and potassium channels on skeletal muscle cells that leads to multiple electrolyte derangements and paralysis identical to that observed in THPP.¹

Hypokalemia may be exacerbated by catecholamine-induced potassium shifts.^1,4,6 This is from the increased β₂-adrenergic stimulation from the concurrent hyperadrenergic state caused by the underlying hyperthyroidism.^1,4,6 Hyperinsulinemia from sympathetic stimulation of the insulin-releasing pancreatic beta cells also exacerbates hypokalemia.^1,4,6

Focus treatment on correcting electrolytes

Acute management of THPP centers on electrolyte correction; definitive treatments include antithyroid medication, radioactive iodine ablation, and/or thyroidectomy. Initial evaluation of a patient suspected of having THPP should include a complete blood count, TSH and serum and urine electrolyte tests, and an EKG. Further work-up may require ultrasound and scan of the thyroid upon confirmation of thyrotoxicosis and hypokalemia. Physical examination may reveal thyromegaly. Exophthalmos and other hyperthyroidism symptoms often are absent.¹

Diagnosis confirmed? Treat the hypokalemia first. Acute management of THPP centers on electrolyte correction. Total body stores of potassium in patients with THPP  are usually normal, so the physician must use care to avoid excessive potassium administration.^1-5 Rebound hyperkalemia can occur in patients who receive >90 mEq/L of potassium chloride within 24 hours.¹

Definitive therapy may include antithyroid medication, radioactive iodine ablation (RIA), and/or thyroidectomy.^1-5 All have the common goal of controlling the hyperthyroidism and preventing recurrent paralysis, which occurs in 62.2% of patients within the first 3 months following diagnosis.³ If antithyroid medications fail, then RIA is the next choice.¹ Beta-blockers work by decreasing the Na⁺,K⁺-ATPase activity from the underlying hyperadrenergic state.¹ Administration of acetazolamide—which is the primary treatment modality for FPP and idiopathic periodic paralysis—can precipitate THPP attacks and is contraindicated.^1,5

Consider thyroidectomy for patients for whom medical management is unsuccessful or who develop compression symptoms. If medical management is unsuccessful or the patient develops compression symptoms, then thyroidectomy should be considered.³ If the patient chooses thyroidectomy, medical optimization with antithyroid medications is indicated to mitigate the risks of anesthesia. When the thyroidectomy is performed by an experienced thyroid surgeon, the long-term results are excellent.

Our patient. Once our patient’s hypokalemia was corrected, she was successfully extubated. Despite appropriate medical therapy, her hyperthyroidism was poorly controlled. The endocrinologist believed that RIA was suboptimal for 3 reasons: 1) it might result in incomplete ablation, 2) it required a long treatment period to be effective, and 3) its prolonged course of treatment extended the time interval that the patient would be at risk for recurrent paralysis.

A surgeon was consulted for definitive treatment with thyroidectomy. Our patient’s medications were changed to propylthiouracil 150 mg every 8 hours and propranolol 10 mg twice a day until a euthyroid state was achieved and she could tolerate a general anesthetic without precipitating a thyroid storm. Two months later, she underwent total thyroidectomy without complication. Her postoperative course was normal.

THE TAKEAWAY

Thyrotoxic hypokalemic periodic paralysis is rare. Patients typically present with myalgia, cramping, and stiffness that progress to paralysis. Prompt electrolyte repletion is paramount for successful outcomes.^1-5 Control of hyperthyroidism is the long-term goal.^1-5 Definitive therapy can be achieved medically or surgically. Total thyroidectomy is a reasonable treatment option for medically refractory hyperthyroidism or when RIA is contraindicated. Long-term prognosis is excellent.

