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Continuity of Care in a VA Substance Abuse Treatment Program
Current Perspectives on Rheumatic Laboratory Tests
Breast Cancer Screening in Older Women
At age 82, Helen was healthy and active and living independently. A mother, grandmother, and great-grandmother, she enjoyed aerobics, tai chi, and walking, painting (which she also taught), writing poetry, and stimulating conversation. She took pride in looking much younger than her age and watched out for her older neighbors.
An active participant in her health care, Helen had been happy when, at 75, she was told by her primary care provider that she no longer needed regular mammograms. But one morning, seven years later, she felt a sharp pain in her right breast. Self-examination revealed a grape-sized lesion under her nipple. Helen sought immediate health care and was diagnosed with a stage IIb tumor.
Given an option of lumpectomy followed by radiation, Helen decided that a double mastectomy would better allow her to return to the life she had been living. After her surgery, however, Helen experienced a steady decline, with increasing pain, debilitating skin lesions, fractures, and edema. Against her will, she was moved to an assisted living facility, where she was too debilitated to participate in activities. Helen died six months later—three years after she discovered her breast lump.
The lack of clear breast cancer screening guidelines has left many providers confused about how to advise their patients, particularly women older than 75. Screening recommendations based on patient age alone are of insufficient value, as health status and life expectancy—which vary widely in this patient population—are also, along with patient preferences, important considerations. The purpose of this article is to present the reported benefits and risks of breast cancer screening among older women, in order to help primary care providers more effectively advise their elderly female patients in the decision-making process.
The Breast Cancer Screening Debate
There is strong consensus among expert advisory groups (the US Preventive Services Task Force,1 the American Cancer Society,2 the American College of Obstetricians and Gynecologists,3 the American Academy of Family Physicians,4 and the American Geriatrics Society5) that mammography is to be recommended to screen for the early detection of breast cancer in women between ages 50 and 75. However, a recent review of the randomized controlled studies on which these recommendations were based suggests that the benefits of mammography may be relatively minimal, and that the risks for overdiagnosis and overtreatment may be significant.6 None of these trials enrolled women older than 74, so further information is needed to make evidence-based decisions regarding breast cancer screening for the older woman. Currently available evidence for such decision making is limited to observational or retrospective analyses.6
Women 75 or older have a greater risk than younger women for breast cancer, but older women are also at greater risk for dying of another disease—even those who have breast cancer.7,8 Thus, as with any health screening, it is advisable that a woman’s health status be carefully considered before screening decisions are made.
Breast Cancer in Older Women
Breast cancer incidence increases with age. Almost half of all invasive breast cancers and breast cancer deaths occur among women 65 and older, and almost one-quarter of all invasive breast cancers occur in women age 80 and older.9 Approximately one in six women diagnosed with breast cancer dies of the disease within 10 years.10 Once the cancer has metastasized, median survival time is two to four years. Older women have about a 1% chance of dying of breast cancer in a 10-year period.11
At the same time, older women are more likely than their younger counterparts to have comorbid illnesses—conditions that can compete with breast cancer as a cause of death and increase treatment-related morbidity. Older women with breast cancer and two or more other comorbid diseases are 20 times more likely to die of one of these diseases than of breast cancer.8
Use of Mammography in Older Women
Regular mammography has been shown to help detect tumors that are smaller and at an earlier stage of development than would be identified without this screening.8 Women who undergo regular mammograms have been shown to outlive those who do not, provided they live for at least five years after starting screening.12
Life expectancy for older women is often underestimated. The average 75-year-old woman has 12 more years of life expectancy, and the healthiest 25% of 80-year-old women will live an additional 13 years.13 Most of these women do not receive regular mammographic screening for breast cancer. However, if health status and life expectancy were considered as screening criteria in addition to age, many of these women would qualify for mammographic screening.
Using the Surveillance, Epidemiology, and End Results (SEER) Medicare database to evaluate 12,358 women age 80 and older who had been diagnosed with breast cancer, Badgwell et al14 found that only 51% had had one or more mammograms within the previous five years. Biennial screening rates were 24% to 27% among women ages 80 to 84 and 14% to 23% among those 85 to 89. In this cohort of elderly women, the researchers found that regular mammographic screening was associated with detection of breast cancer at earlier stages and suggest that the low rates of screening in this age-group may represent a missed opportunity for early detection of disease.
In the US, 57% of breast cancers are detected by mammography; in the remaining cases, patients present with a palpable mass or in response to other breast symptoms. Cancers detected by mammography are found at an earlier stage.15
When statisticians used several models to assess the role of screening mammography in reducing breast cancer mortality, they found that mammography has contributed to about 46% of the overall reduction in breast cancer deaths in the US during the past 20 years.16 Mammography is more effective in detecting breast cancers in older than younger women, and the number of false-positive results decreases among women of advancing age. The sensitivity and specificity of mammography for detection of breast cancer is 85% and 94%, respectively, for women ages 75 to 89.17
Although this strong specificity would seem to suggest that older women are at low risk for overdiagnosis, this is not the case. Many benign and clinically insignificant lesions are also detected through mammography, resulting in unnecessary breast biopsies. In one group of 23,000 women age 65 or older who underwent a one-time screening mammogram, 8% had an abnormal result that required additional evaluation. Among these women, only about 10% actually had cancer.18 Rates of false-positive mammographic findings vary by radiologist but are generally higher among women who are younger than 65.19
Schonberg20 followed 2,011 community-dwelling women 80 and older who underwent mammography screening and found an 11% rate of false-positive results. Ductal carcinoma in situ (DCIS) is a common mammographic finding in older women. Since only one-third of these cases will convert to invasive breast cancer over 10 to 15 years, DCIS likely exemplifies overdiagnosis in older women.20
Clinical Breast Exams and Self-Examination
There is insufficient evidence to determine whether clinical breast exams improve early detection and treatment outcomes in women with breast cancer. Additionally, results from two large randomized controlled trials of breast self-examination suggest that the practice is not of benefit in reducing breast cancer mortality and morbidity.1,21,22
Age, Breast Cancer Types, and Outcomes
It has been suggested that older women may be subject to less aggressive cancers and thus be more vulnerable to overdiagnosis.23 Schonberg et al24 evaluated SEER data to determine the tumor characteristics, treatments, and outcomes in women 80 and older, compared with women ages 67 to 79. They found no difference in tumor grade or hormone receptivity between these groups. It is important to note that women older than 80 were significantly more likely than younger women to die of breast cancer, perhaps in part because the older patients were less likely to receive aggressive treatment (see “Breast Cancer Treatment in Older Women”24-26).
Women between ages 74 and 85 who undergo regular mammographic screenings have been shown to have half the risk for breast cancer–related death, compared with those who are not screened.25 However, risks have been shown to outweigh benefits when mammography is continued into old age without regard to life expectancy.
Walter et al27 studied a group of 216 frail, nursing home–eligible older women who had had at least one mammogram. Seventeen percent had abnormal results, and most opted for further evaluation with breast biopsy. Of these biopsies, 23% yielded positive results, and of these, 75% revealed invasive breast cancer; the remaining 25% of women had DCIS.
All of the women with abnormal biopsy results underwent surgical treatment, but half died of other causes or experienced surgical complications. The investigators found that 1% of the women may have received some benefit from screening, but more women experienced harm as a result of the mammogram and subsequent procedures. The study authors, along with almost all clinicians who have written on this topic, agree that mammography is inappropriate for frail, elderly women with less than five years’ life expectancy.27
Expert Guideline Recommendations
Provider recommendation has been found to be the most important factor in older women’s decisions to have or forego a mammogram.8 Unfortunately, there is little clear, decisive support for providers to help women make this decision. The summary of breast cancer screening recommendations for older women shown in the table reveals that no consensus exists among the expert panels regarding the best approach. In part, these discrepancies can be explained by the low numbers of women older than 75 who have been included in clinical trials evaluating the risks and benefits of mammography screening.
Helpful Criteria for Breast Cancer Screening Decisions
In 2003, the American Geriatrics Society Ethics Committee published a set of basic rules to guide decision making regarding screening tests.5 These include the following:
• In patients with a limited life expectancy, focus should be on treatments that are likely to offer immediate benefit
• Patients with dementia or multiple comorbidities may find routine screening tests burdensome
• Screening decisions should be individualized rather than based on age alone
• Health care systems and insurance plans should not restrict coverage for screening tests in older adults based solely on age.5
Walter and Covinsky13 created a model to facilitate decisions about mammography for older women. They suggest first estimating life expectancy according to age and health status (see Arias28 at www.cdc.gov/nchs/data/nvsr/nvsr58/nvsr58_21.pdf). Factors considered in this decision model include a woman’s risk for dying of breast cancer, the effect of screening on this death rate, the potential risks involved with screening, and the woman’s preferences.
According to this model, Helen, at 82, would have had a life expectancy of 11.5 years. The annual breast cancer mortality rate for a woman of her age is 157/100,000.29 Based on these data, Helen’s risk for dying of breast cancer is calculated to be 1.8%. The number of patients Helen’s age who would have to be screened to prevent one case of breast cancer is 240.
In Helen’s case, the risks involved with screening mammography would include a roughly 8% chance of her needing a subsequent diagnostic mammogram and/or breast biopsy. If Helen underwent biopsy, there would be a 75% chance that the suspicious mammogram would prove to be a false-negative result, possibly causing the patient undue anxiety. In Walter and Covinski’s model,13 these possibilities would be discussed with Helen in advance to help her clarify her own values and reach a screening decision.
By comparison, consider a hypothetical 70-year-old woman who is in the lowest quadrant of health status for her age; based on her age alone, the expert panels would agree that screening mammography is indicated. This patient has a life expectancy of 9.5 years and a 1.2% lifetime risk for dying of breast cancer. To prevent one case of breast cancer, 642 women of this age and health status would have to be screened. Thus, Helen would derive far more benefit from screening than would this hypothetical woman.
Life Expectancy, Health Status
In order to help an older woman make well-reasoned decisions about mammography screening, it is important for the clinician to evaluate her overall health status and life expectancy, as well as her risk for breast cancer and her long-term goals.
The potential benefit of any preventive health screening can be reduced in patients with a limited life span. Schonberg,20 who created a nine-item tool to predict four-year mortality, demonstrated that women with a score higher than the cut-point of 14 were unlikely to benefit from mammography screening, based on their limited life expectancy.
According to Schonberg,20 mortality risk increases with advancing age, male gender, and low BMI; a diagnosis of diabetes, cancer, or COPD; smoking, functional limitations, poor self-rated health, and a recent history of hospitalization. In Helen’s case, a BMI of 25, her nonsmoking status, an absence of significant comorbidities, and good functional status result in a score of 5 on the Schonberg tool. The associated life expectancy of greater than four years would have made mammography screening an advisable option for her.
Several easily administered tools are available to predict mortality or vulnerability. The Vulnerable Elders Survey (VES-13),30,31 for example, is a 13-item tool developed by researchers from the RAND Health Project, the University of California–Los Angeles, and the Veterans Administration to predict vulnerability among older adults. Using a cut-point of 3, researchers who conducted this survey identified one-third of a cohort of 6,205 community-dwelling elders as vulnerable—that is, at four times the risk for functional decline or death, compared with the rest of the elderly population.31 Helen, with a VES-13 score of 0, would not have been considered vulnerable.
Additionally, risk for breast cancer can be calculated in the office setting with the National Cancer Institute’s Breast Cancer Risk Calculator32 (see www.cancer.gov/bcrisktool). Breast cancer risk factors for the older woman that are not included in the calculator but that may further influence decision making include:
• Use of hormone replacement therapy
• Obesity
• Increased bone mineral density.33
It is important to determine a woman’s willingness to undergo mammography and any indicated follow-up procedures. Screening decisions can also be facilitated by discussions about the patient’s values regarding increased longevity, quality-of-life goals, pain and symptom management, and her available support systems.
Conclusion
Decisions about breast cancer screening for older women should be influenced by the health status and life expectancy of each patient, her goals for her remaining years, and her risk for breast cancer. Treatment decisions, when necessary, must take these factors, as well as severity of disease, into account. The reduction in quality of life that is inevitable with a diagnosis of advanced-stage metastatic breast cancer should be factored into the decision.
Helen, whose story began this article, was a real patient. Given her previous good health, she hardly expected her final years to be defined by the pain and disability of metastatic breast cancer. Her case illustrates the potential consequences of restricting breast cancer screening decisions to age-based recommendations alone.
1. US Preventive Services Task Force. Screening for breast cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;151(10):716-726, W-236.
