Aging Patient and AAFP

Which of the following statements about dementia and depression is

true? A) Dementia is an etiology but

depression is a syndrome B) Dementia is a syndrome but

depression is an etiology C) Dementia and depression are

syndromes, not etiologies D) Dementia and depression are

etiologies, not syndromes

Answer

• C) Dementia and depression are syndromes, not etiologies

Cognitive impairment can be a feature of a depressive episode. It

_______ fully remit(s) with treatment.

 A) Always B) May not

Answer

• B) May not

Frontotemporal dementia tends to occur at a younger

age than Alzheimer disease. A) True B) False

Answer

• A) True

All the following are clinical clues to depression in an older patient who denies sadness or

depression, except: A) Memory complaints

 B) Hopelessness C) Anxiety

 D) Increased sexual interest

Answer

•  D) Increased sexual interest

If unsure whether an older patient has depression, dementia, or both, it is

recommended to treat depression first and monitor for a response, and to start treatment

with: A) Serotonin-norepinephrine reuptake

inhibitors (SNRIs) B) Selective serotonin reuptake inhibitors

(SSRIs) C) Tricyclic antidepressants

 D) Benzodiazepines

Answer

•  B) Selective serotonin reuptake inhibitors (SSRIs)

It is estimated that by 2020, approximately _______ of

drivers will be >65 yr of age. A) 25% B) 40% C) 50% D) 66%

Answer

•  A) 25%

Elderly adults have the ______ crash rate per driver of any age group but the _______ rate per

miles driven. A) Highest; lowest

 B) Lowest; second lowest C) Lowest; second highest D) Highest; second highest

Answer

• C) Lowest; second highest

Tests for dementia ________ good

predictors of driving performance.

 A) Are B) Are not

Answer

•  B) Are not

Choose the incorrect statement about the Assessment of Driving-Related Skills

(ADReS) instrument. A) Structured series of in-office tests for

evaluating drivers at risk B) Assesses vision, cognition, and

motor strength C) Functions as a guide but is not

predictive D) Both extremely sensitive and specific

Answer

•  D) Both extremely sensitive and specific

Trail A and B• Trail Making Test (TMT) Parts A & B • Instructions:• Both parts of the Trail Making Test consist of 25 circles distributed over a sheet of paper. In Part • A, the circles are numbered 1 – 25, and the patient should draw lines to connect the numbers in • ascending order. In Part B, the circles include both numbers (1 – 13) and letters (A – L); as in • Part A, the patient draws lines to connect the circles in an ascending pattern, but with the added • task of alternating between the numbers and letters (i.e., 1-A-2-B-3-C, etc.). The patient should • be instructed to connect the circles as quickly as possible, without lifting the pen or pencil from • the paper. Time the patient as he or she connects the "trail." If the patient makes an error, point • it out immediately and allow the patient to correct it. Errors affect the patient's score only in that • the correction of errors is included in the completion time for the task. It is unnecessary to • continue the test if the patient has not completed both parts after five minutes have elapsed. • Step 1: Give the patient a copy of the Trail Making Test Part A worksheet and a pen or • pencil. • Step 2: Demonstrate the test to the patient using the sample sheet (Trail Making Part A – • SAMPLE). • Step 3: Time the patient as he or she follows the “trail” made by the numbers on the test. • Step 4: Record the time. • Step 5: Repeat the procedure for Trail Making Test Part B. • Scoring:• Results for both TMT A and B are reported as the number of seconds required to complete the • task; therefore, higher scores reveal greater impairment. • Average Deficient Rule of Thumb • Trail A 29 seconds > 78 seconds Most in 90 seconds • Trail B 75 seconds > 273 seconds Most in 3 minutes

Timed get up and go test

• Begin timing

• Rise from a standard arm chair

• Walk to a line on the floor approximately 10 feet away from the chair

• Turn and return to the chair

• Sin in the chair again

• End Timing

Timed bet up and Go test

• Precautions and Rules

• May use a cane or walker

• Test is valid only for a person able to walk unassisted

• Patient should be given one practice trial and timed 3 times and average times

Scoring in Seconds

• < 10 Freely mobile

• < 20 Mostly independent

• 20-29 Variable mobility

• >20 Impaired mobility

 Most people eventually have to retire their

driver's license. A) True B) False

Answer

• A) True

The State of California requires manditory reporting of all

patients diagnosed with dementia to the DMV?

• A. Yes

• B. No

Answer

• A. Yes

A MMSE of around _____ has been shown to have some

correlation with reduced driving skills?

• A. 24

• B. 22

• C. 20

• D. Less than 20

• E. 18

Answer

• D. Less than 20

TREATMENT OF ALZHEIMER DISEASE1. Which one of the following statements about the

use of acetylcholinesterase inhibitors for the treatment of Alzheimer disease is correct?

A. Donepezil (Aricept) is more effective than other acetylcholinesterase inhibitors for the treatment of

mild to moderate dementia.B. The benefit may be statistically significant, but

the clinical significance is unclear.C. It increases mortality by prolonging the QT

interval and causing sedation.D. Memantine (Namenda) is more effective than

acetylcholinesterase inhibitors in patients with mild Alzheimer disease.

Answer

• B. The benefit may be statistically significant, but the clinical significance is unclear.

Which one of the following treatment options is appropriate

for patients with moderate to severe Alzheimer disease?A. Selegiline (Eldepryl).

B. An insulin sensitizer plus a statin.

C. Vitamin E.D. Memantine.

Answer

• D. Memantine.

Which of the following interventions are considered

promising for the prevention of Alzheimer disease?

A. Treatment of hypertension.B. Vitamin E.C. Exercise.D. Statins.

Answer

• A. Treatment of hypertension.

• C. Exercise.

Potential Foods/Supplements• Potential Foods/Supplements• Axona (Accera)• Medical food that targets metabolic deficiencies• Resveratrol (red wine)• Anti-oxidant, “anti-aging”• Curcumin (curry spice)• Anti-inflammatory and anti-amyloid• Caffeine• Associated with lower risk for Parkinson’s• Alcohol in moderation

Keeping Your Brain Young

• Risk for brain aging

• 1/3 genetics

• 2/3 lifestyle choices

• Preventing brain cell loss more effective

• than repairing

Brain Healthy Lifestyle Strategies

• Associated with a Lower Risk for

• Dementia

• Physical conditioning

• Stress reduction

• Healthy diet

• Mental challenge/cognitive training

Healthy Brain Diet*• Moderate caloric intake to avoid illnesses associated• with obesity• Antioxidants• Dietary sources• Vitamin supplements• Omega-3 fatty acids• Mediterranean diet: fish, olive oil• Avoiding animal fats• Low glycemic index carbohydrates

Alzheimer’s Disease• Alzheimer disease is the most common form of dementia, affecting more than one-third of Americans older than 85 years. • It is characterized by progressive memory loss and cognitive decline. Amyloid plaque accumulation, neurofibrillary tau

tangles, and depletion of acetylcholine are among the pathologic manifestations of Alzheimer disease. • Although there are no proven modalities for preventing Alzheimer disease, hypertension treatment, omega-3 fatty acid

supplementation, physical activity, and cognitive engagement demonstrate modest potential. • Acetylcholinesterase inhibitors are first-line medications for the treatment of Alzheimer disease, and are associated with

mild improvements in cognitive function, behavior, and activities of daily living; however, the clinical relevance of these effects is unclear.

• The most common adverse effects of acetylcholinesterase inhibitors are nausea, vomiting, diarrhea, dizziness, confusion, and cardiac arrhythmias.

• Short-term use of the N-methyl-D-aspartate receptor antagonist memantine can modestly improve measures of cognition, behavior, and activities of daily living in patients with moderate to severe Alzheimer disease.

• Memantine can also be used in combination with acetylcholinesterase inhibitors. • Memantine is generally well tolerated, but whether its benefits produce clinically meaningful improvement is controversial. • Although N-methyl-D-aspartate receptor antagonists and acetylcholinesterase inhibitors can slow the progression of

Alzheimer disease, no pharmacologic agents can reverse the progression.• Atypical antipsychotics can improve some behavioral symptoms, but have been associated with increased mortality rates in

older patients with dementia. • There is conflicting evidence about the benefit of selegiline, testosterone, and ginkgo for the treatment of Alzheimer disease. • There is no evidence supporting the beneficial effects of vitamin E, estrogen, or nonsteroidal anti-inflammatory drug

therapy.