THE CASE

A 26-year-old Hispanic woman presented to the emergency department (ED) with myalgia and weakness. The work-up revealed profound hyperthyroidism, with a thyroid-stimulating hormone (TSH) <0.01 mIU/mL (normal, 0.4-4.2 mIU/L), potassium 2.4 mEq/L (normal, 3.7-5.2 mEq/L), hypophosphatemia, and low urinary potassium. There were no prior symptoms and family history was negative for endocrinopathies. She was admitted and started on methimazole 10 mg twice a day for thyroid suppression and given propranolol 10 mg twice a day for anticipated hyperadrenergic adverse effects. The remainder of her hospital stay was uneventful and she was discharged 6 days after admission. Soon after, an outpatient thyroid scan ordered by her primary care physician confirmed that the patient had Graves’ disease.

Eight months later, the patient returned to the ED with myalgia and rapidly progressing paralysis from the neck down; she was immediately intubated. Her potassium level was 1.2 mEq/L. An electrocardiogram (EKG) revealed conduction abnormalities consistent with hypokalemia.

THE DIAGNOSIS

Based on our patient’s paralysis, hyperthyroidism, and hypokalemia, we diagnosed thyrotoxic hypokalemic periodic paralysis (THPP), a rare endocrinopathy that causes electrolyte disturbances that can result in paralysis and lethal tachyarrhythmias.^1-6

Patients with THPP typically have a history of myalgia, cramping, and stiffness followed by weakness or paralysis that tends to develop rapidly, most commonly in the late evening or early morning^1-4,6,7 (TABLE^1-9). Proximal muscles are predominantly affected symmetrically and the attacks usually resolve in a period of hours to several days. Ocular, bulbar, and respiratory muscles are usually spared, but these can be affected by the hypokalemia.¹

DISCUSSION

Traditionally THPP has been seen primarily in Asia, with an incidence as high as 2%.^1-6 The incidence in the United States is lower (0.1%-0.2%) and THPP occurs primarily in Asian, African, Hispanic, and Native American populations.^1,4,6

Although thyrotoxicosis is more common in women, THPP has a predilection for men (20:1).^1,3-6 THPP occurs in patients with hyperthyroidism, most commonly from Graves’ disease,^1,6 who are exposed to certain precipitating factors, such as exercise, carbohydrate loading, high-salt diet, excessive alcohol consumption, trauma, cold exposure, infection, menstruation, or emotional stress.^1,6 THPP can also occur in people taking medications such as corticosteroids, β₂-adrenergic bronchodilators, epinephrine, acetazolamide, insulin, nonsteroidal anti-inflammatory drugs, thyroxine, amiodarone, and tiratricol.^1,5,6 THPP is more common in the summer.¹

A genetic basis for THPP. A Kir2.6 mutation results in a thyroid hormone-sensitive channelopathy involving the sodium-potassium-adenosine triphosphate (Na⁺,K⁺-ATPase) pump, which appears to be responsible for THPP.^1-6,8,9 This mutation should not be confused with the pathogenesis of familial periodic paralysis (FPP)—a hereditary disorder resulting in abnormalities in calcium, sodium, and potassium channels on skeletal muscle cells that leads to multiple electrolyte derangements and paralysis identical to that observed in THPP.¹

Hypokalemia may be exacerbated by catecholamine-induced potassium shifts.^1,4,6 This is from the increased β₂-adrenergic stimulation from the concurrent hyperadrenergic state caused by the underlying hyperthyroidism.^1,4,6 Hyperinsulinemia from sympathetic stimulation of the insulin-releasing pancreatic beta cells also exacerbates hypokalemia.^1,4,6

Focus treatment on correcting electrolytes

Acute management of THPP centers on electrolyte correction; definitive treatments include antithyroid medication, radioactive iodine ablation, and/or thyroidectomy. Initial evaluation of a patient suspected of having THPP should include a complete blood count, TSH and serum and urine electrolyte tests, and an EKG. Further work-up may require ultrasound and scan of the thyroid upon confirmation of thyrotoxicosis and hypokalemia. Physical examination may reveal thyromegaly. Exophthalmos and other hyperthyroidism symptoms often are absent.¹