2. American Cancer Society Guidelines for the Early Detection of Cancer. Breast cancer. www.cancer.org/Healthy/FindCancerEarly/Cancer ScreeningGuidelines/american-cancer-society-guidelines-for-the-early-detection-of-cancer. Accessed March 28, 2011.
3. American College of Obstetricians and Gynecologists. Response of The American College of Obstetricians and Gynecologists to New Breast Cancer Screening Recommendations from the US Preventive Services Task Force. www.acog .org/from_home/misc/uspstfresponse.cfm. Accessed March 28, 2011.
4. American Academy of Family Physicians. American Academy of Family Physicians updates breast cancer screening recommendations (2010). www.aafp.org/online/en/home/media/releases/2010b/breast-cancer-screening-recom mendations.html. Accessed March 28, 2011.
5. American Geriatrics Society Ethics Committee. Health screening decisions for older adults: AGS position paper. J Am Geriatr Soc. 2003; 51(2):270-271.
6. Gøtzsche PC, Nielsen M. Screening for breast cancer with mammography. Cochrane Database Syst Rev. 2011 Jan 19;(1):CD001877.
7. Traa MJ, Meijs CM, de Jongh MA, et al. Elderly women with breast cancer often die due to other causes regardless of primary endocrine therapy or primary surgical therapy. Breast. 2011 Feb 14. [Epub ahead of print]
8. Schonberg MA, McCarthy EP. Mammography screening among women age 80 years and older: consider the risks. J Clin Oncol. 2009;27 (4):640-641.
9. Mandelblatt JS, Silliman R. Hanging in the balance: making decisions about the benefits and harms of breast cancer screening among the oldest old without a safety net of scientific evidence. J Clin Oncol. 2009;27(4):487-490.
10. National Cancer Institute. Surveillance Epidemiology and End Results, 1975-2007 (2010). Table 4.17. Cancer of the Female Breast (Ages 50+, Invasive). http://seer.cancer.gov/csr/1975_2007/browse_csr.php?section=4&page=sect_04_table.17.html. Accessed March 28, 2011.
11. National Cancer Institute. Breast Cancer Screening PDQ. Breast cancer diagnosis (2010). www.cancer.gov/cancertopics/pdq/screening/breast/HealthProfessional/page3. Accessed March 28, 2011.
12. Nyström L, Andersson I, Bjurstam N, et al. Long-term effects of mammography screening: updated overview of the Swedish randomised trials. Lancet. 2002;359(9310):909-919.
13. Walter LC, Covinsky KE. Cancer screening in elderly patients: A framework for individualized decision making. JAMA. 2001;285(21): 2750-2756.
14. Badgwell BD, Giordano SH, Duan ZZ, et al. Mammography before diagnosis among women age 80 years and older with breast cancer. J Clin Oncol. 2008;26(15):2482-2488.
15. Mathis KL, Hoskin TL, Boughey JC, et al. Palpable presentation of breast cancer persists in the era of screening mammography. J Am Coll Surg. 2010;210(3):314-318.
16. Kalager M, Zelen M, Langmark F, Adami H-O. Effect of screening mammography on breast-cancer mortality in Norway. N Engl J Med. 2010;363(13):1203-1210.
17. National Cancer Institute Breast Cancer Surveillance Consortium. Performance measures for 3,884,059 screening mammography examinations from 1996 to 2007 by age (2009). http://breastscreening.cancer.gov/data/performance/screening/perf_age.html. Accessed March 28, 2011.
18. Welch HG, Fisher ES. Diagnostic testing following screening mammography in the elderly. J Natl Cancer Inst. 1998;90(18):1389-1392.
19. Tan A, Freeman DH Jr, Goodwin JS, Freeman JL. Variation in false-positive rates of mammography reading among 1067 radiologists: a population-based assessment. Breast Cancer Res Treat. 2006;100(3):309-318.
20. Schonberg M. Breast cancer screening: at what age to stop? www.consultantlive.com/geriatrics/content/article/10162/1563530. Accessed March 28, 2011.
21. Thomas DB, Gao DL, Self SG, et al. Randomized trial of breast self-examination in Shanghai: methodology and preliminary results. J Natl Cancer Inst. 1997;89(5):355-65.
22. Semiglazov VF, Moiseyenko VM, Bavli JL, et al. The role of breast self-examination in early breast cancer detection (results of the 5-year USSR/WHO randomized study in Leningrad). Eur J Epidemiol. 1992;8(4):498-502.
23. de Koning HJ, Boer R, Warmerdam PG, et al. Quantitative interpretation of age-specific mortality reductions from the Swedish breast cancer–screening trials. J Natl Cancer Inst. 1995;87 (16):1217-1223.
24. Schonberg MA, Marcantonio ER, Li D, et al. Breast cancer among the oldest old: tumor characteristics, treatment choices, and survival. J Clin Onc. 2010;28(12):2038-2045.
25. McCarthy EP, Burns RB, Freund KM, et al. Mammography use, breast cancer stage at diagnosis, and survival among older women. J Am Ger Soc. 2000;48(10):1226-1233.
26. Smith BD, Gross CP, Smith GL, et al. Effectiveness of radiation therapy for older women with early breast cancer. J Natl Cancer Inst. 2006;98(10):681-690.
27. Walter LC, Eng C, Covinsky KE. Screening mammography for frail older women: what are the burdens? J Gen Int Med. 2001;16(11): 779-784.
28. Arias E. United States life tables, 2006. Natl Vital Stat Rep. 2010;58(21):1-40.
29. National Cancer Institute. Surveillance Epidemiology and End Results, 1975-2007 (2010). Table 4.12. Cancer of the Breast (Invasive). http://seer.cancer.gov/csr/1975_2007/browse_csr.php?section=4&page=sect_04_table.12 .html. Accessed March 21, 2011.
30. RAND Health Project. Assessing care of vulnerable elders: Vulnerable Elders Survey (VES-13, 2011). www.rand.org/health/projects/acove/survey.html. Accessed March 28, 2011.
31. Saliba S, Elliott M, Rubenstein LA, et al. The Vulnerable Elders Survey: a tool for identifying vulnerable older people in the community. J Am Geriatr Soc. 2001;49(12):1691-1699.
32. National Cancer Institute. Breast Cancer Risk Assessment Tool. www.cancer.gov/bcrisk tool. Accessed March 28, 2011.
33. Vogel VG. Breast cancer (2010). www.merck.com/mmpe/sec18/ch253/ch253e.html. Accessed March 28, 2011.
At age 82, Helen was healthy and active and living independently. A mother, grandmother, and great-grandmother, she enjoyed aerobics, tai chi, and walking, painting (which she also taught), writing poetry, and stimulating conversation. She took pride in looking much younger than her age and watched out for her older neighbors.
An active participant in her health care, Helen had been happy when, at 75, she was told by her primary care provider that she no longer needed regular mammograms. But one morning, seven years later, she felt a sharp pain in her right breast. Self-examination revealed a grape-sized lesion under her nipple. Helen sought immediate health care and was diagnosed with a stage IIb tumor.
Given an option of lumpectomy followed by radiation, Helen decided that a double mastectomy would better allow her to return to the life she had been living. After her surgery, however, Helen experienced a steady decline, with increasing pain, debilitating skin lesions, fractures, and edema. Against her will, she was moved to an assisted living facility, where she was too debilitated to participate in activities. Helen died six months later—three years after she discovered her breast lump.
The lack of clear breast cancer screening guidelines has left many providers confused about how to advise their patients, particularly women older than 75. Screening recommendations based on patient age alone are of insufficient value, as health status and life expectancy—which vary widely in this patient population—are also, along with patient preferences, important considerations. The purpose of this article is to present the reported benefits and risks of breast cancer screening among older women, in order to help primary care providers more effectively advise their elderly female patients in the decision-making process.
The Breast Cancer Screening Debate
There is strong consensus among expert advisory groups (the US Preventive Services Task Force,1 the American Cancer Society,2 the American College of Obstetricians and Gynecologists,3 the American Academy of Family Physicians,4 and the American Geriatrics Society5) that mammography is to be recommended to screen for the early detection of breast cancer in women between ages 50 and 75. However, a recent review of the randomized controlled studies on which these recommendations were based suggests that the benefits of mammography may be relatively minimal, and that the risks for overdiagnosis and overtreatment may be significant.6 None of these trials enrolled women older than 74, so further information is needed to make evidence-based decisions regarding breast cancer screening for the older woman. Currently available evidence for such decision making is limited to observational or retrospective analyses.6
Women 75 or older have a greater risk than younger women for breast cancer, but older women are also at greater risk for dying of another disease—even those who have breast cancer.7,8 Thus, as with any health screening, it is advisable that a woman’s health status be carefully considered before screening decisions are made.
Breast Cancer in Older Women
Breast cancer incidence increases with age. Almost half of all invasive breast cancers and breast cancer deaths occur among women 65 and older, and almost one-quarter of all invasive breast cancers occur in women age 80 and older.9 Approximately one in six women diagnosed with breast cancer dies of the disease within 10 years.10 Once the cancer has metastasized, median survival time is two to four years. Older women have about a 1% chance of dying of breast cancer in a 10-year period.11
At the same time, older women are more likely than their younger counterparts to have comorbid illnesses—conditions that can compete with breast cancer as a cause of death and increase treatment-related morbidity. Older women with breast cancer and two or more other comorbid diseases are 20 times more likely to die of one of these diseases than of breast cancer.8
Use of Mammography in Older Women
Regular mammography has been shown to help detect tumors that are smaller and at an earlier stage of development than would be identified without this screening.8 Women who undergo regular mammograms have been shown to outlive those who do not, provided they live for at least five years after starting screening.12
Life expectancy for older women is often underestimated. The average 75-year-old woman has 12 more years of life expectancy, and the healthiest 25% of 80-year-old women will live an additional 13 years.13 Most of these women do not receive regular mammographic screening for breast cancer. However, if health status and life expectancy were considered as screening criteria in addition to age, many of these women would qualify for mammographic screening.
Using the Surveillance, Epidemiology, and End Results (SEER) Medicare database to evaluate 12,358 women age 80 and older who had been diagnosed with breast cancer, Badgwell et al14 found that only 51% had had one or more mammograms within the previous five years. Biennial screening rates were 24% to 27% among women ages 80 to 84 and 14% to 23% among those 85 to 89. In this cohort of elderly women, the researchers found that regular mammographic screening was associated with detection of breast cancer at earlier stages and suggest that the low rates of screening in this age-group may represent a missed opportunity for early detection of disease.
In the US, 57% of breast cancers are detected by mammography; in the remaining cases, patients present with a palpable mass or in response to other breast symptoms. Cancers detected by mammography are found at an earlier stage.15
When statisticians used several models to assess the role of screening mammography in reducing breast cancer mortality, they found that mammography has contributed to about 46% of the overall reduction in breast cancer deaths in the US during the past 20 years.16 Mammography is more effective in detecting breast cancers in older than younger women, and the number of false-positive results decreases among women of advancing age. The sensitivity and specificity of mammography for detection of breast cancer is 85% and 94%, respectively, for women ages 75 to 89.17
Although this strong specificity would seem to suggest that older women are at low risk for overdiagnosis, this is not the case. Many benign and clinically insignificant lesions are also detected through mammography, resulting in unnecessary breast biopsies. In one group of 23,000 women age 65 or older who underwent a one-time screening mammogram, 8% had an abnormal result that required additional evaluation. Among these women, only about 10% actually had cancer.18 Rates of false-positive mammographic findings vary by radiologist but are generally higher among women who are younger than 65.19
Schonberg20 followed 2,011 community-dwelling women 80 and older who underwent mammography screening and found an 11% rate of false-positive results. Ductal carcinoma in situ (DCIS) is a common mammographic finding in older women. Since only one-third of these cases will convert to invasive breast cancer over 10 to 15 years, DCIS likely exemplifies overdiagnosis in older women.20
Clinical Breast Exams and Self-Examination
There is insufficient evidence to determine whether clinical breast exams improve early detection and treatment outcomes in women with breast cancer. Additionally, results from two large randomized controlled trials of breast self-examination suggest that the practice is not of benefit in reducing breast cancer mortality and morbidity.1,21,22
Age, Breast Cancer Types, and Outcomes
It has been suggested that older women may be subject to less aggressive cancers and thus be more vulnerable to overdiagnosis.23 Schonberg et al24 evaluated SEER data to determine the tumor characteristics, treatments, and outcomes in women 80 and older, compared with women ages 67 to 79. They found no difference in tumor grade or hormone receptivity between these groups. It is important to note that women older than 80 were significantly more likely than younger women to die of breast cancer, perhaps in part because the older patients were less likely to receive aggressive treatment (see “Breast Cancer Treatment in Older Women”24-26).