Recomendations• Acetylcholinesterase inhibitors should be considered first-line therapy for patients with

mild to moderate Alzheimer disease.• A• Combination therapy with an acetylcholinesterase inhibitor and memantine (Namenda)

should be considered in patients with moderate to severe Alzheimer disease.• B• Atypical antipsychotic agents can improve some behavioral manifestations of Alzheimer

disease but are associated with increased mortality in older patients.• B• Nonsteroidal anti-inflammatory drugs, vitamin E, testosterone, estrogen, statins, and

insulin sensitizers are not recommended for the treatment of Alzheimer disease.• B• Physicians should consider discontinuing treatment for Alzheimer disease in patients who

continue to decline despite maximal therapy.• C

Prevention• Numerous studies have assessed factors that may affect the incidence of Alzheimer

disease, such as the use of dietary supplements and pharmacologic agents, diet, socioeconomic factors, medical conditions, and environmental exposures.

• Although many studies have found an association, they have not proven that the relationship is causal or that modification of these factors reduces the risk of Alzheimer disease.

• Of the prevention strategies studied, treatment of hypertension, consumption of omega-3 fatty acids, physical activity, and cognitive engagement demonstrate some promise.

• However, larger randomized controlled trials are needed to further assess these results.6–

10 

• A recent consensus statement from the National Institutes of Health's State-of-the-Science Conference on Preventing Alzheimer's Disease and Cognitive Decline concluded that the current evidence is insufficient to support the association of any modifiable factor, pharmacologic agent, or dietary supplement with a reduction in the risk of Alzheimer disease

Medications• Acetylcholinesterase inhibitors reversibly bind and inactivate the enzyme that degrades acetylcholine, which is involved in

memory.12 • Donepezil (Aricept) is the only acetylcholinesterase inhibitor approved for use in all stages of the disease. • The N-methyl-D-aspartate receptor antagonist memantine (Namenda) is approved for treating moderate to severe disease, and

is thought to prevent excitatory amino acid neurotoxicity without interfering with the physiologic actions of glutamate, a neurotransmitter necessary for learning and memory.

• Studies of these drugs have usually assessed effectiveness using one of several scales, such as the Alzheimer's Disease Assessment Scale for Cognition (ADAS-cog; a 70-point scale), the Alzheimer's Disease Cooperative Study Activities of Daily Living inventory (ADCS-ADL; a 54-point scale), or the Severe Impairment Battery (SIB; a 100-point scale).

• In general, to be clinically significant (defined as a noticeable improvement by the patient or caregiver), an increase should be at least 10 percent of the scale length (i.e., 7 points on the ADAS-cog, 5 points on the ADCS-ADL, or 10 points on the SIB).

• ACETYLCHOLINESTERASE INHIBITORS• Acetylcholinesterase inhibitors are first-line agents for the treatment of mild to moderate Alzheimer disease, according to

existing guidelines.•  Most randomized controlled trials and systematic reviews have found no notable differences in effectiveness among the

various acetylcholinesterase inhibitors.•   Despite small variations in mechanisms of action, these agents have varying adverse effect profiles. The most common

adverse effects are nausea, vomiting, and diarrhea; cardiovascular and neurologic adverse effects are comparable. • The incidence of adverse effects is directly related to the dose administered.•  Rivastigmine (Exelon) patches may be better tolerated than oral rivastigmine.• Tacrine is no longer available because of safety and tolerability concerns.

Acetylcholinesterase inhibitors• A Cochrane review concluded that in patients with Alzheimer disease, treatment with

donepezil, galantamine (Razadyne), or rivastigmine for six months to one year resulted in slightly improved cognitive function by an average of −2.7 points on the ADAS-cog.

•  Improvements in behavior and activities of daily living also have been noted in patients treated with one of these three agents; however, none of the medications has a large treatment effect, and the clinical significance of these effects is questionable.

• Another systematic review concluded that, despite statistical significance, the improvement in patients with dementia taking acetylcholinesterase inhibitors was clinically marginal (−0.1 to −5.3 points on the ADAS-cog).

• Additional trials are needed to determine the benefits of long-term therapy and whether these agents are effective in patients with moderate to severe Alzheimer disease.

• It is reasonable to discontinue treatment if there is no improvement within six to eight weeks.

• Therapy may be restarted if symptoms worsen after the medication is tapered, because acetylcholinesterase inhibitors may be more effective for symptomatic control than previously recognized.

MEMANTINE• Memantine prevents excessive glutamatergic activity.

• A Cochrane review concluded that memantine at a dosage of 20 mg per day over six months slightly improved cognition (3 points on the SIB) and ability to do activities of daily living (1.3 points on the ADCS-ADL) in patients with moderate to severe Alzheimer disease.

• The effect on cognition was statistically significant in patients with mild to moderate dementia (1 point on the ADAS-cog) but is unlikely to have clinical significance.

• A small reduction in agitation was seen in patients taking memantine.

• Seventeen patients with moderate to severe Alzheimer disease would need to be treated for six months to prevent one episode of agitation.

• A meta-analysis concluded that memantine was ineffective for patients with mild Alzheimer disease, and the benefits for patients with moderate Alzheimer disease were inconsistent.

• Memantine is generally well tolerated and is often used with acetylcholinesterase inhibitors. One study randomized patients taking donepezil for moderate to severe Alzheimer disease to receive 20 mg of memantine or placebo every day for 24 weeks.

• Patients taking memantine showed mild improvement in cognition (+0.9 points versus −2.5 points with placebo on the SIB) and activities of daily living (−2.0 points versus −3.4 points with placebo on the ADCS-ADL). Another study evaluated the effectiveness and safety of 20 mg of memantine per day for 24 weeks in patients already taking donepezil, rivastigmine, or galantamine for mild to moderate Alzheimer disease.28 

• Adding memantine was not associated with a statistically significant improvement compared with placebo. The lack of adverse effects was consistent with findings in other memantine monotherapy studies.13,28

• Guidelines from the National Institute for Health and Clinical Excellence cite a study that found no improvement with memantine compared with placebo in patients who had moderate to severe Alzheimer disease.

• Patients taking memantine may have problems with adherence because it is typically taken twice per day. A once-daily extended-release formulation of memantine was approved by the U.S. Food and Drug Administration in June 2010

SELEGILINE• Selegiline (Eldepryl) is a monoamine oxidase type B inhibitor with

minimal anticholinergic effects. • A Cochrane review analyzed 17 double-blind, randomized, placebo-

controlled trials evaluating selegiline at a dosage of 10 mg per day for the treatment of Alzheimer disease.

• The authors concluded that cognition improved at four to six weeks in some trials; however, there were no differences after six weeks.

•  The benefits were found primarily in two studies; other trials did not support these findings.

• No differences in adverse effects were noted compared with placebo. • Currently, there is not enough evidence to recommend selegiline for

the treatment of Alzheimer disease.

ANTIPSYCHOTICS• Antipsychotics are not approved by the U.S. Food and Drug Administration for the treatment of Alzheimer

disease, although they are commonly used to treat behavioral symptoms. • Evidence suggests that olanzapine (Zyprexa) and risperidone (Risperdal) reduce aggression, and risperidone

reduces psychosis in patients with Alzheimer disease.• The Clinical Antipsychotic Trials of Intervention Effectiveness protocol for Alzheimer disease assessed the

effects of atypical antipsychotics on psychiatric and behavioral symptoms.•  It included 421 outpatients with Alzheimer disease and psychosis or agitated/aggressive behavior. • Patients were randomized to receive olanzapine, quetiapine (Seroquel), risperidone, or placebo for up to 36

weeks. • There were no clinically or statistically significant differences in functioning, care needs, or quality of life

between patients taking antipsychotics and those taking placebo. • Some clinical symptoms improved, such as anger, aggression, and paranoia. • Patients taking olanzapine experienced worsening functional ability at week 12 compared with those taking

placebo. • A small randomized, double-blind, placebo-controlled trial failed to demonstrate effectiveness of quetiapine

or rivastigmine for treatment of agitation in patients with Alzheimer disease in care facilities after 26 weeks.• At six weeks, a statistically significant decline in cognition was noted in patients taking quetiapine compared

with those taking placebo.

ANTIPSYCHOTICS• Older patients with dementia who are treated with atypical antipsychotics have a

twofold higher mortality rate than those taking placebo.•  One study found that new use of atypical antipsychotics was associated with an

increased risk of death at 30 days both in community-dwelling patients (hazard ratio = 1.31; 95% confidence interval, 1.02 to 1.70) and in those living in long-term care facilities (hazard ratio = 1.55; 95% confidence interval, 1.15 to 2.07). 33 

• Most of those deaths were related to cardiovascular or infectious causes, possibly because antipsychotics can prolong QT interval and cause sedation, which may increase the risk of aspiration.

• Other common adverse effects of antipsychotics include gait disturbances and extrapyramidal effects.

• Using atypical antipsychotics to treat behavioral symptoms such as agitation in patients with Alzheimer disease generally should be avoided because of adverse effects, although these agents may be appropriate in some situations.