Diagnosis confirmed? Treat the hypokalemia first. Acute management of THPP centers on electrolyte correction. Total body stores of potassium in patients with THPP  are usually normal, so the physician must use care to avoid excessive potassium administration.^1-5 Rebound hyperkalemia can occur in patients who receive >90 mEq/L of potassium chloride within 24 hours.¹

Definitive therapy may include antithyroid medication, radioactive iodine ablation (RIA), and/or thyroidectomy.^1-5 All have the common goal of controlling the hyperthyroidism and preventing recurrent paralysis, which occurs in 62.2% of patients within the first 3 months following diagnosis.³ If antithyroid medications fail, then RIA is the next choice.¹ Beta-blockers work by decreasing the Na⁺,K⁺-ATPase activity from the underlying hyperadrenergic state.¹ Administration of acetazolamide—which is the primary treatment modality for FPP and idiopathic periodic paralysis—can precipitate THPP attacks and is contraindicated.^1,5

Consider thyroidectomy for patients for whom medical management is unsuccessful or who develop compression symptoms. If medical management is unsuccessful or the patient develops compression symptoms, then thyroidectomy should be considered.³ If the patient chooses thyroidectomy, medical optimization with antithyroid medications is indicated to mitigate the risks of anesthesia. When the thyroidectomy is performed by an experienced thyroid surgeon, the long-term results are excellent.

Our patient. Once our patient’s hypokalemia was corrected, she was successfully extubated. Despite appropriate medical therapy, her hyperthyroidism was poorly controlled. The endocrinologist believed that RIA was suboptimal for 3 reasons: 1) it might result in incomplete ablation, 2) it required a long treatment period to be effective, and 3) its prolonged course of treatment extended the time interval that the patient would be at risk for recurrent paralysis.

A surgeon was consulted for definitive treatment with thyroidectomy. Our patient’s medications were changed to propylthiouracil 150 mg every 8 hours and propranolol 10 mg twice a day until a euthyroid state was achieved and she could tolerate a general anesthetic without precipitating a thyroid storm. Two months later, she underwent total thyroidectomy without complication. Her postoperative course was normal.

THE TAKEAWAY

Thyrotoxic hypokalemic periodic paralysis is rare. Patients typically present with myalgia, cramping, and stiffness that progress to paralysis. Prompt electrolyte repletion is paramount for successful outcomes.^1-5 Control of hyperthyroidism is the long-term goal.^1-5 Definitive therapy can be achieved medically or surgically. Total thyroidectomy is a reasonable treatment option for medically refractory hyperthyroidism or when RIA is contraindicated. Long-term prognosis is excellent.

THE CASE

A 26-year-old Hispanic woman presented to the emergency department (ED) with myalgia and weakness. The work-up revealed profound hyperthyroidism, with a thyroid-stimulating hormone (TSH) <0.01 mIU/mL (normal, 0.4-4.2 mIU/L), potassium 2.4 mEq/L (normal, 3.7-5.2 mEq/L), hypophosphatemia, and low urinary potassium. There were no prior symptoms and family history was negative for endocrinopathies. She was admitted and started on methimazole 10 mg twice a day for thyroid suppression and given propranolol 10 mg twice a day for anticipated hyperadrenergic adverse effects. The remainder of her hospital stay was uneventful and she was discharged 6 days after admission. Soon after, an outpatient thyroid scan ordered by her primary care physician confirmed that the patient had Graves’ disease.

Eight months later, the patient returned to the ED with myalgia and rapidly progressing paralysis from the neck down; she was immediately intubated. Her potassium level was 1.2 mEq/L. An electrocardiogram (EKG) revealed conduction abnormalities consistent with hypokalemia.