Women between ages 74 and 85 who undergo regular mammographic screenings have been shown to have half the risk for breast cancer–related death, compared with those who are not screened.25 However, risks have been shown to outweigh benefits when mammography is continued into old age without regard to life expectancy.
Walter et al27 studied a group of 216 frail, nursing home–eligible older women who had had at least one mammogram. Seventeen percent had abnormal results, and most opted for further evaluation with breast biopsy. Of these biopsies, 23% yielded positive results, and of these, 75% revealed invasive breast cancer; the remaining 25% of women had DCIS.
All of the women with abnormal biopsy results underwent surgical treatment, but half died of other causes or experienced surgical complications. The investigators found that 1% of the women may have received some benefit from screening, but more women experienced harm as a result of the mammogram and subsequent procedures. The study authors, along with almost all clinicians who have written on this topic, agree that mammography is inappropriate for frail, elderly women with less than five years’ life expectancy.27
Expert Guideline Recommendations
Provider recommendation has been found to be the most important factor in older women’s decisions to have or forego a mammogram.8 Unfortunately, there is little clear, decisive support for providers to help women make this decision. The summary of breast cancer screening recommendations for older women shown in the table reveals that no consensus exists among the expert panels regarding the best approach. In part, these discrepancies can be explained by the low numbers of women older than 75 who have been included in clinical trials evaluating the risks and benefits of mammography screening.
Helpful Criteria for Breast Cancer Screening Decisions
In 2003, the American Geriatrics Society Ethics Committee published a set of basic rules to guide decision making regarding screening tests.5 These include the following:
• In patients with a limited life expectancy, focus should be on treatments that are likely to offer immediate benefit
• Patients with dementia or multiple comorbidities may find routine screening tests burdensome
• Screening decisions should be individualized rather than based on age alone
• Health care systems and insurance plans should not restrict coverage for screening tests in older adults based solely on age.5
Walter and Covinsky13 created a model to facilitate decisions about mammography for older women. They suggest first estimating life expectancy according to age and health status (see Arias28 at www.cdc.gov/nchs/data/nvsr/nvsr58/nvsr58_21.pdf). Factors considered in this decision model include a woman’s risk for dying of breast cancer, the effect of screening on this death rate, the potential risks involved with screening, and the woman’s preferences.
According to this model, Helen, at 82, would have had a life expectancy of 11.5 years. The annual breast cancer mortality rate for a woman of her age is 157/100,000.29 Based on these data, Helen’s risk for dying of breast cancer is calculated to be 1.8%. The number of patients Helen’s age who would have to be screened to prevent one case of breast cancer is 240.
In Helen’s case, the risks involved with screening mammography would include a roughly 8% chance of her needing a subsequent diagnostic mammogram and/or breast biopsy. If Helen underwent biopsy, there would be a 75% chance that the suspicious mammogram would prove to be a false-negative result, possibly causing the patient undue anxiety. In Walter and Covinski’s model,13 these possibilities would be discussed with Helen in advance to help her clarify her own values and reach a screening decision.
By comparison, consider a hypothetical 70-year-old woman who is in the lowest quadrant of health status for her age; based on her age alone, the expert panels would agree that screening mammography is indicated. This patient has a life expectancy of 9.5 years and a 1.2% lifetime risk for dying of breast cancer. To prevent one case of breast cancer, 642 women of this age and health status would have to be screened. Thus, Helen would derive far more benefit from screening than would this hypothetical woman.
Life Expectancy, Health Status
In order to help an older woman make well-reasoned decisions about mammography screening, it is important for the clinician to evaluate her overall health status and life expectancy, as well as her risk for breast cancer and her long-term goals.
The potential benefit of any preventive health screening can be reduced in patients with a limited life span. Schonberg,20 who created a nine-item tool to predict four-year mortality, demonstrated that women with a score higher than the cut-point of 14 were unlikely to benefit from mammography screening, based on their limited life expectancy.
According to Schonberg,20 mortality risk increases with advancing age, male gender, and low BMI; a diagnosis of diabetes, cancer, or COPD; smoking, functional limitations, poor self-rated health, and a recent history of hospitalization. In Helen’s case, a BMI of 25, her nonsmoking status, an absence of significant comorbidities, and good functional status result in a score of 5 on the Schonberg tool. The associated life expectancy of greater than four years would have made mammography screening an advisable option for her.
Several easily administered tools are available to predict mortality or vulnerability. The Vulnerable Elders Survey (VES-13),30,31 for example, is a 13-item tool developed by researchers from the RAND Health Project, the University of California–Los Angeles, and the Veterans Administration to predict vulnerability among older adults. Using a cut-point of 3, researchers who conducted this survey identified one-third of a cohort of 6,205 community-dwelling elders as vulnerable—that is, at four times the risk for functional decline or death, compared with the rest of the elderly population.31 Helen, with a VES-13 score of 0, would not have been considered vulnerable.
Additionally, risk for breast cancer can be calculated in the office setting with the National Cancer Institute’s Breast Cancer Risk Calculator32 (see www.cancer.gov/bcrisktool). Breast cancer risk factors for the older woman that are not included in the calculator but that may further influence decision making include:
• Use of hormone replacement therapy
• Obesity
• Increased bone mineral density.33
It is important to determine a woman’s willingness to undergo mammography and any indicated follow-up procedures. Screening decisions can also be facilitated by discussions about the patient’s values regarding increased longevity, quality-of-life goals, pain and symptom management, and her available support systems.
Conclusion
Decisions about breast cancer screening for older women should be influenced by the health status and life expectancy of each patient, her goals for her remaining years, and her risk for breast cancer. Treatment decisions, when necessary, must take these factors, as well as severity of disease, into account. The reduction in quality of life that is inevitable with a diagnosis of advanced-stage metastatic breast cancer should be factored into the decision.
Helen, whose story began this article, was a real patient. Given her previous good health, she hardly expected her final years to be defined by the pain and disability of metastatic breast cancer. Her case illustrates the potential consequences of restricting breast cancer screening decisions to age-based recommendations alone.
At age 82, Helen was healthy and active and living independently. A mother, grandmother, and great-grandmother, she enjoyed aerobics, tai chi, and walking, painting (which she also taught), writing poetry, and stimulating conversation. She took pride in looking much younger than her age and watched out for her older neighbors.
An active participant in her health care, Helen had been happy when, at 75, she was told by her primary care provider that she no longer needed regular mammograms. But one morning, seven years later, she felt a sharp pain in her right breast. Self-examination revealed a grape-sized lesion under her nipple. Helen sought immediate health care and was diagnosed with a stage IIb tumor.
Given an option of lumpectomy followed by radiation, Helen decided that a double mastectomy would better allow her to return to the life she had been living. After her surgery, however, Helen experienced a steady decline, with increasing pain, debilitating skin lesions, fractures, and edema. Against her will, she was moved to an assisted living facility, where she was too debilitated to participate in activities. Helen died six months later—three years after she discovered her breast lump.
The lack of clear breast cancer screening guidelines has left many providers confused about how to advise their patients, particularly women older than 75. Screening recommendations based on patient age alone are of insufficient value, as health status and life expectancy—which vary widely in this patient population—are also, along with patient preferences, important considerations. The purpose of this article is to present the reported benefits and risks of breast cancer screening among older women, in order to help primary care providers more effectively advise their elderly female patients in the decision-making process.
The Breast Cancer Screening Debate
There is strong consensus among expert advisory groups (the US Preventive Services Task Force,1 the American Cancer Society,2 the American College of Obstetricians and Gynecologists,3 the American Academy of Family Physicians,4 and the American Geriatrics Society5) that mammography is to be recommended to screen for the early detection of breast cancer in women between ages 50 and 75. However, a recent review of the randomized controlled studies on which these recommendations were based suggests that the benefits of mammography may be relatively minimal, and that the risks for overdiagnosis and overtreatment may be significant.6 None of these trials enrolled women older than 74, so further information is needed to make evidence-based decisions regarding breast cancer screening for the older woman. Currently available evidence for such decision making is limited to observational or retrospective analyses.6
Women 75 or older have a greater risk than younger women for breast cancer, but older women are also at greater risk for dying of another disease—even those who have breast cancer.7,8 Thus, as with any health screening, it is advisable that a woman’s health status be carefully considered before screening decisions are made.
Breast Cancer in Older Women
Breast cancer incidence increases with age. Almost half of all invasive breast cancers and breast cancer deaths occur among women 65 and older, and almost one-quarter of all invasive breast cancers occur in women age 80 and older.9 Approximately one in six women diagnosed with breast cancer dies of the disease within 10 years.10 Once the cancer has metastasized, median survival time is two to four years. Older women have about a 1% chance of dying of breast cancer in a 10-year period.11
At the same time, older women are more likely than their younger counterparts to have comorbid illnesses—conditions that can compete with breast cancer as a cause of death and increase treatment-related morbidity. Older women with breast cancer and two or more other comorbid diseases are 20 times more likely to die of one of these diseases than of breast cancer.8
Use of Mammography in Older Women
Regular mammography has been shown to help detect tumors that are smaller and at an earlier stage of development than would be identified without this screening.8 Women who undergo regular mammograms have been shown to outlive those who do not, provided they live for at least five years after starting screening.12
Life expectancy for older women is often underestimated. The average 75-year-old woman has 12 more years of life expectancy, and the healthiest 25% of 80-year-old women will live an additional 13 years.13 Most of these women do not receive regular mammographic screening for breast cancer. However, if health status and life expectancy were considered as screening criteria in addition to age, many of these women would qualify for mammographic screening.
Using the Surveillance, Epidemiology, and End Results (SEER) Medicare database to evaluate 12,358 women age 80 and older who had been diagnosed with breast cancer, Badgwell et al14 found that only 51% had had one or more mammograms within the previous five years. Biennial screening rates were 24% to 27% among women ages 80 to 84 and 14% to 23% among those 85 to 89. In this cohort of elderly women, the researchers found that regular mammographic screening was associated with detection of breast cancer at earlier stages and suggest that the low rates of screening in this age-group may represent a missed opportunity for early detection of disease.
In the US, 57% of breast cancers are detected by mammography; in the remaining cases, patients present with a palpable mass or in response to other breast symptoms. Cancers detected by mammography are found at an earlier stage.15
When statisticians used several models to assess the role of screening mammography in reducing breast cancer mortality, they found that mammography has contributed to about 46% of the overall reduction in breast cancer deaths in the US during the past 20 years.16 Mammography is more effective in detecting breast cancers in older than younger women, and the number of false-positive results decreases among women of advancing age. The sensitivity and specificity of mammography for detection of breast cancer is 85% and 94%, respectively, for women ages 75 to 89.17
Although this strong specificity would seem to suggest that older women are at low risk for overdiagnosis, this is not the case. Many benign and clinically insignificant lesions are also detected through mammography, resulting in unnecessary breast biopsies. In one group of 23,000 women age 65 or older who underwent a one-time screening mammogram, 8% had an abnormal result that required additional evaluation. Among these women, only about 10% actually had cancer.18 Rates of false-positive mammographic findings vary by radiologist but are generally higher among women who are younger than 65.19
Schonberg20 followed 2,011 community-dwelling women 80 and older who underwent mammography screening and found an 11% rate of false-positive results. Ductal carcinoma in situ (DCIS) is a common mammographic finding in older women. Since only one-third of these cases will convert to invasive breast cancer over 10 to 15 years, DCIS likely exemplifies overdiagnosis in older women.20
Clinical Breast Exams and Self-Examination
There is insufficient evidence to determine whether clinical breast exams improve early detection and treatment outcomes in women with breast cancer. Additionally, results from two large randomized controlled trials of breast self-examination suggest that the practice is not of benefit in reducing breast cancer mortality and morbidity.1,21,22
Age, Breast Cancer Types, and Outcomes
It has been suggested that older women may be subject to less aggressive cancers and thus be more vulnerable to overdiagnosis.23 Schonberg et al24 evaluated SEER data to determine the tumor characteristics, treatments, and outcomes in women 80 and older, compared with women ages 67 to 79. They found no difference in tumor grade or hormone receptivity between these groups. It is important to note that women older than 80 were significantly more likely than younger women to die of breast cancer, perhaps in part because the older patients were less likely to receive aggressive treatment (see “Breast Cancer Treatment in Older Women”24-26).