Ineffective Therapies• Estrogen has been studied for the prevention and treatment of dementia. • A Cochrane review found no beneficial effect of long-term estrogen use on

cognitive function in patients with Alzheimer disease.• Estrogen does not enhance the effects of acetylcholinesterase inhibitors; no

benefit was found when it was used in combination with rivastigmine.• An updated Cochrane review concluded that there is no evidence supporting

the use of vitamin E for the prevention or treatment of Alzheimer disease, and it may be harmful in higher doses.

• Studies have demonstrated no beneficial effect of nonsteroidal anti-inflammatory drugs for the treatment of Alzheimer disease.

•  Statins and insulin sensitizers have not demonstrated benefit in clinical trials in patients with Alzheimer disease.

•  Systematic reviews have found no clear benefit of lecithin or acetyl-L-carnitine

Therapies with Conflicting Evidence• TESTOSTERONE• There is conflicting evidence on the benefit of testosterone in men with Alzheimer disease. • Two randomized, double-blind, placebo-controlled studies demonstrated benefit in

visuospatial cognition, but it is unclear if this effect is clinically meaningful.• A randomized, placebo-controlled trial examined the effect of 1% testosterone gel

supplementation (75 mg per day) in men with mild to moderate Alzheimer disease over a period of six months.

• No statistically significant benefits were detected, although testosterone treatment mildly improved patients' quality of life.

• A randomized, double-blind, placebo-controlled trial of men older than 65 years with limited mobility and low testosterone levels evaluated treatment with testosterone gel or placebo.

• The results showed a significantly increased incidence of adverse cardiovascular effects in the treatment group over six months (22 versus 5 percent in the placebo group; P = .05; number needed to harm = 6).

• Because of the risk of serious adverse effects and the paucity of clinically helpful effects, testosterone therapy in men with Alzheimer disease is not recommended.

GINKGO• A Cochrane Review evaluated 36 studies of ginkgo for the treatment of cognitive impairment and

dementia.• All but one study used the standard ginkgo extract EGb 761, at a dosage of 80 to 600 mg per day. • Ginkgo was not associated with a consistent, clinically significant benefit in persons with Alzheimer

disease. • A European study of 96 patients with Alzheimer disease demonstrated equal effectiveness among a

prescription ginkgo extract (240 mg per day), donepezil (5 to 10 mg per day), and a combination of the two agents.

• Because ginkgo is not available as a regulated prescription product in the United States, it is possible that the variability in dietary supplement quality may account for the difference in findings.

• Clinical evidence appears to support the safety of ginkgo, with no additional adverse effects reported compared with placebo.

• However, possible drug-supplement interactions must be considered in patients with Alzheimer disease who use ginkgo, especially the risk of bleeding with the use of aspirin, nonsteroidal anti-inflammatory drugs, or anticoagulants.

• This is noteworthy because many patients with Alzheimer disease take aspirin for cardiovascular health.

Approach to the Patient• Guidelines on the treatment of Alzheimer disease are available from a number of

organizations, including one developed by the American Academy of Family Physicians, in conjunction with the American College of Physicians.15 

• All guidelines emphasize the importance of educating patients and their families about the disease process and its expected course.

• Early referral to local support groups is recommended, and medicolegal issues such as driving and end-of-life planning should be addressed.

• The decision to treat with medication should be shared with the patient and caregivers, including a discussion of the modest clinical benefit, adverse effects, and cost.

• Physicians should consider discontinuing therapy in patients who continue to decline despite maximal therapy.

• The National Institute on Aging and the Alzheimer's Association have released recommendations on the diagnosis of dementia and mild cognitive impairment from Alzheimer disease; however, these guidelines do not address the treatment of Alzheimer disease and do not recommend the clinical use of biomarkers.

Possible Future Treatments• Many potential therapeutic agents are currently under investigation for the treatment of

Alzheimer disease.

• Amyloid precursor protein and enzymes involved in β-amyloid formation are thought to contribute to genetic forms of Alzheimer disease; therefore, interventions to reduce amyloid plaque burden by altering amyloid metabolism are being evaluated.

• Immunotherapy to promote clearance of β-amyloid from the central nervous system is being assessed.

• Advanced glycation end products are associated with aging.

• The advanced glycation end products receptor is a potential target to decrease plaque formation and inflammation.

• Other potential treatments include resveratrol, a compound from the skin of red grapes that may have beneficial effects on aging in mice, and latrepirdine, a N-methyl-D-aspartate receptor antagonist that may also weakly inhibit acetylcholinesterase, which may improve cognitive performance and is currently in phase 3 trials. Agents targeted against tau are other possible options

UPDATE ON VITAMIN B12 DEFICIENCY 4. A patient with paresthesias, weakness, and gait

abnormalities is found to have a vitamin B12 level of 100 pg per mL (73.78 pmol per L). Which one of the

following is indicated before starting treatment?A. Measurement of serum methylmalonic acid.

B. Measurement of serum homocysteine.C. Measurement of serum holotranscobalamin.

D. Use of Schilling test.E. No confirmatory testing is generally needed

before starting treatment.

Answer

• E. No confirmatory testing is generally needed before starting treatment.

 A patient with pernicious anemia is starting treatment. Which one of the following

statements about vitamin B12 supplementation is correct?

A. The patient should not breastfeed while undergoing treatment.

B. The patient must continue treatment indefinitely.

C. Intramuscular preparations are more effective than oral treatments.

D. Oral dosages in excess of 1 mg daily are considered unsafe.

Answer

• B. The patient must continue treatment indefinitely.

Which of the following patients require vitamin B12 supplementation?

A. Patients on a strict vegetarian diet.B. Patients with coronary artery disease

and high homocysteine levels.C. Patients with normal vitamin

B12 levels who want to prevent dementia.D. Pregnant women at high risk of

vitamin B12 deficiency.

Answer

• A. Patients on a strict vegetarian diet.

• D. Pregnant women at high risk of vitamin B12 deficiency

Vitamin B12 (cobalamin) deficiency• Vitamin B12 (cobalamin) deficiency is a common cause of megaloblastic anemia, a variety of neuropsychiatric

symptoms, and elevated serum homocysteine levels, especially in older persons.

• There are a number of risk factors for vitamin B12 deficiency, including prolonged use of metformin and proton pump inhibitors.

• No major medical organizations, including the U.S. Preventive Services Task Force, have published guidelines on screening asymptomatic or low-risk adults for vitamin B12 deficiency, but high-risk patients, such as those with malabsorptive disorders, may warrant screening.

• The initial laboratory assessment of a patient with suspected vitamin B12 deficiency should include a complete blood count and a serum vitamin B12 level.

• Measurements of serum vitamin B12 may not reliably detect deficiency, and measurement of serum homocysteine and/or methylmalonic acid should be used to confirm deficiency in asymptomatic high-risk patients with low normal levels of vitamin B12. Oral administration of high-dose vitamin B12 (1 to 2 mg daily) is as effective as intramuscular administration in correcting the deficiency, regardless of etiology.

• Because crystalline formulations are better absorbed than naturally occurring vitamin B 12, patients older than 50 years and strict vegetarians should consume foods fortified with vitamin B 12 and vitamin B12 supplements, rather than attempting to get vitamin B12 strictly from dietary sources.

• Administration of vitamin B12 to patients with elevated serum homocysteine levels has not been shown to reduce cardiovascular outcomes in high-risk patients or alter the cognitive decline of patients with mild to moderate Alzheimer disease.

Recommendations• Because it is as effective as intramuscular vitamin B12 injections, high-

dose oral vitamin B12 might be a reasonable choice for replacement in many patients with vitamin B12 deficiency, regardless of the etiology.

• B

• Vitamin B12 supplementation to reduce elevated serum homocysteine levels in patients with mild to moderate Alzheimer disease should not be given because it does not alter the rate of cognitive decline.

• B

• Vitamin B12 supplementation to reduce levels of serum homocysteine in high-risk patients is not recommended because it does not reduce cardiovascular mortality.

• A

B12• Pernicious anemia, which is characterized by an autoimmune-

mediated chronic atrophic gastritis, is a classically described cause of vitamin B12 deficiency

• other common causes include postsurgical malabsorption, dietary deficiencies, and vitamin B12 malabsorption from food.

• Because of extensive hepatic stores of vitamin B12, there may be a five- to 10-year delay between the onset of deficiency and the appearance of clinical symptoms.4

• In asymptomatic patients with low-normal levels of vitamin B12 (200 to 350 pg per mL [147.56 to 258.23 pmol per L]), elevated levels of the precursor compounds homocysteine and methylmalonic acid may prompt a decision to supplement patients with vitamin B12

B12• The true prevalence of vitamin B12 deficiency is difficult to estimate

because reports are based on values that vary because of inclusion criteria and individual laboratory methodology.