THE DIAGNOSIS

Based on our patient’s paralysis, hyperthyroidism, and hypokalemia, we diagnosed thyrotoxic hypokalemic periodic paralysis (THPP), a rare endocrinopathy that causes electrolyte disturbances that can result in paralysis and lethal tachyarrhythmias.^1-6

Patients with THPP typically have a history of myalgia, cramping, and stiffness followed by weakness or paralysis that tends to develop rapidly, most commonly in the late evening or early morning^1-4,6,7 (TABLE^1-9). Proximal muscles are predominantly affected symmetrically and the attacks usually resolve in a period of hours to several days. Ocular, bulbar, and respiratory muscles are usually spared, but these can be affected by the hypokalemia.¹

DISCUSSION

Traditionally THPP has been seen primarily in Asia, with an incidence as high as 2%.^1-6 The incidence in the United States is lower (0.1%-0.2%) and THPP occurs primarily in Asian, African, Hispanic, and Native American populations.^1,4,6

Although thyrotoxicosis is more common in women, THPP has a predilection for men (20:1).^1,3-6 THPP occurs in patients with hyperthyroidism, most commonly from Graves’ disease,^1,6 who are exposed to certain precipitating factors, such as exercise, carbohydrate loading, high-salt diet, excessive alcohol consumption, trauma, cold exposure, infection, menstruation, or emotional stress.^1,6 THPP can also occur in people taking medications such as corticosteroids, β₂-adrenergic bronchodilators, epinephrine, acetazolamide, insulin, nonsteroidal anti-inflammatory drugs, thyroxine, amiodarone, and tiratricol.^1,5,6 THPP is more common in the summer.¹

A genetic basis for THPP. A Kir2.6 mutation results in a thyroid hormone-sensitive channelopathy involving the sodium-potassium-adenosine triphosphate (Na⁺,K⁺-ATPase) pump, which appears to be responsible for THPP.^1-6,8,9 This mutation should not be confused with the pathogenesis of familial periodic paralysis (FPP)—a hereditary disorder resulting in abnormalities in calcium, sodium, and potassium channels on skeletal muscle cells that leads to multiple electrolyte derangements and paralysis identical to that observed in THPP.¹

Hypokalemia may be exacerbated by catecholamine-induced potassium shifts.^1,4,6 This is from the increased β₂-adrenergic stimulation from the concurrent hyperadrenergic state caused by the underlying hyperthyroidism.^1,4,6 Hyperinsulinemia from sympathetic stimulation of the insulin-releasing pancreatic beta cells also exacerbates hypokalemia.^1,4,6

Focus treatment on correcting electrolytes

Acute management of THPP centers on electrolyte correction; definitive treatments include antithyroid medication, radioactive iodine ablation, and/or thyroidectomy. Initial evaluation of a patient suspected of having THPP should include a complete blood count, TSH and serum and urine electrolyte tests, and an EKG. Further work-up may require ultrasound and scan of the thyroid upon confirmation of thyrotoxicosis and hypokalemia. Physical examination may reveal thyromegaly. Exophthalmos and other hyperthyroidism symptoms often are absent.¹

Diagnosis confirmed? Treat the hypokalemia first. Acute management of THPP centers on electrolyte correction. Total body stores of potassium in patients with THPP  are usually normal, so the physician must use care to avoid excessive potassium administration.^1-5 Rebound hyperkalemia can occur in patients who receive >90 mEq/L of potassium chloride within 24 hours.¹

Definitive therapy may include antithyroid medication, radioactive iodine ablation (RIA), and/or thyroidectomy.^1-5 All have the common goal of controlling the hyperthyroidism and preventing recurrent paralysis, which occurs in 62.2% of patients within the first 3 months following diagnosis.³ If antithyroid medications fail, then RIA is the next choice.¹ Beta-blockers work by decreasing the Na⁺,K⁺-ATPase activity from the underlying hyperadrenergic state.¹ Administration of acetazolamide—which is the primary treatment modality for FPP and idiopathic periodic paralysis—can precipitate THPP attacks and is contraindicated.^1,5

Consider thyroidectomy for patients for whom medical management is unsuccessful or who develop compression symptoms. If medical management is unsuccessful or the patient develops compression symptoms, then thyroidectomy should be considered.³ If the patient chooses thyroidectomy, medical optimization with antithyroid medications is indicated to mitigate the risks of anesthesia. When the thyroidectomy is performed by an experienced thyroid surgeon, the long-term results are excellent.