Women between ages 74 and 85 who undergo regular mammographic screenings have been shown to have half the risk for breast cancer–related death, compared with those who are not screened.25 However, risks have been shown to outweigh benefits when mammography is continued into old age without regard to life expectancy.
Walter et al27 studied a group of 216 frail, nursing home–eligible older women who had had at least one mammogram. Seventeen percent had abnormal results, and most opted for further evaluation with breast biopsy. Of these biopsies, 23% yielded positive results, and of these, 75% revealed invasive breast cancer; the remaining 25% of women had DCIS.
All of the women with abnormal biopsy results underwent surgical treatment, but half died of other causes or experienced surgical complications. The investigators found that 1% of the women may have received some benefit from screening, but more women experienced harm as a result of the mammogram and subsequent procedures. The study authors, along with almost all clinicians who have written on this topic, agree that mammography is inappropriate for frail, elderly women with less than five years’ life expectancy.27
Expert Guideline Recommendations
Provider recommendation has been found to be the most important factor in older women’s decisions to have or forego a mammogram.8 Unfortunately, there is little clear, decisive support for providers to help women make this decision. The summary of breast cancer screening recommendations for older women shown in the table reveals that no consensus exists among the expert panels regarding the best approach. In part, these discrepancies can be explained by the low numbers of women older than 75 who have been included in clinical trials evaluating the risks and benefits of mammography screening.
Helpful Criteria for Breast Cancer Screening Decisions
In 2003, the American Geriatrics Society Ethics Committee published a set of basic rules to guide decision making regarding screening tests.5 These include the following:
• In patients with a limited life expectancy, focus should be on treatments that are likely to offer immediate benefit
• Patients with dementia or multiple comorbidities may find routine screening tests burdensome
• Screening decisions should be individualized rather than based on age alone
• Health care systems and insurance plans should not restrict coverage for screening tests in older adults based solely on age.5
Walter and Covinsky13 created a model to facilitate decisions about mammography for older women. They suggest first estimating life expectancy according to age and health status (see Arias28 at www.cdc.gov/nchs/data/nvsr/nvsr58/nvsr58_21.pdf). Factors considered in this decision model include a woman’s risk for dying of breast cancer, the effect of screening on this death rate, the potential risks involved with screening, and the woman’s preferences.
According to this model, Helen, at 82, would have had a life expectancy of 11.5 years. The annual breast cancer mortality rate for a woman of her age is 157/100,000.29 Based on these data, Helen’s risk for dying of breast cancer is calculated to be 1.8%. The number of patients Helen’s age who would have to be screened to prevent one case of breast cancer is 240.
In Helen’s case, the risks involved with screening mammography would include a roughly 8% chance of her needing a subsequent diagnostic mammogram and/or breast biopsy. If Helen underwent biopsy, there would be a 75% chance that the suspicious mammogram would prove to be a false-negative result, possibly causing the patient undue anxiety. In Walter and Covinski’s model,13 these possibilities would be discussed with Helen in advance to help her clarify her own values and reach a screening decision.
By comparison, consider a hypothetical 70-year-old woman who is in the lowest quadrant of health status for her age; based on her age alone, the expert panels would agree that screening mammography is indicated. This patient has a life expectancy of 9.5 years and a 1.2% lifetime risk for dying of breast cancer. To prevent one case of breast cancer, 642 women of this age and health status would have to be screened. Thus, Helen would derive far more benefit from screening than would this hypothetical woman.
Life Expectancy, Health Status
In order to help an older woman make well-reasoned decisions about mammography screening, it is important for the clinician to evaluate her overall health status and life expectancy, as well as her risk for breast cancer and her long-term goals.
The potential benefit of any preventive health screening can be reduced in patients with a limited life span. Schonberg,20 who created a nine-item tool to predict four-year mortality, demonstrated that women with a score higher than the cut-point of 14 were unlikely to benefit from mammography screening, based on their limited life expectancy.
According to Schonberg,20 mortality risk increases with advancing age, male gender, and low BMI; a diagnosis of diabetes, cancer, or COPD; smoking, functional limitations, poor self-rated health, and a recent history of hospitalization. In Helen’s case, a BMI of 25, her nonsmoking status, an absence of significant comorbidities, and good functional status result in a score of 5 on the Schonberg tool. The associated life expectancy of greater than four years would have made mammography screening an advisable option for her.
Several easily administered tools are available to predict mortality or vulnerability. The Vulnerable Elders Survey (VES-13),30,31 for example, is a 13-item tool developed by researchers from the RAND Health Project, the University of California–Los Angeles, and the Veterans Administration to predict vulnerability among older adults. Using a cut-point of 3, researchers who conducted this survey identified one-third of a cohort of 6,205 community-dwelling elders as vulnerable—that is, at four times the risk for functional decline or death, compared with the rest of the elderly population.31 Helen, with a VES-13 score of 0, would not have been considered vulnerable.
Additionally, risk for breast cancer can be calculated in the office setting with the National Cancer Institute’s Breast Cancer Risk Calculator32 (see www.cancer.gov/bcrisktool). Breast cancer risk factors for the older woman that are not included in the calculator but that may further influence decision making include:
• Use of hormone replacement therapy
• Obesity
• Increased bone mineral density.33
It is important to determine a woman’s willingness to undergo mammography and any indicated follow-up procedures. Screening decisions can also be facilitated by discussions about the patient’s values regarding increased longevity, quality-of-life goals, pain and symptom management, and her available support systems.
Conclusion
Decisions about breast cancer screening for older women should be influenced by the health status and life expectancy of each patient, her goals for her remaining years, and her risk for breast cancer. Treatment decisions, when necessary, must take these factors, as well as severity of disease, into account. The reduction in quality of life that is inevitable with a diagnosis of advanced-stage metastatic breast cancer should be factored into the decision.
Helen, whose story began this article, was a real patient. Given her previous good health, she hardly expected her final years to be defined by the pain and disability of metastatic breast cancer. Her case illustrates the potential consequences of restricting breast cancer screening decisions to age-based recommendations alone.
1. US Preventive Services Task Force. Screening for breast cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;151(10):716-726, W-236.
2. American Cancer Society Guidelines for the Early Detection of Cancer. Breast cancer. www.cancer.org/Healthy/FindCancerEarly/Cancer ScreeningGuidelines/american-cancer-society-guidelines-for-the-early-detection-of-cancer. Accessed March 28, 2011.
3. American College of Obstetricians and Gynecologists. Response of The American College of Obstetricians and Gynecologists to New Breast Cancer Screening Recommendations from the US Preventive Services Task Force. www.acog .org/from_home/misc/uspstfresponse.cfm. Accessed March 28, 2011.
4. American Academy of Family Physicians. American Academy of Family Physicians updates breast cancer screening recommendations (2010). www.aafp.org/online/en/home/media/releases/2010b/breast-cancer-screening-recom mendations.html. Accessed March 28, 2011.
5. American Geriatrics Society Ethics Committee. Health screening decisions for older adults: AGS position paper. J Am Geriatr Soc. 2003; 51(2):270-271.
6. Gøtzsche PC, Nielsen M. Screening for breast cancer with mammography. Cochrane Database Syst Rev. 2011 Jan 19;(1):CD001877.
7. Traa MJ, Meijs CM, de Jongh MA, et al. Elderly women with breast cancer often die due to other causes regardless of primary endocrine therapy or primary surgical therapy. Breast. 2011 Feb 14. [Epub ahead of print]
8. Schonberg MA, McCarthy EP. Mammography screening among women age 80 years and older: consider the risks. J Clin Oncol. 2009;27 (4):640-641.
9. Mandelblatt JS, Silliman R. Hanging in the balance: making decisions about the benefits and harms of breast cancer screening among the oldest old without a safety net of scientific evidence. J Clin Oncol. 2009;27(4):487-490.
10. National Cancer Institute. Surveillance Epidemiology and End Results, 1975-2007 (2010). Table 4.17. Cancer of the Female Breast (Ages 50+, Invasive). http://seer.cancer.gov/csr/1975_2007/browse_csr.php?section=4&page=sect_04_table.17.html. Accessed March 28, 2011.
11. National Cancer Institute. Breast Cancer Screening PDQ. Breast cancer diagnosis (2010). www.cancer.gov/cancertopics/pdq/screening/breast/HealthProfessional/page3. Accessed March 28, 2011.
12. Nyström L, Andersson I, Bjurstam N, et al. Long-term effects of mammography screening: updated overview of the Swedish randomised trials. Lancet. 2002;359(9310):909-919.
13. Walter LC, Covinsky KE. Cancer screening in elderly patients: A framework for individualized decision making. JAMA. 2001;285(21): 2750-2756.
14. Badgwell BD, Giordano SH, Duan ZZ, et al. Mammography before diagnosis among women age 80 years and older with breast cancer. J Clin Oncol. 2008;26(15):2482-2488.
15. Mathis KL, Hoskin TL, Boughey JC, et al. Palpable presentation of breast cancer persists in the era of screening mammography. J Am Coll Surg. 2010;210(3):314-318.
16. Kalager M, Zelen M, Langmark F, Adami H-O. Effect of screening mammography on breast-cancer mortality in Norway. N Engl J Med. 2010;363(13):1203-1210.
17. National Cancer Institute Breast Cancer Surveillance Consortium. Performance measures for 3,884,059 screening mammography examinations from 1996 to 2007 by age (2009). http://breastscreening.cancer.gov/data/performance/screening/perf_age.html. Accessed March 28, 2011.
18. Welch HG, Fisher ES. Diagnostic testing following screening mammography in the elderly. J Natl Cancer Inst. 1998;90(18):1389-1392.
19. Tan A, Freeman DH Jr, Goodwin JS, Freeman JL. Variation in false-positive rates of mammography reading among 1067 radiologists: a population-based assessment. Breast Cancer Res Treat. 2006;100(3):309-318.
20. Schonberg M. Breast cancer screening: at what age to stop? www.consultantlive.com/geriatrics/content/article/10162/1563530. Accessed March 28, 2011.
21. Thomas DB, Gao DL, Self SG, et al. Randomized trial of breast self-examination in Shanghai: methodology and preliminary results. J Natl Cancer Inst. 1997;89(5):355-65.
22. Semiglazov VF, Moiseyenko VM, Bavli JL, et al. The role of breast self-examination in early breast cancer detection (results of the 5-year USSR/WHO randomized study in Leningrad). Eur J Epidemiol. 1992;8(4):498-502.
23. de Koning HJ, Boer R, Warmerdam PG, et al. Quantitative interpretation of age-specific mortality reductions from the Swedish breast cancer–screening trials. J Natl Cancer Inst. 1995;87 (16):1217-1223.
24. Schonberg MA, Marcantonio ER, Li D, et al. Breast cancer among the oldest old: tumor characteristics, treatment choices, and survival. J Clin Onc. 2010;28(12):2038-2045.
25. McCarthy EP, Burns RB, Freund KM, et al. Mammography use, breast cancer stage at diagnosis, and survival among older women. J Am Ger Soc. 2000;48(10):1226-1233.
26. Smith BD, Gross CP, Smith GL, et al. Effectiveness of radiation therapy for older women with early breast cancer. J Natl Cancer Inst. 2006;98(10):681-690.
27. Walter LC, Eng C, Covinsky KE. Screening mammography for frail older women: what are the burdens? J Gen Int Med. 2001;16(11): 779-784.
28. Arias E. United States life tables, 2006. Natl Vital Stat Rep. 2010;58(21):1-40.
29. National Cancer Institute. Surveillance Epidemiology and End Results, 1975-2007 (2010). Table 4.12. Cancer of the Breast (Invasive). http://seer.cancer.gov/csr/1975_2007/browse_csr.php?section=4&page=sect_04_table.12 .html. Accessed March 21, 2011.
30. RAND Health Project. Assessing care of vulnerable elders: Vulnerable Elders Survey (VES-13, 2011). www.rand.org/health/projects/acove/survey.html. Accessed March 28, 2011.
31. Saliba S, Elliott M, Rubenstein LA, et al. The Vulnerable Elders Survey: a tool for identifying vulnerable older people in the community. J Am Geriatr Soc. 2001;49(12):1691-1699.
32. National Cancer Institute. Breast Cancer Risk Assessment Tool. www.cancer.gov/bcrisk tool. Accessed March 28, 2011.
33. Vogel VG. Breast cancer (2010). www.merck.com/mmpe/sec18/ch253/ch253e.html. Accessed March 28, 2011.
1. US Preventive Services Task Force. Screening for breast cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;151(10):716-726, W-236.