• In 1994, the Framingham Heart Study reported the prevalence of vitamin B12 deficiency, as defined by a serum vitamin B12 level less than 200 pg per mL and elevated levels of serum homocysteine, methylmalonic acid, or both, to be 12 percent among 548 community-dwelling older patients.

• However, most deficient patients did not have hematologic manifestations, and neurologic manifestations were not assessed

• According to unpublished data from the National Health and Nutrition Examination Survey, 3.2 percent of U.S. adults older than 50 years are estimated to have a serum vitamin B12 level less than 200 pg per mL

B12• Of particular interest to family physicians, an association between metformin

(Glucophage) use and vitamin B12 deficiency has been observed.

• A multicenter trial of 390 patients with diabetes mellitus receiving insulin therapy who were randomized to receive metformin, 850 mg three times daily, or placebo assessed the risk of vitamin B12 deficiency and low vitamin B12 levels over four years.7

• Compared with placebo, patients taking metformin had an increased risk of vitamin B12 deficiency (number needed to harm = 14 per 4.3 years) and low vitamin B12 levels (number needed to harm = 9 per 4.3 years).

• The effect increased with the duration of therapy.

• Although it is not known if prophylactic vitamin B12 supplementation prevents deficiency, it seems prudent to monitor vitamin B12 levels periodically in patients taking metformin

B12• Although the classic hematologic expression of vitamin B12 deficiency is a megaloblastic macrocytic anemia

characterized by an elevated mean corpuscular volume and mean corpuscular hemoglobin, and a peripheral smear containing macroovalocytes and hypersegmented neutrophils, up to 28 percent of affected patients may have a normal hemoglobin level, and up to 17 percent may have a normal mean corpuscular volume.

• Although folate deficiency may also produce a megaloblastic anemia, it is less common in the United States because of required folate fortification of enriched grain and cereal products.

•  Clinical manifestations of megaloblastic anemia include pallor, tachycardia, weakness, fatigue, and palpitations. The evaluation and management of macrocytosis has been recently reviewed inAmerican Family Physician (http://www.aafp.org/afp/2009/0201/p203.html).

• Unlike hematologic manifestations, the specific mechanism by which vitamin B12 deficiency affects the neurologic system is unknown.

• Common neurologic manifestations include paresthesias, weakness, gait abnormalities, and cognitive or behavioral changes.

• Vitamin B12 crosses the placenta and is present in breast milk.

• Pregnant women with low or marginal levels of vitamin B12 are at increased risk of having children with neural tube defects.

•  Exclusively breastfed children of mothers with vitamin B12 deficiency are at increased risk of failure to thrive, hypotonia, ataxia, developmental delays, anemia, and general weakness.

• Women at high risk of or with known vitamin B12 deficiency should supplement with vitamin B12 while pregnant or breastfeeding.1

Screening and Laboratory Assessment• Currently, the U.S. Preventive Services Task Force does not have published guidelines on screening asymptomatic adults for vitamin

B12 deficiency.

•   Other major medical organizations do not have any recommendations for screening low-risk patients.

• Family physicians should consider screening patients who have any risk factors listed in Table 1.1–3,6,7

• The initial laboratory assessment of a patient with suspected vitamin B12 deficiency should include a complete blood count and a serum vitamin B12 level.

• Several coexisting conditions may falsely lower serum B12 levels, including oral contraceptive use, multiple myeloma, pregnancy, and folate deficiency.

• In contrast, falsely normal levels may be seen in patients with liver disease, myeloproliferative disorders, or renal disease.

• Although many research studies and clinical laboratories define vitamin B12 deficiency at a level of less than 150 pg per mL (110.67 pmol per L), or in some cases 200 pg per mL, patients with values above these levels may be symptomatic and benefit from treatment.

• Vitamin B12 levels greater than 350 pg per mL seem to be protective against symptoms of vitamin B12 deficiency.

• In patients with clinical symptoms of vitamin B12 deficiency and low levels of serum vitamin B12, no further confirmatory testing is generally needed before treatment is initiated.

• Verification with serum methylmalonic acid and/or serum homocysteine level may be necessary in asymptomatic patients with high-risk conditions, symptomatic patients with low-normal levels of vitamin B12 (200 to 350 pg per mL), or symptomatic patients in whom vitamin B12 deficiency is unlikely but must be excluded.

• Elevated levels of serum homocysteine and methylmalonic acid have been shown to be highly sensitive markers for vitamin B12 deficiency.

• Testing is widely available,5,8  but expensive, and multiple conditions may falsely elevate serum homocysteine and methylmalonic acid levels (Table 3).15 Because serum methylmalonic acid level is as sensitive as, but more specific than, serum homocysteine level for vitamin B12 deficiency, it is the confirmatory test of choice.8,15 Serum holotranscobalamin level, which is reduced in vitamin B12deficiency, compared favorably with homocysteine and methylmalonic acid levels as a confirmatory test in one study, but further trials are needed before its widespread use for this purpose can be recommended

Treatment• Treatment of clinical vitamin B12 deficiency has traditionally been accomplished by intramuscular injection of crystalline

vitamin B12 at a dosage of 1 mg weekly for eight weeks, followed by 1 mg monthly for life.

• In a 2005 Cochrane review, patients who received high dosages of oral vitamin B12 (1 to 2 mg daily) for 90 to 120 days had an improvement in serum vitamin B12 similar to patients who received intramuscular injections of vitamin B12.

• These results were consistent in patients regardless of the etiology of their vitamin B12 deficiency, including malabsorption states and pernicious anemia.

• Given the lower cost and ease of administration of oral vitamin B12, this might be a reasonable choice for replacement in many patients.

• In cases of megaloblastic anemia, reticulocytosis generally occurs within a few days, and the hematocrit generally normalizes over several weeks.

• Advanced neurologic symptoms may not respond to replacement.

• Vitamin B12 has been demonstrated to be safe in doses up to 1,000 times the recommended dietary allowance and is safe in pregnancy.

• The bioavailability of sublingual vitamin B12 appears to be equivalent to oral vitamin B12, but there is no evidence that sublingual delivery offers any advantage over oral preparations.22

• There are no clinical guidelines for the treatment of subclinical vitamin B12 deficiency (asymptomatic patients with decreased levels of vitamin B12 and elevated levels of homocysteine and/or methylmalonic acid). Physicians may opt to treat these patients and monitor for improvement of metabolic markers, particularly in populations at high risk of clinical vitamin B12 deficiency, or observe these patients and periodically reassess their levels of vitamin B12, homocysteine, and/or methylmalonic acid.

• Patients with subclinical vitamin B12 deficiency will need at least 1 mg of vitamin B12 daily

HERPES ZOSTER AND POSTHERPETIC NEURALGIA:

PREVENTION AND MANAGEMENT7. Which one of the following statements about the clinical features of acute herpes

zoster (shingles) is correct?A. The prodrome may include abnormal skin

sensation.B. The ophthalmic area is the most common

site of eruption.C. The rash is usually bilateral.

D. Lesions typically heal within seven to 10 days.

Answer

• A. The prodrome may include abnormal skin sensation.

Which one of the following statements about the management of acute herpes zoster is correct?

A. Antiviral therapy during the acute phase has been proven to prevent postherpetic neuralgia.

B. Topical antiviral agents reduce the severity and duration of symptoms.

C. Antiviral therapy alone is usually sufficient to control pain in patients with acute herpes zoster.

D. Adding corticosteroids to antiviral therapy decreases the pain associated with acute herpes

zoster.

Answer

• D. Adding corticosteroids to antiviral therapy decreases the pain associated with acute herpes zoster.

Which of the following increase the risk of developing neuralgia

after acute herpes zoster?A. Male sex.

B. History of prodromal pain.C. Mild pain during the acute

phase.D. Older age.

Answer

• B. History of prodromal pain.

• D. Older age.

Herpes Zoster and Postherpetic Neuralgia: Prevention and Management

• Herpes zoster (shingles) is diagnosed clinically by recognition of the distinctive, painful vesicular rash appearing in a unilateral, dermatomal distribution.

• An estimated 1 million cases occur in the United States each year, and increasing age is the primary risk factor.

• Laboratory testing, including polymerase chain reaction, can confirm atypical cases. • Treatment with acyclovir, famciclovir, or valacyclovir decreases the duration of the rash. • Adjunct medications, including opioid analgesics, tricyclic antidepressants, or corticosteroids,

may relieve the pain associated with acute herpes zoster. • There is conflicting evidence that antiviral therapy during the acute phase prevents

postherpetic neuralgia. • Postherpetic neuralgia in the cutaneous nerve distribution may last from 30 days to more

than six months after the lesions have healed. • Evidence supports treating postherpetic neuralgia with tricyclic antidepressants, gabapentin,

pregabalin, long-acting opioids, or tramadol; moderate evidence supports the use of capsaicin cream or a lidocaine patch as a second-line agent.