Our patient. Once our patient’s hypokalemia was corrected, she was successfully extubated. Despite appropriate medical therapy, her hyperthyroidism was poorly controlled. The endocrinologist believed that RIA was suboptimal for 3 reasons: 1) it might result in incomplete ablation, 2) it required a long treatment period to be effective, and 3) its prolonged course of treatment extended the time interval that the patient would be at risk for recurrent paralysis.

A surgeon was consulted for definitive treatment with thyroidectomy. Our patient’s medications were changed to propylthiouracil 150 mg every 8 hours and propranolol 10 mg twice a day until a euthyroid state was achieved and she could tolerate a general anesthetic without precipitating a thyroid storm. Two months later, she underwent total thyroidectomy without complication. Her postoperative course was normal.

THE TAKEAWAY

Thyrotoxic hypokalemic periodic paralysis is rare. Patients typically present with myalgia, cramping, and stiffness that progress to paralysis. Prompt electrolyte repletion is paramount for successful outcomes.^1-5 Control of hyperthyroidism is the long-term goal.^1-5 Definitive therapy can be achieved medically or surgically. Total thyroidectomy is a reasonable treatment option for medically refractory hyperthyroidism or when RIA is contraindicated. Long-term prognosis is excellent.

To the Editor: We read with interest the article by Ching Sun et al¹ on the relationship between diabetes therapy and cancer risk. We noted that there was no reference in the text to the long-acting insulins detemir and degludec, and we would like to add some relevant information.

With regard to detemir, a meta-analysis published in 2009 showed that patients treated with this insulin had a lower or similar rate of occurrence of a cancer compared with patients treated with neutral protamine Hagedorn insulin or insulin glargine.² In addition, in a cohort study, no difference in cancer risk between insulin detemir users and nonusers was reported.³

Insulin detemir has a lower binding affinity for human insulin receptor isoform A  (IR-A) relative to human insulin, and a much lower affinity for isoform B  (IR-B). The binding affinity ratio of insulinlike growth factor-1 (IGF-1) receptor to insulin receptor for detemir is less than or equal to 1 relative to human insulin and displays a dissociation pattern from the insulin receptor that is similar to or faster than that of human insulin. Consequently, the relative mitogenic potency of detemir in cell types predominantly expressing either the IGF-1 receptor or the insulin receptor is low and corresponds to its IGF-1 receptor and insulin receptor affinities.⁴

Regarding insulin degludec, its affinity for both IR-A and IR-B, as well as for the IGF-1 receptor, has been found to be lower than human insulin. Its mitogenic response, in the absence of albumin, was reported to range from 4% to 14% relative to human insulin.⁵ Furthermore, in cellular assays, in which no albumin was added, the in vitro metabolic potency was determined to be in the range of 8% to 20%, resulting in a mitogenic-to-metabolic potency ratio of 1 or lower.⁵

It appears that insulins detemir and degludec have low mitogenic potential. However, additional studies are needed, especially with degludec, to further determine long-term safety.

To the Editor: We read with interest the article by Ching Sun et al¹ on the relationship between diabetes therapy and cancer risk. We noted that there was no reference in the text to the long-acting insulins detemir and degludec, and we would like to add some relevant information.