2. American Cancer Society Guidelines for the Early Detection of Cancer. Breast cancer. www.cancer.org/Healthy/FindCancerEarly/Cancer ScreeningGuidelines/american-cancer-society-guidelines-for-the-early-detection-of-cancer. Accessed March 28, 2011.
3. American College of Obstetricians and Gynecologists. Response of The American College of Obstetricians and Gynecologists to New Breast Cancer Screening Recommendations from the US Preventive Services Task Force. www.acog .org/from_home/misc/uspstfresponse.cfm. Accessed March 28, 2011.
4. American Academy of Family Physicians. American Academy of Family Physicians updates breast cancer screening recommendations (2010). www.aafp.org/online/en/home/media/releases/2010b/breast-cancer-screening-recom mendations.html. Accessed March 28, 2011.
5. American Geriatrics Society Ethics Committee. Health screening decisions for older adults: AGS position paper. J Am Geriatr Soc. 2003; 51(2):270-271.
6. Gøtzsche PC, Nielsen M. Screening for breast cancer with mammography. Cochrane Database Syst Rev. 2011 Jan 19;(1):CD001877.
7. Traa MJ, Meijs CM, de Jongh MA, et al. Elderly women with breast cancer often die due to other causes regardless of primary endocrine therapy or primary surgical therapy. Breast. 2011 Feb 14. [Epub ahead of print]
8. Schonberg MA, McCarthy EP. Mammography screening among women age 80 years and older: consider the risks. J Clin Oncol. 2009;27 (4):640-641.
9. Mandelblatt JS, Silliman R. Hanging in the balance: making decisions about the benefits and harms of breast cancer screening among the oldest old without a safety net of scientific evidence. J Clin Oncol. 2009;27(4):487-490.
10. National Cancer Institute. Surveillance Epidemiology and End Results, 1975-2007 (2010). Table 4.17. Cancer of the Female Breast (Ages 50+, Invasive). http://seer.cancer.gov/csr/1975_2007/browse_csr.php?section=4&page=sect_04_table.17.html. Accessed March 28, 2011.
11. National Cancer Institute. Breast Cancer Screening PDQ. Breast cancer diagnosis (2010). www.cancer.gov/cancertopics/pdq/screening/breast/HealthProfessional/page3. Accessed March 28, 2011.
12. Nyström L, Andersson I, Bjurstam N, et al. Long-term effects of mammography screening: updated overview of the Swedish randomised trials. Lancet. 2002;359(9310):909-919.
13. Walter LC, Covinsky KE. Cancer screening in elderly patients: A framework for individualized decision making. JAMA. 2001;285(21): 2750-2756.
14. Badgwell BD, Giordano SH, Duan ZZ, et al. Mammography before diagnosis among women age 80 years and older with breast cancer. J Clin Oncol. 2008;26(15):2482-2488.
15. Mathis KL, Hoskin TL, Boughey JC, et al. Palpable presentation of breast cancer persists in the era of screening mammography. J Am Coll Surg. 2010;210(3):314-318.
16. Kalager M, Zelen M, Langmark F, Adami H-O. Effect of screening mammography on breast-cancer mortality in Norway. N Engl J Med. 2010;363(13):1203-1210.
17. National Cancer Institute Breast Cancer Surveillance Consortium. Performance measures for 3,884,059 screening mammography examinations from 1996 to 2007 by age (2009). http://breastscreening.cancer.gov/data/performance/screening/perf_age.html. Accessed March 28, 2011.
18. Welch HG, Fisher ES. Diagnostic testing following screening mammography in the elderly. J Natl Cancer Inst. 1998;90(18):1389-1392.
19. Tan A, Freeman DH Jr, Goodwin JS, Freeman JL. Variation in false-positive rates of mammography reading among 1067 radiologists: a population-based assessment. Breast Cancer Res Treat. 2006;100(3):309-318.
20. Schonberg M. Breast cancer screening: at what age to stop? www.consultantlive.com/geriatrics/content/article/10162/1563530. Accessed March 28, 2011.
21. Thomas DB, Gao DL, Self SG, et al. Randomized trial of breast self-examination in Shanghai: methodology and preliminary results. J Natl Cancer Inst. 1997;89(5):355-65.
22. Semiglazov VF, Moiseyenko VM, Bavli JL, et al. The role of breast self-examination in early breast cancer detection (results of the 5-year USSR/WHO randomized study in Leningrad). Eur J Epidemiol. 1992;8(4):498-502.
23. de Koning HJ, Boer R, Warmerdam PG, et al. Quantitative interpretation of age-specific mortality reductions from the Swedish breast cancer–screening trials. J Natl Cancer Inst. 1995;87 (16):1217-1223.
24. Schonberg MA, Marcantonio ER, Li D, et al. Breast cancer among the oldest old: tumor characteristics, treatment choices, and survival. J Clin Onc. 2010;28(12):2038-2045.
25. McCarthy EP, Burns RB, Freund KM, et al. Mammography use, breast cancer stage at diagnosis, and survival among older women. J Am Ger Soc. 2000;48(10):1226-1233.
26. Smith BD, Gross CP, Smith GL, et al. Effectiveness of radiation therapy for older women with early breast cancer. J Natl Cancer Inst. 2006;98(10):681-690.
27. Walter LC, Eng C, Covinsky KE. Screening mammography for frail older women: what are the burdens? J Gen Int Med. 2001;16(11): 779-784.
28. Arias E. United States life tables, 2006. Natl Vital Stat Rep. 2010;58(21):1-40.
29. National Cancer Institute. Surveillance Epidemiology and End Results, 1975-2007 (2010). Table 4.12. Cancer of the Breast (Invasive). http://seer.cancer.gov/csr/1975_2007/browse_csr.php?section=4&page=sect_04_table.12 .html. Accessed March 21, 2011.
30. RAND Health Project. Assessing care of vulnerable elders: Vulnerable Elders Survey (VES-13, 2011). www.rand.org/health/projects/acove/survey.html. Accessed March 28, 2011.
31. Saliba S, Elliott M, Rubenstein LA, et al. The Vulnerable Elders Survey: a tool for identifying vulnerable older people in the community. J Am Geriatr Soc. 2001;49(12):1691-1699.
32. National Cancer Institute. Breast Cancer Risk Assessment Tool. www.cancer.gov/bcrisk tool. Accessed March 28, 2011.
33. Vogel VG. Breast cancer (2010). www.merck.com/mmpe/sec18/ch253/ch253e.html. Accessed March 28, 2011.
Man, 54, With Delusions and Seizures
A 54-year-old African-American man was brought by police officers to the emergency department (ED) after he called 911 several times to report seeing a Rottweiler looking into his second-story window. At the scene, the police were unable to confirm his story, thought the man seemed intoxicated, and brought him to the ED for evaluation.
The patient reported that he had been drinking the previous evening but denied current intoxication or illicit drug use. He denied experiencing symptoms of alcohol withdrawal.
Regarding his medical history, the patient admitted to having had seizures, including two episodes that he said required hospitalization. He described these episodes as right-hand “tingling” (paresthesias), accompanied by right-facial numbness and aphasia. The patient said his physician had instructed him to take “a few phenytoin pills” whenever these episodes occurred. He reported that the medication usually helped resolve his symptoms. He said he had taken phenytoin shortly before his current presentation.
According to friends of the patient who were questioned, he had had noticeable memory problems during the previous six to eight months. They said that he often told the same joke, day after day. His speech had become increasingly slurred, even when he was not drinking.
Once the patient’s medical records were retrieved, it was revealed that he had been hospitalized twice for witnessed grand mal seizures about six months before his current admission; he had been drinking alcohol prior to both episodes. He underwent electroencephalography (EEG) during one of these hospitalizations, with results reported as normal. On both occasions, the patient was discharged with phenytoin and was instructed to follow up with his primary care provider and neurologist.
The patient, who reported working in customer service, had no known allergies. He claimed to drink one or two 40-ounce beers twice per week and admitted to occasional cocaine use. Of significance in his family history was a fatal MI in his mother. Although the patient denied any history of rashes or lesions, his current delirium made it impossible to obtain a reliable sexual history; a friend who was questioned, however, described the patient as promiscuous.
On initial physical examination, the man was afebrile, tachycardic, and somewhat combative with the ED staff. He was fully oriented to self but only partially to place and time.
His right pupil was 3+ and his left pupil was 2+, with neither reactive to light. He spoke with tangential speech and his gait was unsteady, but no other significant abnormalities were noted. A full assessment revealed no rashes or other lesions.
Significant laboratory findings included a low level of phenytoin, a negative blood alcohol level, presence of cocaine on urine drug screening, and normal levels of thyroid-stimulating hormone (TSH), vitamin B12, and folate. The patient’s serum VDRL (venereal disease research laboratory) titer was positive at 1:256.
Electroencephalography showed diffuse slowing, and brain CT performed in the ED showed atrophy that was mild but appropriate for a person of the patient’s age, with no evidence of a cerebrovascular accident (CVA). Aneurysm was ruled out by CT angiography of the brain. MRI revealed persistent increased signal in the subarachnoid space.
The patient was admitted with an initial diagnosis of paranoid delusional psychosis and monitored for alcohol withdrawal. He was given lorazepam as needed for agitation. Consultations were arranged with the psychiatry service regarding his delusions, and with neurology to determine whether to continue phenytoin.
The patient showed little response during the next several days. Based on positive results on serum VDRL with high titer, the presence of Argyll-Robertson pupils on exam, and his history of dementia-like symptoms, a lumbar puncture was performed to rule out neurosyphilis. In the patient’s cerebral spinal fluid (CSF) analysis, the first tube was clear and colorless, with 72 cells (28% neutrophils, 59% lymphocytes); glucose, 64 mg/dL; and total protein, 117 mg/dL. The fourth tube had 34 cells (17% neutrophils, 65% lymphocytes) and a positive VDRL titer at 1:128. Results from a serum syphilis immunoglobulin G (IgG) test were positive, and HIV antibody testing was nonreactive, confirming the diagnosis of neurosyphilis.
The hospital’s infectious disease (ID) team recommended treatment with IV penicillin for 14 days. Once this was completed, the patient was discharged with instructions to follow up at the ID clinic in three months for a repeat CSF VDRL titer to monitor for resolution of the disease. His prescription for phenytoin was discontinued.
At the time of discharge, it was noted that the patient showed no evidence of having regained cognitive function. He was deemed by the psychiatry service to lack decision-making capacity—a likely sequelae of untreated neurosyphilis of unknown duration.
He did return to the ID clinic six months after his discharge. At that visit, a VDRL serum titer was drawn with a result of 1:64, a decrease from 1:128. His syphilis IgG remained positive, however.