• Immunization to prevent herpes zoster and postherpetic neuralgia is recommended for most adults 60 years and older.

Herpes Zoster• Antiviral therapy should be initiated within 72 hours of onset of the rash in

patients with acute herpes zoster to increase the rate of healing and decrease pain.• A• Based on individual patient characteristics, a tricyclic antidepressant, tramadol

(Ultram), long-acting opioid, or anticonvulsant (i.e., gabapentin [Neurontin] or pregabalin [Lyrica]) should be selected to decrease the pain of postherpetic neuralgia.

• A• If topical therapy is indicated, capsaicin cream (Zostrix) or a lidocaine patch

(Lidoderm) may decrease pain in patients with postherpetic neuralgia.• B• Herpes zoster vaccine (Zostavax) should be given to most persons 60 years and

older to prevent herpes zoster and postherpetic neuralgia.• B

Clinical Presentation• Prodromal symptoms include malaise, headache, photophobia, abnormal skin

sensations, and occasionally fever. • These symptoms may occur one to five days before the appearance of the rash.• Abnormal skin sensations range from itching and burning to hyperesthesia and

severe pain. • The intensity of the pain may lead to a misdiagnosis, such as renal colic or

myocardial infarction, depending on location.• The rash (Figure 1) begins as maculopapular lesions in a unilateral, dermatomal

distribution that rarely crosses the midline. • Lesions progress to clear vesicles that become cloudy within three to five days,

then crust and heal within two to four weeks. • Scarring and changes in pigmentation may occur. Dermatomes of the back and

face are most often affected, although multiple dermatome involvement is possible.

Diagnosis• The diagnosis of herpes zoster is usually clinical, based

on recognition of the distinctive presentation and rash. • Cases of herpes zoster without a rash (zoster sine

herpete) are difficult to diagnose and require laboratory confirmation of varicella-zoster virus reactivation.

• Fluid obtained from vesicles may be evaluated with polymerase chain reaction testing, viral culture, or direct immunofluorescent antigen staining.

• lists the accuracy of diagnostic testing for herpes zoster

Complications• Postherpetic neuralgia is the most common complication of herpes zoster.

• It occurs in approximately 30 percent of patients older than 80 years and in approximately 20 percent of patients 60 to 65 years; it is rare in patients younger than 50 years.

• Replication of the varicella-zoster virus in the basal ganglia destroys the nerves, leading to pain in the affected dermatome.

• Postherpetic pain may take several forms, including allodynia (nonpainful stimulus perceived as painful), hyperpathia (slightly painful stimulus perceived as very painful), and dysesthesia (abnormal sensation with no stimuli).

• Women are at greater risk of postherpetic neuralgia.

• Additional risk factors include older age, moderate to severe rash, moderate to severe acute pain during the rash, ophthalmic involvement, and history of prodromal pain.

• Postherpetic neuralgia may persist from 30 days to more than six months after the lesions have healed, and most cases resolve spontaneously.

• Herpes zoster ophthalmicus (ophthalmic zoster) occurs in 5 to 10 percent of patients with herpes zoster and may lead to permanent vision loss and cranial nerve palsies.

•  Urgent ophthalmology referral is recommended in these patients. Superimposed bacterial skin infections with streptococci and staphylococci should be treated with appropriate oral antibiotics.

• Encephalitis, meningitis, myelitis, and disseminated cutaneous and visceral disease may occur in patients with severe immunosuppression.

Management of Acute Herpes Zoster• Antiviral therapy is first-line treatment and should be initiated within 72 hours of rash

onset to increase the rate of healing and decrease pain.

•  No study has investigated the effectiveness of later initiation of antiviral therapy, but it is believed to benefit patients with active vesicle eruptions.

• Acyclovir (Zovirax), famciclovir (Famvir), and valacyclovir (Valtrex) are approved by the U.S. Food and Drug Administration (FDA) for the treatment of acute herpes zoster. These agents are considered safe and are well tolerated with minimal adverse effects (e.g., headache, nausea).

• All three drugs are available in a generic form, although acyclovir is significantly less expensive than famciclovir or valacyclovir.

• These antiviral agents decrease the severity and duration of acute herpes zoster.

• In one randomized controlled trial, valacyclovir led to complete pain resolution sooner than acyclovir (44 versus 51 days) and required less frequent dosing

• Famciclovir has shown similar effectiveness to valacyclovir.

•  Topical antiviral agents are not effective

Herpes Zoster• Although antiviral medications slow the production of the virus and decrease the viral load in the dorsal root ganglia,

evidence showing that these medications alter the incidence and course of postherpetic neuralgia is inconsistent.• Some studies suggest that no antiviral agent prevents postherpetic neuralgia, whereas others report reduced duration of

symptoms.• Famciclovir and valacyclovir are associated with better outcomes than placebo or acyclovir.• Antivirals alone are usually insufficient to relieve the often debilitating pain of acute herpes zoster.• Mild to moderate pain may be controlled with acetaminophen or nonsteroidal anti-inflammatory drugs, alone or in

combination with a weak opioid or tramadol (Ultram).•  Moderate to severe pain requires scheduled opioids (e.g., oxycodone, morphine).•  The intensity of pain during the acute attack is an important predictor for the development of postherpetic neuralgia,

and medications given during this phase may influence the outcome of later interventions for postherpetic neuralgia.• If pain does not rapidly respond to opioid analgesics or if opioids are not tolerated, the prompt addition of an adjunctive

therapy should be considered.3 Nortriptyline (Pamelor), gabapentin (Neurontin), and pregabalin (Lyrica) have been recommended, but they have not been extensively studied for pain relief in patients with acute herpes zoster.

• The addition of corticosteroids to acyclovir decreases the pain of acute herpes zoster  and speeds lesion healing and return to daily activities.

• Combination therapy with corticosteroids and antivirals should be considered in older patients with no contraindications.

•  Although corticosteroids have anti-inflammatory effects that could be expected to decrease nerve damage and the risk of postherpetic neuralgia, a Cochrane review found no significant difference between corticosteroids and placebo in preventing postherpetic neuralgia six months after onset of the rash.

Management of Postherpetic Neuralgia

• Theoretical models suggest that reducing pain during the acute phase of herpes zoster may stop the initiation of the mechanisms that cause chronic pain, thus reducing the risk of postherpetic neuralgia.

• If the condition develops, treatment focuses on preventing a chronic pain syndrome.

• Several medications have proved effective for postherpetic neuralgia and should be selected based on individual patient characteristics.

• Many of these medications require dosing adjustment in older patients and in those with reduced creatinine clearance.

Treatment PHN• Tricyclic antidepressants, such as amitriptyline, desipramine (Norpramin), and nortriptyline, have pain-modulating effects in neuropathic and other chronic pain

states.

• They are the mainstay of treatment for postherpetic neuralgia, and evidence supports their effectiveness.

• In older patients, tricyclic antidepressants should be started at lower doses given at bedtime, and the patient should be monitored for adverse effects, including interactions with other medications.

• Opioid medications have analgesic effects and are helpful for postherpetic neuralgia.

• Studies have shown that patients taking oxycodone, morphine, or methadone have better pain relief than those taking placebo.

• Opioids should be carefully adjusted in all patients for clinical response.

• Oxycodone is of special concern because of a 50 percent higher serum concentration when creatinine clearance is less than 60 mL per minute per 1.73 m 2 (1.00 mL per second per m2).

•  Morphine and methadone have been shown to provide better pain relief than tricyclic antidepressants.

• A Cochrane review of seven trials found tramadol to be effective for neuropathic pain, including postherpetic neuralgia.

• Studies involving anticonvulsants showed that gabapentin and pregabalin reduce pain from postherpetic neuralgia by approximately 50 percent.

• Another study comparing the maximum tolerated dosages of gabapentin and nortriptyline found that both reduced pain scores, but gabapentin was associated with fewer adverse effects.

• The FDA has approved two topical medications for treatment of postherpetic neuralgia. A Cochrane review that included a few small studies of topical lidocaine patches (Lidoderm) reported benefit in some patients, but found insufficient evidence to recommend them as first-line therapy

• Based on poor-quality studies, capsaicin cream (Zostrix), which is derived from peppers, provides limited reduction in postherpetic neuralgia.

• Topical antiviral agents, such as idoxuridine (not available in the United States), may reduce the prevalence of postherpetic neuralgia in immunocompetent patients, but the evidence is low-quality.