With regard to detemir, a meta-analysis published in 2009 showed that patients treated with this insulin had a lower or similar rate of occurrence of a cancer compared with patients treated with neutral protamine Hagedorn insulin or insulin glargine.² In addition, in a cohort study, no difference in cancer risk between insulin detemir users and nonusers was reported.³

Insulin detemir has a lower binding affinity for human insulin receptor isoform A  (IR-A) relative to human insulin, and a much lower affinity for isoform B  (IR-B). The binding affinity ratio of insulinlike growth factor-1 (IGF-1) receptor to insulin receptor for detemir is less than or equal to 1 relative to human insulin and displays a dissociation pattern from the insulin receptor that is similar to or faster than that of human insulin. Consequently, the relative mitogenic potency of detemir in cell types predominantly expressing either the IGF-1 receptor or the insulin receptor is low and corresponds to its IGF-1 receptor and insulin receptor affinities.⁴

Regarding insulin degludec, its affinity for both IR-A and IR-B, as well as for the IGF-1 receptor, has been found to be lower than human insulin. Its mitogenic response, in the absence of albumin, was reported to range from 4% to 14% relative to human insulin.⁵ Furthermore, in cellular assays, in which no albumin was added, the in vitro metabolic potency was determined to be in the range of 8% to 20%, resulting in a mitogenic-to-metabolic potency ratio of 1 or lower.⁵

It appears that insulins detemir and degludec have low mitogenic potential. However, additional studies are needed, especially with degludec, to further determine long-term safety.

To the Editor: We read with interest the article by Ching Sun et al¹ on the relationship between diabetes therapy and cancer risk. We noted that there was no reference in the text to the long-acting insulins detemir and degludec, and we would like to add some relevant information.

With regard to detemir, a meta-analysis published in 2009 showed that patients treated with this insulin had a lower or similar rate of occurrence of a cancer compared with patients treated with neutral protamine Hagedorn insulin or insulin glargine.² In addition, in a cohort study, no difference in cancer risk between insulin detemir users and nonusers was reported.³

Insulin detemir has a lower binding affinity for human insulin receptor isoform A  (IR-A) relative to human insulin, and a much lower affinity for isoform B  (IR-B). The binding affinity ratio of insulinlike growth factor-1 (IGF-1) receptor to insulin receptor for detemir is less than or equal to 1 relative to human insulin and displays a dissociation pattern from the insulin receptor that is similar to or faster than that of human insulin. Consequently, the relative mitogenic potency of detemir in cell types predominantly expressing either the IGF-1 receptor or the insulin receptor is low and corresponds to its IGF-1 receptor and insulin receptor affinities.⁴

Regarding insulin degludec, its affinity for both IR-A and IR-B, as well as for the IGF-1 receptor, has been found to be lower than human insulin. Its mitogenic response, in the absence of albumin, was reported to range from 4% to 14% relative to human insulin.⁵ Furthermore, in cellular assays, in which no albumin was added, the in vitro metabolic potency was determined to be in the range of 8% to 20%, resulting in a mitogenic-to-metabolic potency ratio of 1 or lower.⁵

It appears that insulins detemir and degludec have low mitogenic potential. However, additional studies are needed, especially with degludec, to further determine long-term safety.

In Reply: Dr. Fountas et al highlight further data on insulin therapy and cancer risk, specifically in regard to insulin detemir and insulin degludec. Detemir first gained US Food and Drug Administration (FDA) approval in 2005 as a basal insulin, dosed once or twice daily.¹ Compared with regular human insulin, detemir has demonstrated proliferative and antiapoptotic activities in vitro in various cancer cell lines—eg, HCT-116 (colorectal cancer), PC-3 (prostate cancer), and MCF-7 (breast adenocarcinoma).² But clinically, detemir has not demonstrated increased cancer risk compared with other basal insulins in randomized controlled trials or cohort studies.^3–5

Degludec (U-200 insulin) is equal to twice the concentration of the usual U-100 insulin therapies presently available. In February 2013, the drug application for insulin degludec failed to obtain FDA approval, and the FDA requested additional data on cardiovascular safety. Thus, degludec is not currently available in the United States.⁶