Discussion
Definition and Epidemiology
Syphilis is commonly known as a sexually transmitted disease with primary, secondary, and tertiary (early and late latent) stages.1 Neurosyphilis is defined as a manifestation of the inflammatory response to invasion over decades by the Treponema pallidum spirochete in the CSF as a result of untreated primary and/or secondary syphilis.2 About one in 10 patients with untreated syphilis will experience neurologic involvement.3,4 Before 2005, neurosyphilis was required to be reported as a specific stage of syphilis (ie, a manifestation of tertiary syphilis4), but now should be reported as syphilis with neurologic manifestations.5
A reportable infectious disease, syphilis was widespread until the advent of penicillin. According to CDC statistics,6 the number of reported cases of primary and secondary syphilis has declined steadily since 1943. In the late 1970s and early 1980s, the number of tertiary cases also began to plateau, likely as a result of earlier diagnosis and more widespread use of penicillin. Recent case reports suggest greater prevalence of syphilis among men than women and increased incidence among men who have sex with men.7
Pathogenesis
Syphilis is most commonly spread by sexual contact or contact with an infected primary lesion (chancre). Less likely routes of transmission are placental passage or blood transfusion. Infectivity is greatest in the early disease stages.8
Primary syphilis is marked by transmission of the spirochete, ending with development of secondary syphilis (usually two to 12 weeks after transmission). A chancre commonly develops but is often missed by patients because it is painless and can heal spontaneously.7 The chancre is also often confused with two other sources of genital lesions, herpes simplex (genital herpes) and Haemophilus ducreyi (chancroid). In two-thirds of cases of untreated primary syphilis, the infection clears spontaneously, but in the remaining one-third, the disease progresses.8
Secondary syphilis, with or without presence of a chancre, manifests with constitutional symptoms, including lymphadenopathy, fever, headache, and malaise. Patients in this disease phase may also present with a generalized, nonpruritic, macular to maculopapular or pustular rash. The rash can affect the skin of the trunk, the proximal extremities, and the palms and soles. Ocular involvement may occur, especially in patients who are coinfected with HIV.8 In either primary or secondary syphilis, infection can invade the central nervous system.1
During latent syphilis, patients show serologic conversion without overt symptoms. Early latent syphilis is defined as infection within the previous year, as demonstrated by conversion from negative to positive testing, or an increase in titers within the previous year. Any case occurring after one year is defined as late or unknown latent syphilis.8
Tertiary syphilis is marked by complications resulting from untreated syphilis; affected patients commonly experience central nervous system and cardiovascular involvement. Gummatous disease is seen in 15% of patients.1
The early stages of neurosyphilis may be asymptomatic, acute meningeal, and meningovascular.1,4,8,9 Only 5% of patients with early neurosyphilis are symptomatic, with the added potential for cranial neuritis or ocular involvement.1 The late stages of neurosyphilis are detailed in the table.1,4,8
Diagnosis
A diagnosis of syphilis is made by testing blood samples or scrapings from a lesion. In patients with suspected syphilis, rapid plasma reagin (RPR) testing or a VDRL titer is commonly ordered. When results are positive, a serum treponemal test is recommended to confirm a diagnosis of syphilis. Options include the fluorescent treponemal antibody absorption test (FTA-ABS) and the microhemagglutinin assay for antibody to T pallidum (MHA-TP).5
If neurologic symptoms are present, a CSF sample should be obtained, followed by the same testing. A confirmed diagnosis of neurosyphilis is defined by the CDC as syphilis at any stage that meets laboratory criteria for neurosyphilis5; these include increased CSF protein or an elevated CSF leukocyte count with no other known cause, and clinical signs or symptoms without other known causes.7
Treatment
Treatment of syphilis generally consists of penicillin, administered intramuscularly (IM) or IV, depending on the stage. According to 2006 guidelines from the CDC,10,11 treatment for adults with primary and secondary syphilis is a single dose of IM penicillin G, 2.4 million units. If neurosyphilis is suspected, recommended treatment is IV penicillin G, 18 to 24 million units per day divided into six doses (ie, 3 to 4 million units every four hours) or continuous pump infusion for 10 to 14 days.10-12 Follow-up is recommended by monitoring CSF titers to ensure clearance of infection; retreatment may be required if CSF abnormalities persist after two years.11
Patients with a penicillin allergy should undergo desensitization, as penicillin is the preferred agent; the potential exists for cross-reactivity with ceftriaxone, a possible alternative for patients with neurosyphilis.11 All patients diagnosed with syphilis should also be tested for HIV and other sexually transmitted diseases.10-12
The prognosis of patients treated for neurosyphilis is generally good if the condition is diagnosed and treated early. In patients with cerebral atrophy, frontal lesions, dementia, or tabes dorsalis, the potential for recovery decreases.2,13,14
Teaching Points
There are several teaching points to take away from this case:
• Remember to rule out a CVA in any patient who presents with numbness, paresthesias, or slurred speech. In this case, a brain CT and CT angiography of the brain were both obtained in the ED before the patient was admitted. They both yielded negative results; because the patient’s history was consistent with alcohol and drug use and he had a history of seizures, he was monitored closely for signs of withdrawal or further seizure.
• Phenytoin is an antiepileptic agent whose use requires proper patient education and drug level monitoring. Appropriate follow-up must be ensured before phenytoin therapy is begun, as toxicity can result in nystagmus, ataxia, slurred speech, decreased coordination, mental confusion, and possibly death.15,16
• For patients with a suspected acute change in mental status, a workup is required and should be tailored appropriately, based on findings. This should include, but not be limited to, a thorough history and physical exam, CT of the brain (to rule out an acute brain injury17), and, if warranted, MRI of the brain. Also, a urine drug screen and alcohol level, a complete blood count, a TSH level (to evaluate for altered thyroid function that may explain mental status changes), comprehensive panel, RPR testing and/or a VDRL titer should be obtained, depending on the facility’s protocol18,19; at some facilities, a treponemal test, rather than VDRL, is being obtained at the outset.20 Levels of vitamin B12 (as part of the dementia workup), folate, thiamine, and ammonia (in patients with suspected liver disease) can also be obtained in patients with change in mental status.18,19 Urinalysis should not be overlooked to check for a urinary tract infection, especially in elderly patients.21
• If primary syphilis is suspected, treatment must be undertaken.20
Conclusion
Despite the decline seen since the 1940s in cases of primary and secondary syphilis, and the effectiveness of penicillin in treating the infection early, patients with late-stage syphilis, including those with neurosyphilis, may still present to the emergency care, urgent care, or primary care setting. Immediate treatment with penicillin is recommended to achieve an optimal prognosis for the affected patient.
1. Golden MR, Marra CM, Holmes KK. Update on syphilis: resurgence of an old problem. JAMA. 2003;290(11):1510-1514.
2. Simon RP. Chapter 20. Neurosyphilis. In: Klausner JD, Hook EW III, eds. Current Diagnosis & Treatment of Sexually Transmitted Diseases. USA: The McGraw-Hill Companies; 2007:130-137.
3. Sanchez FM, Zisselman MH. Treatment of psychiatric symptoms associated with neurosyphilis. Psychosomatics. 2007;48:440-445.
4. Marra CM. Neurosyphilis. Curr Neurol Neurosci Rep. 2004;4(6):435-440.
5. CDC. Sexually transmitted diseases surveillance, 2007: STD surveillance case definitions. www.cdc.gov/std/stats07/app-casedef.htm. Accessed March 23, 2011.
6. CDC. 2008 Sexually Transmitted Diseases Surveillance: Table 1. Cases of sexually transmitted diseases reported by state health departments and rates per 100,000 population: United States, 1941-2008. www.cdc.gov/std/stats08/tables/1.htm. Accessed March 23, 2011.
7. CDC. Sexually transmitted diseases (STDs): Syphilis: CDC fact sheet. www.cdc.gov/std/syphilis/STDfact-syphilis.htm. Accessed March 23, 2011.
8. Tramont EC. Chapter 238. Treponema pallidum (syphilis). In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 7th ed. Philadelphia: Elsevier Churchill Livingstone; 2009.
9. Ghanem KG. Neurosyphilis: a historical perspective and review. CNS Neurosci Ther. 2010; 16(5):e157-e168.
10. Workowski KA, Berman SM; CDC. Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep. 2006;55(RR-11):1-94.
11. CDC. Sexually transmitted diseases: treatment guidelines 2006. www.cdc.gov/std/treatment/2006/genital-ulcers.htm#genulc6. Accessed March 29, 2011.
12. Drugs for sexually transmitted infections. Treatment Guidelines from the Medical Letter. 2010;95:95a. http://secure.medicalletter.org. Accessed March 23, 2011.
13. Russouw HG, Roberts MC, Emsley RA, et al. Psychiatric manifestations and magnetic resonance imaging in HIV-negative neurosyphilis. Biol Psychiatry. 1997;41(4):467-473.
14. Hooshmand H, Escobar MR, Kopf SW. Neurosyphylis: a study of 241 patients. JAMA. 1972;219 (6):726-729.
15. Miller CA, Joyce DM. Toxicity, phenytoin. http://emedicine.medscape.com/article/816447-overview. Accessed March 23, 2011.
16. Earnest MP, Marx JA, Drury LR. Complications of intravenous phenytoin for acute treatment of seizures: recommendations for usage. JAMA. 1983; 246(6):762-765.
17. Geschwind MD, Shu H, Haman A, et al. Rapidly progressive dementia. Ann Neurol. 2008;64(1): 97-108.
18. Mechem CC. Chapter 143. Altered mental status and coma. In: Ma J, Cline DM, Tintinalli JE, et al, eds. Emergency Medicine Manual, 6e. www.access emergencymedicine.com/content.aspx?aID=2020. Accessed March 23, 2011.
19. Knopman DS, DeKosky ST, Cummings JL, et al; Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: diagnosis of dementia (an evidence-based review). Neurology. 2001;56(9):1143-1153.
20. CDC. Syphilis testing algorithms using treponemal tests for initial screening—four laboratories, New York City, 2005-2006. MMWR Morb Mortal Wkly Rep. 2008;57(32):872-875.
21. Anderson CA, Filley CM. Chapter 33. Behavioral presentations of medical and neurologic disorders. In: Jacobson JL, Jacobson AM, eds. Psychiatric Secrets. 2nd ed. St. Louis, MO: Hanley & Belfus; 2001.
A 54-year-old African-American man was brought by police officers to the emergency department (ED) after he called 911 several times to report seeing a Rottweiler looking into his second-story window. At the scene, the police were unable to confirm his story, thought the man seemed intoxicated, and brought him to the ED for evaluation.
The patient reported that he had been drinking the previous evening but denied current intoxication or illicit drug use. He denied experiencing symptoms of alcohol withdrawal.
Regarding his medical history, the patient admitted to having had seizures, including two episodes that he said required hospitalization. He described these episodes as right-hand “tingling” (paresthesias), accompanied by right-facial numbness and aphasia. The patient said his physician had instructed him to take “a few phenytoin pills” whenever these episodes occurred. He reported that the medication usually helped resolve his symptoms. He said he had taken phenytoin shortly before his current presentation.
According to friends of the patient who were questioned, he had had noticeable memory problems during the previous six to eight months. They said that he often told the same joke, day after day. His speech had become increasingly slurred, even when he was not drinking.
Once the patient’s medical records were retrieved, it was revealed that he had been hospitalized twice for witnessed grand mal seizures about six months before his current admission; he had been drinking alcohol prior to both episodes. He underwent electroencephalography (EEG) during one of these hospitalizations, with results reported as normal. On both occasions, the patient was discharged with phenytoin and was instructed to follow up with his primary care provider and neurologist.
The patient, who reported working in customer service, had no known allergies. He claimed to drink one or two 40-ounce beers twice per week and admitted to occasional cocaine use. Of significance in his family history was a fatal MI in his mother. Although the patient denied any history of rashes or lesions, his current delirium made it impossible to obtain a reliable sexual history; a friend who was questioned, however, described the patient as promiscuous.
On initial physical examination, the man was afebrile, tachycardic, and somewhat combative with the ED staff. He was fully oriented to self but only partially to place and time.
His right pupil was 3+ and his left pupil was 2+, with neither reactive to light. He spoke with tangential speech and his gait was unsteady, but no other significant abnormalities were noted. A full assessment revealed no rashes or other lesions.
Significant laboratory findings included a low level of phenytoin, a negative blood alcohol level, presence of cocaine on urine drug screening, and normal levels of thyroid-stimulating hormone (TSH), vitamin B12, and folate. The patient’s serum VDRL (venereal disease research laboratory) titer was positive at 1:256.
Electroencephalography showed diffuse slowing, and brain CT performed in the ED showed atrophy that was mild but appropriate for a person of the patient’s age, with no evidence of a cerebrovascular accident (CVA). Aneurysm was ruled out by CT angiography of the brain. MRI revealed persistent increased signal in the subarachnoid space.
The patient was admitted with an initial diagnosis of paranoid delusional psychosis and monitored for alcohol withdrawal. He was given lorazepam as needed for agitation. Consultations were arranged with the psychiatry service regarding his delusions, and with neurology to determine whether to continue phenytoin.
The patient showed little response during the next several days. Based on positive results on serum VDRL with high titer, the presence of Argyll-Robertson pupils on exam, and his history of dementia-like symptoms, a lumbar puncture was performed to rule out neurosyphilis. In the patient’s cerebral spinal fluid (CSF) analysis, the first tube was clear and colorless, with 72 cells (28% neutrophils, 59% lymphocytes); glucose, 64 mg/dL; and total protein, 117 mg/dL. The fourth tube had 34 cells (17% neutrophils, 65% lymphocytes) and a positive VDRL titer at 1:128. Results from a serum syphilis immunoglobulin G (IgG) test were positive, and HIV antibody testing was nonreactive, confirming the diagnosis of neurosyphilis.
The hospital’s infectious disease (ID) team recommended treatment with IV penicillin for 14 days. Once this was completed, the patient was discharged with instructions to follow up at the ID clinic in three months for a repeat CSF VDRL titer to monitor for resolution of the disease. His prescription for phenytoin was discontinued.
At the time of discharge, it was noted that the patient showed no evidence of having regained cognitive function. He was deemed by the psychiatry service to lack decision-making capacity—a likely sequelae of untreated neurosyphilis of unknown duration.