• Intrathecal preservative-free methylprednisolone (not available in the United States) is effective for intractable postherpetic neuralgia.

• However, it should be used only if other agents have been ineffective.

• Other treatments for postherpetic neuralgia have been investigated, but not all are effective.

• Aspirin cream has been helpful in a few small studies, but the benefit is not considered significant.

• No recommendations can be made for the anticonvulsants valproate (Depakote)19 and carbamazepine (Tegretol)20 because of limited data. Anesthetic agents such as N-methyl-D-aspartate receptor antagonists play a role in processing pain signals and could potentially benefit patients with postherpetic neuralgia. Ketamine (Ketalar), dextromethorphan, and memantine (Namenda) have not been shown to improve pain compared with placebo

Prevention• Herpes zoster and postherpetic neuralgia are preventable conditions. • The Centers for Disease Control and Prevention recommends one

dose of the herpes zoster vaccine (Zostavax) for persons 60 years and older.

•  The FDA recently approved the herpes zoster vaccine for healthy patients between 50 and 59 years of age, and the Advisory Committee on Immunization Practices is expected to vote on recommending the vaccine for this population in late 2011.

•  Patients may be immunized without serologic testing and regardless of any history of varicella virus infection or herpes zoster.

•  Coadministration with other inactivated vaccines common in this age group is considered safe

Prevention• The Shingles Prevention Study found the herpes zoster vaccine to be 51.3 percent effective in

preventing herpes zoster and 66.5 percent effective in preventing postherpetic neuralgia (when defined as pain rated as at least a 3 out of 10 on a severity scale that persisted for at least 90 days after rash onset).

• Vaccination has also been shown to reduce the incidence of postherpetic neuralgia by 39 percent among patients who develop herpes zoster.

• The number needed to treat to prevent one case over three years is 58 for herpes zoster and 364 for postherpetic neuralgia.

• Fewer than 10 percent of eligible persons receive the herpes zoster vaccine.•  Patient surveys show that many do not know about it or believe it is not needed.• Cost is a significant issue with the vaccine. The average wholesale cost of Zostavax is $194 per

dose, and many insurance plans do not cover it. • Another concern is storage. The vaccine must be frozen, and in-office administration requires a

monitored, temperature-controlled freezer. • Patients may be referred to a pharmacy for immunization or given a prescription for the vaccine, which

must be kept cold and administered within 30 minutes.• Physicians can play a key role in overcoming these barriers and should encourage vaccination to

prevent herpes zoster and postherpetic neuralgia

Food allergy• Food allergy can be difficult to diagnose. Currently, there is no treatment, and it can be managed

only by avoidance of allergens and treatment of symptoms.

• Because diagnosis and management options vary, the National Institute of Allergy and Infectious Diseases (NIAID) helped develop guidelines to provide physicians with “best practices” for diagnosing and treating patients with food allergy.

• This summary guideline will review some of the diagnostic recommendations.

• Specific clinical syndromes may occur as a result of food allergy. These include:

• Food-induced anaphylaxis (a serious allergic reaction with a rapid onset that may cause death)

• Gastrointestinal food allergies (i.e., immediate gastrointestinal hypersensitivity, eosinophilic esophagitis, eosinophilic gastroenteritis, food protein–induced allergic proctocolitis, food protein–induced enterocolitis syndrome, and oral allergy syndrome)

• Cutaneous reactions (i.e., acute urticaria, angioedema, atopic dermatitis, allergic contact dermatitis, and contact urticaria)

• Respiratory manifestations of immunoglobulin E (IgE)-mediated food allergy

• Heiner syndrome (a rare disease in infants and young children caused primarily by the ingestion of milk)

COMMON ADVERSE EFFECTS OF ANTIRETROVIRAL THERAPY FOR HIV

DISEASE10. Which one of the following statements about

antiretroviral therapy (ART) is correct?A. Lipid disorders associated with ART can be

managed with lipid-lowering medications.B. When a rash occurs in patients taking the non-

nucleoside reverse transcriptase inhibitor etravirine (Intelence), the medication generally can be

continued safely.C. Heavy alcohol use can offset ART-induced

cardiovascular risk.D. Treatment for patients with ART-induced

proteinuria includes dietary protein restriction.

Answer

• A. Lipid disorders associated with ART can be managed with lipid-lowering medications.

Which one of the following types of medications generally should not be used in combination with

ART?A. Most psychiatric medications.

B. Most antiemetics.C. Herbal medications.D. Oral contraceptives.

Answer

• C. Herbal medications.

Which of the following should be recommended in patients with human

immunodeficiency virus infection?A. Initiating ART in patients with CD4 cell

counts of 500 per mm3 or less.B. Screening for dyslipidemia at least

annually in patients taking ART.C. Annual or biannual calculation of

glomerular filtration rate.D. Dual-energy x-ray absorptiometry in select

patients taking ART.

Answer

• A. Initiating ART in patients with CD4 cell counts of 500 per mm3 or less.

• B. Screening for dyslipidemia at least annually in patients taking ART.

• C. Annual or biannual calculation of glomerular filtration rate.

• D. Dual-energy x-ray absorptiometry in select patients taking ART.

PUTTING PREVENTION INTO PRACTICE: AN EVIDENCE-BASED APPROACH 

ASPIRIN FOR THE PREVENTION OF CARDIOVASCULAR DISEASE

13. Which one of the following statements about aspirin use and cardiovascular disease (CVD) is correct?

A. The optimal dosage of aspirin for preventing CVD is 75 mg per day.

B. The optimal dosage of aspirin for preventing CVD is not known, but 75 mg per day seems to be as effective as a higher

dosage.C. Nonsteroidal anti-inflammatory drug therapy combined with aspirin use neither increases nor decreases the risk of

serious gastrointestinal bleeding.D. The U.S. Preventive Services Task Force recommends against the use of aspirin for CVD prevention in men and

women 80 years and older.

Answer

• B. The optimal dosage of aspirin for preventing CVD is not known, but 75 mg per day seems to be as effective as a higher dosage.

CLINICAL EVIDENCE HANDBOOKCROHN DISEASE

14. A 28-year-old man with Crohn disease presents to the emergency department with

abdominal pain and decreased bowel sounds on auscultation. Evaluation confirms an acute

exacerbation. Which of the following treatments have been shown to induce

remission in patients with Crohn disease?A. Oral corticosteroids.

B. Infliximab.C. Antibiotics.D. Probiotics.

Answer

• A. Oral corticosteroids.

• B. Infliximab.

Prevalence• The prevalence of peanut and tree nut allergies in the United States is 0.6

percent and 0.4 to 0.5 percent, respectively. • Approximately 0.6 percent of children and 2.8 percent of adults in the United

States have a seafood allergy. • A Danish cohort study of children followed from birth to three years of age

determined that 2.2 percent of children had confirmed milk allergy.• Guidelines• Food allergy should be suspected in the following persons: those with

anaphylaxis or any combination of symptoms in that occur within minutes to hours of ingesting food, especially in young children; those with symptoms that have occurred more than once with the ingestion of a particular food; children with certain conditions, including moderate to severe atopic dermatitis, eosinophilic esophagitis, enterocolitis, enteropathy, and allergic proctocolitis; and adults with eosinophilic esophagitis.

• History is useful for identifying foods that may be responsible for IgE-mediated allergic reactions, but when used alone, it lacks sensitivity and specificity.

• It may be more useful for diagnosing immediate food-induced allergic reactions versus delayed reactions. • Further assessment (e.g., laboratory studies, food challenges) is needed to confirm a diagnosis. • Physical examination alone also cannot be considered diagnostic for food allergy, but it can provide signs consistent with an allergic reaction or

disorder associated with food allergy. • History and physical examination should be used in combination to help with the diagnosis of food allergy.• Studies have shown that 50 to 90 percent of presumed food allergies are not actually allergies; therefore parent- and patient-reported food allergy must

be confirmed by appropriate evaluation. • A skin prick test should be used to help determine which foods could be causing IgE-mediated food-induced allergic reactions; however, when used

alone, a skin prick test cannot be considered diagnostic. • Insufficient evidence exists to support the use of intradermal testing or total serum IgE measurements for diagnosing food allergy; therefore, neither

test should be used. • Allergen-specific IgE tests can be useful for identifying foods that are thought to provoke IgE-mediated food-induced allergic reactions, and specified

cutoff levels (defined as 95 percent predictive values) may be more predictive than skin prick tests in certain patients, but are not diagnostic of food allergy when used alone.

• There is insufficient evidence to support the use of the atopy patch test for the evaluation of food allergy; therefore, it should not be routinely used in the evaluation of non-contact food allergy.