Besides ameliorating nocturnal hypoglycemia,⁷ U-200 insulin may mitigate potential mitogenic effects.⁸ However, there are still very few data on degludec compared with the amount of data on insulin glargine. Insulin analogues with a decreased dissociation rate from the insulin receptor are associated with higher mitogenic potency than metabolic potency compared with human insulin.^9,10 Degludec, like detemir, has an elevated dissociation rate from the insulin receptor, a low affinity for IGF-1 receptors, and a low mitogenic activity in vitro.⁸

At this juncture, neither detemir nor degludec has been associated with higher cancer risk, but these therapies are relatively new. And as Dr. Fountas et al indicated, their safety, particularly in regard to cancer risk in diabetes patients, should continue to be assessed.

In Reply: Dr. Fountas et al highlight further data on insulin therapy and cancer risk, specifically in regard to insulin detemir and insulin degludec. Detemir first gained US Food and Drug Administration (FDA) approval in 2005 as a basal insulin, dosed once or twice daily.¹ Compared with regular human insulin, detemir has demonstrated proliferative and antiapoptotic activities in vitro in various cancer cell lines—eg, HCT-116 (colorectal cancer), PC-3 (prostate cancer), and MCF-7 (breast adenocarcinoma).² But clinically, detemir has not demonstrated increased cancer risk compared with other basal insulins in randomized controlled trials or cohort studies.^3–5

Degludec (U-200 insulin) is equal to twice the concentration of the usual U-100 insulin therapies presently available. In February 2013, the drug application for insulin degludec failed to obtain FDA approval, and the FDA requested additional data on cardiovascular safety. Thus, degludec is not currently available in the United States.⁶

Besides ameliorating nocturnal hypoglycemia,⁷ U-200 insulin may mitigate potential mitogenic effects.⁸ However, there are still very few data on degludec compared with the amount of data on insulin glargine. Insulin analogues with a decreased dissociation rate from the insulin receptor are associated with higher mitogenic potency than metabolic potency compared with human insulin.^9,10 Degludec, like detemir, has an elevated dissociation rate from the insulin receptor, a low affinity for IGF-1 receptors, and a low mitogenic activity in vitro.⁸

At this juncture, neither detemir nor degludec has been associated with higher cancer risk, but these therapies are relatively new. And as Dr. Fountas et al indicated, their safety, particularly in regard to cancer risk in diabetes patients, should continue to be assessed.

In Reply: Dr. Fountas et al highlight further data on insulin therapy and cancer risk, specifically in regard to insulin detemir and insulin degludec. Detemir first gained US Food and Drug Administration (FDA) approval in 2005 as a basal insulin, dosed once or twice daily.¹ Compared with regular human insulin, detemir has demonstrated proliferative and antiapoptotic activities in vitro in various cancer cell lines—eg, HCT-116 (colorectal cancer), PC-3 (prostate cancer), and MCF-7 (breast adenocarcinoma).² But clinically, detemir has not demonstrated increased cancer risk compared with other basal insulins in randomized controlled trials or cohort studies.^3–5

Degludec (U-200 insulin) is equal to twice the concentration of the usual U-100 insulin therapies presently available. In February 2013, the drug application for insulin degludec failed to obtain FDA approval, and the FDA requested additional data on cardiovascular safety. Thus, degludec is not currently available in the United States.⁶

Besides ameliorating nocturnal hypoglycemia,⁷ U-200 insulin may mitigate potential mitogenic effects.⁸ However, there are still very few data on degludec compared with the amount of data on insulin glargine. Insulin analogues with a decreased dissociation rate from the insulin receptor are associated with higher mitogenic potency than metabolic potency compared with human insulin.^9,10 Degludec, like detemir, has an elevated dissociation rate from the insulin receptor, a low affinity for IGF-1 receptors, and a low mitogenic activity in vitro.⁸

At this juncture, neither detemir nor degludec has been associated with higher cancer risk, but these therapies are relatively new. And as Dr. Fountas et al indicated, their safety, particularly in regard to cancer risk in diabetes patients, should continue to be assessed.