He did return to the ID clinic six months after his discharge. At that visit, a VDRL serum titer was drawn with a result of 1:64, a decrease from 1:128. His syphilis IgG remained positive, however.
Discussion
Definition and Epidemiology
Syphilis is commonly known as a sexually transmitted disease with primary, secondary, and tertiary (early and late latent) stages.1 Neurosyphilis is defined as a manifestation of the inflammatory response to invasion over decades by the Treponema pallidum spirochete in the CSF as a result of untreated primary and/or secondary syphilis.2 About one in 10 patients with untreated syphilis will experience neurologic involvement.3,4 Before 2005, neurosyphilis was required to be reported as a specific stage of syphilis (ie, a manifestation of tertiary syphilis4), but now should be reported as syphilis with neurologic manifestations.5
A reportable infectious disease, syphilis was widespread until the advent of penicillin. According to CDC statistics,6 the number of reported cases of primary and secondary syphilis has declined steadily since 1943. In the late 1970s and early 1980s, the number of tertiary cases also began to plateau, likely as a result of earlier diagnosis and more widespread use of penicillin. Recent case reports suggest greater prevalence of syphilis among men than women and increased incidence among men who have sex with men.7
Pathogenesis
Syphilis is most commonly spread by sexual contact or contact with an infected primary lesion (chancre). Less likely routes of transmission are placental passage or blood transfusion. Infectivity is greatest in the early disease stages.8
Primary syphilis is marked by transmission of the spirochete, ending with development of secondary syphilis (usually two to 12 weeks after transmission). A chancre commonly develops but is often missed by patients because it is painless and can heal spontaneously.7 The chancre is also often confused with two other sources of genital lesions, herpes simplex (genital herpes) and Haemophilus ducreyi (chancroid). In two-thirds of cases of untreated primary syphilis, the infection clears spontaneously, but in the remaining one-third, the disease progresses.8
Secondary syphilis, with or without presence of a chancre, manifests with constitutional symptoms, including lymphadenopathy, fever, headache, and malaise. Patients in this disease phase may also present with a generalized, nonpruritic, macular to maculopapular or pustular rash. The rash can affect the skin of the trunk, the proximal extremities, and the palms and soles. Ocular involvement may occur, especially in patients who are coinfected with HIV.8 In either primary or secondary syphilis, infection can invade the central nervous system.1
During latent syphilis, patients show serologic conversion without overt symptoms. Early latent syphilis is defined as infection within the previous year, as demonstrated by conversion from negative to positive testing, or an increase in titers within the previous year. Any case occurring after one year is defined as late or unknown latent syphilis.8
Tertiary syphilis is marked by complications resulting from untreated syphilis; affected patients commonly experience central nervous system and cardiovascular involvement. Gummatous disease is seen in 15% of patients.1
The early stages of neurosyphilis may be asymptomatic, acute meningeal, and meningovascular.1,4,8,9 Only 5% of patients with early neurosyphilis are symptomatic, with the added potential for cranial neuritis or ocular involvement.1 The late stages of neurosyphilis are detailed in the table.1,4,8
Diagnosis
A diagnosis of syphilis is made by testing blood samples or scrapings from a lesion. In patients with suspected syphilis, rapid plasma reagin (RPR) testing or a VDRL titer is commonly ordered. When results are positive, a serum treponemal test is recommended to confirm a diagnosis of syphilis. Options include the fluorescent treponemal antibody absorption test (FTA-ABS) and the microhemagglutinin assay for antibody to T pallidum (MHA-TP).5
If neurologic symptoms are present, a CSF sample should be obtained, followed by the same testing. A confirmed diagnosis of neurosyphilis is defined by the CDC as syphilis at any stage that meets laboratory criteria for neurosyphilis5; these include increased CSF protein or an elevated CSF leukocyte count with no other known cause, and clinical signs or symptoms without other known causes.7
Treatment
Treatment of syphilis generally consists of penicillin, administered intramuscularly (IM) or IV, depending on the stage. According to 2006 guidelines from the CDC,10,11 treatment for adults with primary and secondary syphilis is a single dose of IM penicillin G, 2.4 million units. If neurosyphilis is suspected, recommended treatment is IV penicillin G, 18 to 24 million units per day divided into six doses (ie, 3 to 4 million units every four hours) or continuous pump infusion for 10 to 14 days.10-12 Follow-up is recommended by monitoring CSF titers to ensure clearance of infection; retreatment may be required if CSF abnormalities persist after two years.11
Patients with a penicillin allergy should undergo desensitization, as penicillin is the preferred agent; the potential exists for cross-reactivity with ceftriaxone, a possible alternative for patients with neurosyphilis.11 All patients diagnosed with syphilis should also be tested for HIV and other sexually transmitted diseases.10-12
The prognosis of patients treated for neurosyphilis is generally good if the condition is diagnosed and treated early. In patients with cerebral atrophy, frontal lesions, dementia, or tabes dorsalis, the potential for recovery decreases.2,13,14
Teaching Points
There are several teaching points to take away from this case:
• Remember to rule out a CVA in any patient who presents with numbness, paresthesias, or slurred speech. In this case, a brain CT and CT angiography of the brain were both obtained in the ED before the patient was admitted. They both yielded negative results; because the patient’s history was consistent with alcohol and drug use and he had a history of seizures, he was monitored closely for signs of withdrawal or further seizure.
• Phenytoin is an antiepileptic agent whose use requires proper patient education and drug level monitoring. Appropriate follow-up must be ensured before phenytoin therapy is begun, as toxicity can result in nystagmus, ataxia, slurred speech, decreased coordination, mental confusion, and possibly death.15,16
• For patients with a suspected acute change in mental status, a workup is required and should be tailored appropriately, based on findings. This should include, but not be limited to, a thorough history and physical exam, CT of the brain (to rule out an acute brain injury17), and, if warranted, MRI of the brain. Also, a urine drug screen and alcohol level, a complete blood count, a TSH level (to evaluate for altered thyroid function that may explain mental status changes), comprehensive panel, RPR testing and/or a VDRL titer should be obtained, depending on the facility’s protocol18,19; at some facilities, a treponemal test, rather than VDRL, is being obtained at the outset.20 Levels of vitamin B12 (as part of the dementia workup), folate, thiamine, and ammonia (in patients with suspected liver disease) can also be obtained in patients with change in mental status.18,19 Urinalysis should not be overlooked to check for a urinary tract infection, especially in elderly patients.21
• If primary syphilis is suspected, treatment must be undertaken.20
Conclusion
Despite the decline seen since the 1940s in cases of primary and secondary syphilis, and the effectiveness of penicillin in treating the infection early, patients with late-stage syphilis, including those with neurosyphilis, may still present to the emergency care, urgent care, or primary care setting. Immediate treatment with penicillin is recommended to achieve an optimal prognosis for the affected patient.
A 54-year-old African-American man was brought by police officers to the emergency department (ED) after he called 911 several times to report seeing a Rottweiler looking into his second-story window. At the scene, the police were unable to confirm his story, thought the man seemed intoxicated, and brought him to the ED for evaluation.
The patient reported that he had been drinking the previous evening but denied current intoxication or illicit drug use. He denied experiencing symptoms of alcohol withdrawal.
Regarding his medical history, the patient admitted to having had seizures, including two episodes that he said required hospitalization. He described these episodes as right-hand “tingling” (paresthesias), accompanied by right-facial numbness and aphasia. The patient said his physician had instructed him to take “a few phenytoin pills” whenever these episodes occurred. He reported that the medication usually helped resolve his symptoms. He said he had taken phenytoin shortly before his current presentation.
According to friends of the patient who were questioned, he had had noticeable memory problems during the previous six to eight months. They said that he often told the same joke, day after day. His speech had become increasingly slurred, even when he was not drinking.
Once the patient’s medical records were retrieved, it was revealed that he had been hospitalized twice for witnessed grand mal seizures about six months before his current admission; he had been drinking alcohol prior to both episodes. He underwent electroencephalography (EEG) during one of these hospitalizations, with results reported as normal. On both occasions, the patient was discharged with phenytoin and was instructed to follow up with his primary care provider and neurologist.
The patient, who reported working in customer service, had no known allergies. He claimed to drink one or two 40-ounce beers twice per week and admitted to occasional cocaine use. Of significance in his family history was a fatal MI in his mother. Although the patient denied any history of rashes or lesions, his current delirium made it impossible to obtain a reliable sexual history; a friend who was questioned, however, described the patient as promiscuous.
On initial physical examination, the man was afebrile, tachycardic, and somewhat combative with the ED staff. He was fully oriented to self but only partially to place and time.
His right pupil was 3+ and his left pupil was 2+, with neither reactive to light. He spoke with tangential speech and his gait was unsteady, but no other significant abnormalities were noted. A full assessment revealed no rashes or other lesions.
Significant laboratory findings included a low level of phenytoin, a negative blood alcohol level, presence of cocaine on urine drug screening, and normal levels of thyroid-stimulating hormone (TSH), vitamin B12, and folate. The patient’s serum VDRL (venereal disease research laboratory) titer was positive at 1:256.
Electroencephalography showed diffuse slowing, and brain CT performed in the ED showed atrophy that was mild but appropriate for a person of the patient’s age, with no evidence of a cerebrovascular accident (CVA). Aneurysm was ruled out by CT angiography of the brain. MRI revealed persistent increased signal in the subarachnoid space.
The patient was admitted with an initial diagnosis of paranoid delusional psychosis and monitored for alcohol withdrawal. He was given lorazepam as needed for agitation. Consultations were arranged with the psychiatry service regarding his delusions, and with neurology to determine whether to continue phenytoin.
The patient showed little response during the next several days. Based on positive results on serum VDRL with high titer, the presence of Argyll-Robertson pupils on exam, and his history of dementia-like symptoms, a lumbar puncture was performed to rule out neurosyphilis. In the patient’s cerebral spinal fluid (CSF) analysis, the first tube was clear and colorless, with 72 cells (28% neutrophils, 59% lymphocytes); glucose, 64 mg/dL; and total protein, 117 mg/dL. The fourth tube had 34 cells (17% neutrophils, 65% lymphocytes) and a positive VDRL titer at 1:128. Results from a serum syphilis immunoglobulin G (IgG) test were positive, and HIV antibody testing was nonreactive, confirming the diagnosis of neurosyphilis.
The hospital’s infectious disease (ID) team recommended treatment with IV penicillin for 14 days. Once this was completed, the patient was discharged with instructions to follow up at the ID clinic in three months for a repeat CSF VDRL titer to monitor for resolution of the disease. His prescription for phenytoin was discontinued.
At the time of discharge, it was noted that the patient showed no evidence of having regained cognitive function. He was deemed by the psychiatry service to lack decision-making capacity—a likely sequelae of untreated neurosyphilis of unknown duration.
He did return to the ID clinic six months after his discharge. At that visit, a VDRL serum titer was drawn with a result of 1:64, a decrease from 1:128. His syphilis IgG remained positive, however.