• The literature does not support the idea that using skin prick tests, allergen-specific IgE tests, and atopy patch tests in combination provides any significant advantage over the use of skin prick tests or allergen-specific IgE tests alone; therefore, routinely using these tests in combination for diagnosis of food allergy is not recommended.

• Elimination of at least one specific food from the diet may be useful in diagnosing food allergy, especially foods that may cause some non–IgE-mediated (e.g., food protein–induced enterocolitis syndrome, allergic proctocolitis, Heiner syndrome) and some mixed IgE- and non–IgE-mediated (e.g., eosinophilic esophagitis) food-induced allergic disorders.

• Treatment for food allergies consists of dietary avoidance of certain allergens. For more information on treatments for specific food allergies, please refer to the full guidelines.

ASA• Cardiovascular disease (CVD) is the leading cause of death in adults, accounting for one out of every 2.8 deaths in the United States.• Daily use of low-dose (75 to 325 mg) aspirin as a secondary preventive measure reduces all-cause mortality by 18 percent, and subsequent myocardial infarctions by

30 percent in persons with known CVD.

• Aspirin use prevents CVD by inhibiting cyclooxygenase, which blocks the formation of thromboxane A2 and thus disrupts platelet aggregation and prevents vasoconstriction.

•  The American Heart Association recommends that daily aspirin be used indefinitely in all patients with known CVD, unless contraindicated, for secondary prevention.

• There is interest in and controversy over daily use of aspirin for primary prevention of CVD in persons who have yet to demonstrate clinical evidence of CVD. • Several major randomized clinical trials and subsequent meta-analyses involving more than 96,000 participants have demonstrated that daily aspirin use in persons at

moderate to high risk of CVD can reduce the risk of a first-time CVD event by at least 28 percent.• However, recent studies have questioned whether the benefits of daily aspirin for primary cardioprevention outweigh the risks of gastrointestinal (GI) and

intracerebral hemorrhage.•  In addition, a recent randomized controlled trial involving 39,876 relatively healthy women 45 years and older suggested that daily aspirin therapy may not decrease

the risk of acute myocardial infarction in women, although there was a 17 percent decreased risk of stroke.• Currently, two large, international randomized controlled trials (n > 10,000) are investigating the benefit of daily aspirin therapy for primary cardioprevention in

select populations: the ASCEND trial (a study of cardiovascular events in diabetes) and the ASPREE trial (aspirin in reducing events in the elderly). Results from these trials should be available within the next five years.

• After critically analyzing the evidence of potential benefits and harms of aspirin therapy, the U.S. Preventive Services Task Force (USPSTF) reaffirmed and clarified its position in 2009, concluding that aspirin is effective for primary CVD prevention.11 Aspirin should be recommended when benefits outweigh risks. The USPSTF found good evidence that aspirin use decreases myocardial infarctions in men 45 to 79 years of age, and strokes in women 55 to 79 years of age who are at increased risk of, but have not yet experienced, these events. Compared with its 2002 recommendation,6 the USPSTF's 2009 recommendation differentiates CVD risk by age group and sex, complicating physicians' task of determining patients' CVD risk.

• Physicians must now consider the 10-year myocardial infarction risk for men and 10-year stroke risk for women.• Aspirin therapy should be considered in men with a 10-year CVD risk of at least 4 percent in those 45 to 59 years of age, 9 percent in those 60 to 69 years of age, and

12 percent in those 70 to 79 years of age. • Aspirin therapy should be considered in women with a 10-year stroke risk of at least 3 percent in those 50 to 59 years of age, 8 percent in those 60 to 69 years of age,

and 11 percent in those 70 to 79 years of age. Several online calculators are available to help physicians determine these risks. • To assist physicians in better identifying patients who potentially would benefit from aspirin therapy, the American College of Preventive Medicine is studying the

use of a patient-friendly decision table.

ASA• When advising aspirin use, the USPSTF recommends considering the risk of GI bleeding. • The most widely recognized adverse effect of aspirin therapy is a modestly increased risk of GI bleeding; 769

persons need to be treated with aspirin to cause one additional major bleeding episode annually.• Aspirin-induced GI toxicity appears to be dose-dependent; higher aspirin doses increase the risk of bleeding.• It appears that in most persons, low-dose aspirin (81 mg) is best.• Increasing the dose to 325 mg does not increase the effectiveness, but does increase the risk of GI bleeding.• Aspirin for primary cardioprevention should be avoided in persons who have had a GI or cerebral bleeding

episode, and in those who are at risk of bleeding problems (e.g., bleeding disorder, severe liver disease, thrombocytopenia, concomitant anticoagulant therapy).

• For persons with an aspirin- induced bleeding ulcer, aspirin use in combination with a proton pump inhibitor may be safely restarted after the ulcer has healed.

•  A randomized controlled trial found that in those taking low-dose aspirin who had GI bleeding, continuous aspirin therapy may increase the risk of recurrent GI bleeding, but potentially reduces cardiovascular and cerebrovascular mortality rates.

•  Eradication of Helicobacter pyloridecreases the risk of recurrent GI bleeding in those taking low-dose aspirin.• Enteric-coated or buffered aspirin does not decrease the risk of GI toxicity.

ASA• As with any medication, the key to aspirin therapy for CVD prevention is appropriate use.

• A study evaluating 24 clinical preventive services considered effective by the USPSTF found that advising at-risk adults to consider taking daily aspirin was the most cost-effective preventive measure available for physicians.

•  If 90 percent of those who should be taking aspirin were doing so, it is estimated that an additional 45,000 lives would be saved each year.

• Despite this benefit, less than one-half of those who should be taking aspirin regularly are actually taking it.

• Although not reported, there are also persons taking daily aspirin for primary cardioprevention in whom the benefit is negligible or the risk is high.

• These persons should be cautioned against this practice until the benefit outweighs the risk.

• The factor most strongly associated with appropriate aspirin use is a conversation between the patient and physician.

• The National Committee for Quality Assurance has proposed that health plans measure their members' use of aspirin, as well as the extent to which physicians discuss aspirin use with their patients.

• Determining patients' CVD risk and discussing appropriate aspirin use with them should be a priority for all family physicians.

Syndrome vs etiology• dementia and depression syndromes, not• etiologies• Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) definitions• dementia—impairment in memory and 1 of following (aphasia; apraxia; agnosia; impaired executive function)• functional impairment• deficits not due to delirium• major depressive episode—5 of following• within 2-wk period (depressed or sad mood• diminished interest or pleasure• weight loss or gain• insomnia or hypersomnia• psychomotor agitation or retardation• fatigue or loss of energy• feelings of worthlessness or excessive or inappropriate guilt• poor concentration or indecisiveness• recurrent thoughts of death or suicidality)• not bipolar mixed episode• functional impairment• not better accounted for by another condition

Etiologies• dementia—Alzheimer disease (AD)• Cerebrovascular disease (CVD)• Lewy body disease• other brain diseases (eg, HIV)• Depression• depression—AD CVD• substance induced• genetic predisposition• reaction to psychosocial stress

Relationship between depression and dementia• cognitive impairment can be feature of depressive episode (may not always

fully remit with treatment)

• in late-life depression, often see slowed information processing that affects all cognitive domains

• depression occurs in 50% of patients with dementia

• recent meta-analysis showed depression doubles chance of developing AD

• unclear if depression first symptom (prodrome) or independent risk factor for dementia

• evidence exists for both explanations

• risk factor—more plaques tangles seen in brains of people with AD who had lifelong depression

• prodrome—most people who had depression with cognitive features never recovered and went on to develop dementia

Pathways linking depression to persistent cognitive impairmentand dementia:

• patient who has some depression-associated neuropathology (eg, hippocampal volume loss) may develop mild cognitive impairment (MCI), and this may remain stable over time

• patient with depression and underlying AD neuropathology can progress to frank dementia (AD)

• Patients with CVD develop frontal lobe damage, and often get depression with MCI (ie, vascular depression), which can progress over time to vascular dementia (VaD)

Frontotemporal dementia (FTD)

• tends to occur at younger age than AD (incidence peaks in 60s)

• earliest symptoms can resemble depression or mood disorder

Clinical clues to depression in older patient who denies sadnessor depression

• unexplained somatic complaints• hopelessness• Helplessness• Anxiety• memory complaints• Anhedonia• Slowed movement• Irritability• lack of interest in personal care

Evaluation of older patient presenting with depression

• look for red flags for dementia• detailed patient history—personality changes• risk factors (RFs) for dementia• thorough review of systems• complete physical and neurologic examination—look for focal neurologic findings• Parkinsonism• gait abnormalities• cognitive evaluation—at minimum, Mini-Mental State Examination (MMSE) in all patients• consider more extensive evaluation if dementia red flags present (options include modified MMSE• clock-drawing test• trail-making test• Montreal Cognitive Assessment )• laboratory evaluation—routine screening tests• Consider erythrocyte sedimentation rate or C-reactive protein• Antinuclear antibody or rheumatoid factor• HIV• Lyme disease• Lumbar puncture• Electroencephalography• neuroimaging—head computed tomography or (preferably) brain magnetic resonance imaging• positron emission tomography or single-photon emission• computer tomography for distinguishing AD from FTD