Discussion
Definition and Epidemiology
Syphilis is commonly known as a sexually transmitted disease with primary, secondary, and tertiary (early and late latent) stages.1 Neurosyphilis is defined as a manifestation of the inflammatory response to invasion over decades by the Treponema pallidum spirochete in the CSF as a result of untreated primary and/or secondary syphilis.2 About one in 10 patients with untreated syphilis will experience neurologic involvement.3,4 Before 2005, neurosyphilis was required to be reported as a specific stage of syphilis (ie, a manifestation of tertiary syphilis4), but now should be reported as syphilis with neurologic manifestations.5
A reportable infectious disease, syphilis was widespread until the advent of penicillin. According to CDC statistics,6 the number of reported cases of primary and secondary syphilis has declined steadily since 1943. In the late 1970s and early 1980s, the number of tertiary cases also began to plateau, likely as a result of earlier diagnosis and more widespread use of penicillin. Recent case reports suggest greater prevalence of syphilis among men than women and increased incidence among men who have sex with men.7
Pathogenesis
Syphilis is most commonly spread by sexual contact or contact with an infected primary lesion (chancre). Less likely routes of transmission are placental passage or blood transfusion. Infectivity is greatest in the early disease stages.8
Primary syphilis is marked by transmission of the spirochete, ending with development of secondary syphilis (usually two to 12 weeks after transmission). A chancre commonly develops but is often missed by patients because it is painless and can heal spontaneously.7 The chancre is also often confused with two other sources of genital lesions, herpes simplex (genital herpes) and Haemophilus ducreyi (chancroid). In two-thirds of cases of untreated primary syphilis, the infection clears spontaneously, but in the remaining one-third, the disease progresses.8
Secondary syphilis, with or without presence of a chancre, manifests with constitutional symptoms, including lymphadenopathy, fever, headache, and malaise. Patients in this disease phase may also present with a generalized, nonpruritic, macular to maculopapular or pustular rash. The rash can affect the skin of the trunk, the proximal extremities, and the palms and soles. Ocular involvement may occur, especially in patients who are coinfected with HIV.8 In either primary or secondary syphilis, infection can invade the central nervous system.1
During latent syphilis, patients show serologic conversion without overt symptoms. Early latent syphilis is defined as infection within the previous year, as demonstrated by conversion from negative to positive testing, or an increase in titers within the previous year. Any case occurring after one year is defined as late or unknown latent syphilis.8
Tertiary syphilis is marked by complications resulting from untreated syphilis; affected patients commonly experience central nervous system and cardiovascular involvement. Gummatous disease is seen in 15% of patients.1
The early stages of neurosyphilis may be asymptomatic, acute meningeal, and meningovascular.1,4,8,9 Only 5% of patients with early neurosyphilis are symptomatic, with the added potential for cranial neuritis or ocular involvement.1 The late stages of neurosyphilis are detailed in the table.1,4,8
Diagnosis
A diagnosis of syphilis is made by testing blood samples or scrapings from a lesion. In patients with suspected syphilis, rapid plasma reagin (RPR) testing or a VDRL titer is commonly ordered. When results are positive, a serum treponemal test is recommended to confirm a diagnosis of syphilis. Options include the fluorescent treponemal antibody absorption test (FTA-ABS) and the microhemagglutinin assay for antibody to T pallidum (MHA-TP).5
If neurologic symptoms are present, a CSF sample should be obtained, followed by the same testing. A confirmed diagnosis of neurosyphilis is defined by the CDC as syphilis at any stage that meets laboratory criteria for neurosyphilis5; these include increased CSF protein or an elevated CSF leukocyte count with no other known cause, and clinical signs or symptoms without other known causes.7
Treatment
Treatment of syphilis generally consists of penicillin, administered intramuscularly (IM) or IV, depending on the stage. According to 2006 guidelines from the CDC,10,11 treatment for adults with primary and secondary syphilis is a single dose of IM penicillin G, 2.4 million units. If neurosyphilis is suspected, recommended treatment is IV penicillin G, 18 to 24 million units per day divided into six doses (ie, 3 to 4 million units every four hours) or continuous pump infusion for 10 to 14 days.10-12 Follow-up is recommended by monitoring CSF titers to ensure clearance of infection; retreatment may be required if CSF abnormalities persist after two years.11
Patients with a penicillin allergy should undergo desensitization, as penicillin is the preferred agent; the potential exists for cross-reactivity with ceftriaxone, a possible alternative for patients with neurosyphilis.11 All patients diagnosed with syphilis should also be tested for HIV and other sexually transmitted diseases.10-12
The prognosis of patients treated for neurosyphilis is generally good if the condition is diagnosed and treated early. In patients with cerebral atrophy, frontal lesions, dementia, or tabes dorsalis, the potential for recovery decreases.2,13,14
Teaching Points
There are several teaching points to take away from this case:
• Remember to rule out a CVA in any patient who presents with numbness, paresthesias, or slurred speech. In this case, a brain CT and CT angiography of the brain were both obtained in the ED before the patient was admitted. They both yielded negative results; because the patient’s history was consistent with alcohol and drug use and he had a history of seizures, he was monitored closely for signs of withdrawal or further seizure.
• Phenytoin is an antiepileptic agent whose use requires proper patient education and drug level monitoring. Appropriate follow-up must be ensured before phenytoin therapy is begun, as toxicity can result in nystagmus, ataxia, slurred speech, decreased coordination, mental confusion, and possibly death.15,16
• For patients with a suspected acute change in mental status, a workup is required and should be tailored appropriately, based on findings. This should include, but not be limited to, a thorough history and physical exam, CT of the brain (to rule out an acute brain injury17), and, if warranted, MRI of the brain. Also, a urine drug screen and alcohol level, a complete blood count, a TSH level (to evaluate for altered thyroid function that may explain mental status changes), comprehensive panel, RPR testing and/or a VDRL titer should be obtained, depending on the facility’s protocol18,19; at some facilities, a treponemal test, rather than VDRL, is being obtained at the outset.20 Levels of vitamin B12 (as part of the dementia workup), folate, thiamine, and ammonia (in patients with suspected liver disease) can also be obtained in patients with change in mental status.18,19 Urinalysis should not be overlooked to check for a urinary tract infection, especially in elderly patients.21
• If primary syphilis is suspected, treatment must be undertaken.20
Conclusion
Despite the decline seen since the 1940s in cases of primary and secondary syphilis, and the effectiveness of penicillin in treating the infection early, patients with late-stage syphilis, including those with neurosyphilis, may still present to the emergency care, urgent care, or primary care setting. Immediate treatment with penicillin is recommended to achieve an optimal prognosis for the affected patient.
1. Golden MR, Marra CM, Holmes KK. Update on syphilis: resurgence of an old problem. JAMA. 2003;290(11):1510-1514.
2. Simon RP. Chapter 20. Neurosyphilis. In: Klausner JD, Hook EW III, eds. Current Diagnosis & Treatment of Sexually Transmitted Diseases. USA: The McGraw-Hill Companies; 2007:130-137.
3. Sanchez FM, Zisselman MH. Treatment of psychiatric symptoms associated with neurosyphilis. Psychosomatics. 2007;48:440-445.
4. Marra CM. Neurosyphilis. Curr Neurol Neurosci Rep. 2004;4(6):435-440.
5. CDC. Sexually transmitted diseases surveillance, 2007: STD surveillance case definitions. www.cdc.gov/std/stats07/app-casedef.htm. Accessed March 23, 2011.
6. CDC. 2008 Sexually Transmitted Diseases Surveillance: Table 1. Cases of sexually transmitted diseases reported by state health departments and rates per 100,000 population: United States, 1941-2008. www.cdc.gov/std/stats08/tables/1.htm. Accessed March 23, 2011.
7. CDC. Sexually transmitted diseases (STDs): Syphilis: CDC fact sheet. www.cdc.gov/std/syphilis/STDfact-syphilis.htm. Accessed March 23, 2011.
8. Tramont EC. Chapter 238. Treponema pallidum (syphilis). In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 7th ed. Philadelphia: Elsevier Churchill Livingstone; 2009.
9. Ghanem KG. Neurosyphilis: a historical perspective and review. CNS Neurosci Ther. 2010; 16(5):e157-e168.
10. Workowski KA, Berman SM; CDC. Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep. 2006;55(RR-11):1-94.
11. CDC. Sexually transmitted diseases: treatment guidelines 2006. www.cdc.gov/std/treatment/2006/genital-ulcers.htm#genulc6. Accessed March 29, 2011.
12. Drugs for sexually transmitted infections. Treatment Guidelines from the Medical Letter. 2010;95:95a. http://secure.medicalletter.org. Accessed March 23, 2011.
13. Russouw HG, Roberts MC, Emsley RA, et al. Psychiatric manifestations and magnetic resonance imaging in HIV-negative neurosyphilis. Biol Psychiatry. 1997;41(4):467-473.
14. Hooshmand H, Escobar MR, Kopf SW. Neurosyphylis: a study of 241 patients. JAMA. 1972;219 (6):726-729.
15. Miller CA, Joyce DM. Toxicity, phenytoin. http://emedicine.medscape.com/article/816447-overview. Accessed March 23, 2011.
16. Earnest MP, Marx JA, Drury LR. Complications of intravenous phenytoin for acute treatment of seizures: recommendations for usage. JAMA. 1983; 246(6):762-765.
17. Geschwind MD, Shu H, Haman A, et al. Rapidly progressive dementia. Ann Neurol. 2008;64(1): 97-108.
18. Mechem CC. Chapter 143. Altered mental status and coma. In: Ma J, Cline DM, Tintinalli JE, et al, eds. Emergency Medicine Manual, 6e. www.access emergencymedicine.com/content.aspx?aID=2020. Accessed March 23, 2011.
19. Knopman DS, DeKosky ST, Cummings JL, et al; Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: diagnosis of dementia (an evidence-based review). Neurology. 2001;56(9):1143-1153.
20. CDC. Syphilis testing algorithms using treponemal tests for initial screening—four laboratories, New York City, 2005-2006. MMWR Morb Mortal Wkly Rep. 2008;57(32):872-875.
21. Anderson CA, Filley CM. Chapter 33. Behavioral presentations of medical and neurologic disorders. In: Jacobson JL, Jacobson AM, eds. Psychiatric Secrets. 2nd ed. St. Louis, MO: Hanley & Belfus; 2001.
1. Golden MR, Marra CM, Holmes KK. Update on syphilis: resurgence of an old problem. JAMA. 2003;290(11):1510-1514.
2. Simon RP. Chapter 20. Neurosyphilis. In: Klausner JD, Hook EW III, eds. Current Diagnosis & Treatment of Sexually Transmitted Diseases. USA: The McGraw-Hill Companies; 2007:130-137.
3. Sanchez FM, Zisselman MH. Treatment of psychiatric symptoms associated with neurosyphilis. Psychosomatics. 2007;48:440-445.
4. Marra CM. Neurosyphilis. Curr Neurol Neurosci Rep. 2004;4(6):435-440.
5. CDC. Sexually transmitted diseases surveillance, 2007: STD surveillance case definitions. www.cdc.gov/std/stats07/app-casedef.htm. Accessed March 23, 2011.
6. CDC. 2008 Sexually Transmitted Diseases Surveillance: Table 1. Cases of sexually transmitted diseases reported by state health departments and rates per 100,000 population: United States, 1941-2008. www.cdc.gov/std/stats08/tables/1.htm. Accessed March 23, 2011.
7. CDC. Sexually transmitted diseases (STDs): Syphilis: CDC fact sheet. www.cdc.gov/std/syphilis/STDfact-syphilis.htm. Accessed March 23, 2011.
8. Tramont EC. Chapter 238. Treponema pallidum (syphilis). In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 7th ed. Philadelphia: Elsevier Churchill Livingstone; 2009.
9. Ghanem KG. Neurosyphilis: a historical perspective and review. CNS Neurosci Ther. 2010; 16(5):e157-e168.
10. Workowski KA, Berman SM; CDC. Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep. 2006;55(RR-11):1-94.
11. CDC. Sexually transmitted diseases: treatment guidelines 2006. www.cdc.gov/std/treatment/2006/genital-ulcers.htm#genulc6. Accessed March 29, 2011.
12. Drugs for sexually transmitted infections. Treatment Guidelines from the Medical Letter. 2010;95:95a. http://secure.medicalletter.org. Accessed March 23, 2011.
13. Russouw HG, Roberts MC, Emsley RA, et al. Psychiatric manifestations and magnetic resonance imaging in HIV-negative neurosyphilis. Biol Psychiatry. 1997;41(4):467-473.
14. Hooshmand H, Escobar MR, Kopf SW. Neurosyphylis: a study of 241 patients. JAMA. 1972;219 (6):726-729.
15. Miller CA, Joyce DM. Toxicity, phenytoin. http://emedicine.medscape.com/article/816447-overview. Accessed March 23, 2011.
16. Earnest MP, Marx JA, Drury LR. Complications of intravenous phenytoin for acute treatment of seizures: recommendations for usage. JAMA. 1983; 246(6):762-765.
17. Geschwind MD, Shu H, Haman A, et al. Rapidly progressive dementia. Ann Neurol. 2008;64(1): 97-108.
18. Mechem CC. Chapter 143. Altered mental status and coma. In: Ma J, Cline DM, Tintinalli JE, et al, eds. Emergency Medicine Manual, 6e. www.access emergencymedicine.com/content.aspx?aID=2020. Accessed March 23, 2011.
19. Knopman DS, DeKosky ST, Cummings JL, et al; Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: diagnosis of dementia (an evidence-based review). Neurology. 2001;56(9):1143-1153.
20. CDC. Syphilis testing algorithms using treponemal tests for initial screening—four laboratories, New York City, 2005-2006. MMWR Morb Mortal Wkly Rep. 2008;57(32):872-875.
21. Anderson CA, Filley CM. Chapter 33. Behavioral presentations of medical and neurologic disorders. In: Jacobson JL, Jacobson AM, eds. Psychiatric Secrets. 2nd ed. St. Louis, MO: Hanley & Belfus; 2001.