Beware of delirium• sad mood does not equal depression

• Delirium common in acute care settings and may present with depressive symptoms

Prevention of dementia• potentially modifiable RFs for dementia vascular RFs

(smoking; hypertension [HTN], high body mass index and/or high cholesterol in midlife; diabetes)

• Steps to reduce vascular RFs—control of HTN and cholesterol

• smoking cessation

• weight loss

• Mediterranean diet

• Cognitive protective factors—education

• exercise

Treatment• if unsure whether patient has depression, dementia, or both— treat

depression first and monitor for response• In general, antidepressants effective and have favorable risk-benefit

profiles• start with selective serotonin reuptake inhibitors (SSRIs)• avoid those that have many drug-drug interactions, eg, paroxetine,

fluoxetine• if ineffective, serotonin–norepinephrine reuptake inhibitors (SNRIs;

eg, duloxetine, venlafaxine, and mirtazapine) also good for depression and anxiety

• avoid tricyclic antidepressants• use benzodiazepines with caution

Driving in the Elderly• Introductory remarks• driving important medical, social, and public health issue• normal aging and associated conditions may compromise

ability to drive safely• most older drivers self-adjust driving habits• growing apprehension about older drivers, and evidence

suggests families and patients increasingly turn to health care providers (HCPs) for guidance

• Issue requires balancing public safety vs individual autonomy, and currently no clear guidelines

Older drivers• by 2020, 25% of drivers will be >65 yr of age• older adults see driving as key to independence, self-esteem,

and socialization• loss of license can be devastating and may result in

depression, isolation, and sometimes loss of home• 33% of people >90 yr of age still driving• study of patients referred to geriatric assessment clinic found

25% still driving• (>50% had MMSE scores <24/30; 33% to 50% had problems

with activities of daily living [ADLs and instrumental ADLs )

Performance of older drivers• elderly have lowest crash rate

• per driver of any age group (in context of low-risk driving) but

• have second highest rate per miles driven; motor vehicle

• crashes by older adults more often due to inattention and difficulty

• with visual processing; much more likely to result in injury,

• hospitalization, and death; much of morbidity and mortality attributed to drivers’ poor physical condition

• Also related to cars driven

• crashes usually low impact

Violations by older drivers

• occur at complicated traffic patterns that require quick response, full peripheral vision, and interaction with other drivers (typically occur in merging and yielding right of way)

Types of crashes

• typically multiple-vehicle at intersections

• left-hand turn significant cause of crashes by older adults (requires judgment of speed and distance, which becomes impaired with aging)

Impact of aging on driving skills

• driving complex but highly practiced skill (and older people can drive safely despite significant losses)

• primary areas of concern when assessing older driver for safety visual problems, effect of chronic medical conditions and associated medications, mobility, and cognition

Age-related visual changes• decreased visual acuity

• restriction of horizontal peripheral field of vision

• lens changes and problems with glare (result in decreased ability to see low-contrast items at night)

• useful field of view (UFOV)—area over which driver can absorb visual information and make rapid decisions

• UFOV test assesses dynamic visual acuity and cognitive processing

• Strong correlation between size of UFOV and risk for crashes

Chronic medical conditions• affect driving skills and increase crash rates (true in

any age group)• medications associated with conditions (eg,

benzodiazepines, narcotics) can also influence crash rates

• Alcohol• contribution of alcohol to crashes well known• More common problem in elderly than realized• important to recognize risk and ask patients about alcohol

use

Mobility and function• driving physical activity requiring muscle strength and endurance

• osteoarthritis (OA)—prevalent problem in older adults

• affects joints involved in driving

• driving ability impaired by aches, pain, and weakness caused by OA and by effects of medications

• Dementia and driving

• controversial issue

• long assumed cognitive deficits associated with dementia impact driving

• People with dementia often do not self-restrict (1-2 yr after diagnosis, 50% continue to drive [50% get lost and/or crash on regular basis

• yet 50% of caregivers consider them safe drivers])

• Tests for dementia not good predictors of driving performance

Physician’s Guide to Assessing and Counseling Older Drivers

• developed by American Medical Association (AMA) in cooperation with National Highway Traffic Safety Administration

• available online at www.ama-assn.org/go/olderdrivers; provides• algorithm for office-based assessment of medical fitness to drive• Reporting laws: vary from state to state• important to know state law regarding older drivers• eg, in Maryland, no mandatory reporting by HCPs for medical

concerns• immunity given if report made in good faith; anonymity granted if

requested

Assessment of Driving-Related Skills (ADReS)• structured series of office tests for evaluating drivers at risk• assesses vision, cognition, and motor strength• functions as guide (not predictive)• when discussing tests with patient, be straightforward, kind, but tactful and clear• explain goal to keep patient driving and that tests may help identify areas that need to be

worked on to keep him or her safely on road as long as possible• Vision: tested with Snellen E chart• based on last full row patient can read clearly• assessment of visual fields done by confrontation• Cognition: evaluated with trail-making test, Part B (assesses working memory and selective

and divided attention; correlates well with ability to drive safely) and clock-drawing test• Mobility and motor strength: assessed with 20-ft rapid-pace walk (measures strength,

endurance, and balance) and manual test of motor strength (on 5/5 scale)• in addition, ask patient to demonstrate what it looks like when he or she tries to back up,

brake, and grip steering wheel (for evaluation of range of motion and grip strength)

What to do with ADReS score• score (as well as any red flags, eg, crash history, concern of family members)

directs intervention

• intervention requires tactful, candid discussion and may involve counseling patient on driving restrictions, physical therapy, or car adaptations

• observing driver provides critical information for deciding appropriate intervention

• gold standard is observation by driver rehabilitation specialist

• driving schools, American Automobile Association, or American Association of Retired Persons may also offer resources for skills assessment

• second best alternative to ask family member or other person patient trusts to drive with him or her and provide feedback

• recommended that any abnormal ADReS score should trigger intervention

• however, keep in mind ADReS extremely sensitive but not very specific (>33% of patients who fail ADReS still pass driving test with ease)

If driving needs to stop• most people eventually have to retire driver’s license (on average, women go for 10 yr at

end of life without driving, and men 7 yr)• recommended to talk to patient and involve family if possible• goal to reach collaborative agreement where all agree best thing to retire patient’s license• Transportation options available• best if it does not require that patient move• how to start discussion—depends on physician’s style and relationship with patient• focus on safety (risk to self and others)• Economic arguments have not proven successful• make sure patient understands what is being said• write prescription that says “do not drive”• may want to inform patient about state reporting laws and how they affect decision making• be sure to follow up for adherence to recommendations and for evidence of impact of

cessation of driving• do not put responsibility on patient’s family

If patient refuses to cooperate with assessment

• Guidelines and booklets available that can help patient and family deal with driving issues

• encourage patient to drive with family member or friend to get feedback on driving abilities

• Dealing with patient who lacks decision-making capacity

• Involve family/guardian/surrogate decision makers

• goals to re- tire driver and avoid conflict

• helpful interventions include hiding car, changing or hiding keys, or disabling car

Society’s role in controlling older adults’ ability to drive

• HCPs will get better tools for assessment and may get more involved and take on more responsibility

• governments have role in how they build roads and left-hand turn signs, and how they focus on age-based licensing

• insurance companies may limit ability to drive simply by raising rates for older drivers

• automobile industry can make smart cars that may help keep patients safe on road

Questions and Answers• Are there pieces of driving assessment algorithm

more highyield than others that could be used when physician has only few minutes to see patient?

• many components of algorithm can be done by person in office other than physician, and may interface with other assessments being done

• hard for speaker to say to not do trail-making test, Part B, because it has highest correlation with crash rates

• Any questions that can be added to review of systems that have higher predictability for identifying patients who need to undergo all parts of assessment algorithm?

• Other than general assessment of cognition, patient who has crashed once has high risk of crashing again (problem patient not always willing to offer that information or accept fault for crash)

• people who have fallen also at higher risk for crashes• Is there any data on 33% of patients who fail ADReS but go on to pass driving

test—are they more likely to crash than people who pass both? • no studies on this subset of patients• If patient disagrees with assessment that he or she should not drive, does

reporting him or her to Motor Vehicle Department run afoul of Health Insurance Portability and Accountability Act law?

• no, it should not• most states provide immunity if report made in good faith