Letters

The Editors welcome submissions for possible publication in the Letters section. Authors of letters should: • Include no more than 400 words of text, three authors, and five references • Type with double-spacing • Send with the letter a transfer-of-copyright form (see Table of Contents for location) signed by all authors • Provide a self-addressed envelope if they want to be notified that the letter was received Letters commenting on an Annals article will be considered if they are received within 6 weeks of the time the article was published. Only some of the letters received can be published. Published letters are edited and may be shortened; tables and figures are included only selectively. Authors will be notified only if their letter is accepted. Unpublished letters cannot be returned.

Elimination of Staphylococcus

aureus

1. Reagan DR, Doebbeling BN, Pfaller MA, et al. Elimination of coincident Staphylococcus aureus nasal and hand carriage with intranasal application of mupirocin calcium ointment. Ann Intern Med. 1991; 114:101-6. 2. Yu VL, Goetz A, Wagener M, Smith PB, Ribs JD, Hanchett J. Staphylococcus aureus nasal carriage and infection in patients on hemodialysis. Efficacy on antibiotic prophylaxis. N Engl J Med. 1986;315:91-6. 3. Boelaert JR, De Smeldt RA, De Baere YA, Godard CA, Matthys EG. The influence of calcium mupirocin nasal ointment on the incidence of Staphylococcus aureus infection in haemodialysis patients. Nephrol Dial Transplant. 1989;4:278-81. 4. Muder RR, Brennen C, Wagener MM, et al. Methicillin-resistant staphylococcal colonization and infection in a long-term care facility. Ann Intern Med. 1991;114:107-12. 5. Light U, Sutherland JM, Cochran, ML, Sutorius JS. Ecological relation between Staphylococcus aureus and Pseudomonas in a nursery population. N Engl J Med. 1968;278:1243-7.

Carriage

To the Editors: Reagan and colleagues (1) have described a method to eliminate Staphylococcus aureus nasal and hand carriage. Although it appears that decreasing S. aureus colonization is associated with a decreased incidence of S. aureus infections in patients on dialysis (2, 3), this phenomenon has not been well documented for a more general hospital population. Further, it would appear that factors other than specific patient population may effect this relation. For example, Muder and colleagues (4) found that the association between colonization and infection was significant only for methicillinresistant S. aureus (MRSA), and not for methicillin-sensitive S. aureus. In light of this difference, knowledge of the antibiotic resistance patterns in Reagan and colleagues' study sample would make the utility of mupirocin more completely understood. In addition, the authors conclude that because there was a decrease in hand colonization in the treated subjects, the nares must be the primary site of colonization. However, the authors do not state whether the subjects wore gloves to prevent application to the hands during mupirocin application. Without gloves, nose-to-hand spread could occur when the hands were washed. If this precaution was not taken, the data on hand colonization may not be valid. The authors also describe some commonly identified side effects seen with topical therapies. However, they did not address the changes in the flora resulting from the decreased S. aureus colonization. Light and colleagues (5) used topical antiseptics to decrease the incidence of S. aureus colonization in newborns. They found that decreased S. aureus colonization was associated with an increase in Pseudomonas aeruginosa colonization, another potential nosocomial pathogen. Finally, the authors appropriately did not recommend mupirocin for all cases of S. aureus colonization. We hope that until colonized populations at risk for infection can be clearly determined and hospital ecological effects of alterations in flora are studied, the use of topical mupirocin will be reserved only for those specific situations where colonization has been shown to present a significant risk for infection. Gregg C. Lund, DO David W. Green, MD Nee I B. Acker man, Jr., MD North Texas Neonatal Associates Dallas, TX 75231 990

References

In response: The objective of our study (1) was to determine the safety and efficacy of mupirocin calcium ointment in the elimination of S. aureus nasal and hand carriage from healthy volunteers. Because all of our isolates were susceptible to methicillin, we cannot comment on the efficacy of mupirocin for eradication of MRSA. Other investigators have successfully used mupirocin in the treatment of colonization with MRSA (1, 2). Importantly, for over 30 years, investigators have noted an association between nasal colonization with methicillin-susceptible S. aureus and infection (3, 4). Lund and colleagues question when an effort should be made to eradicate colonization by S. aureus. Our study did not address this issue. In our opinion, the mere presence of colonization with S. aureus does not require intervention for most persons. As with many antimicrobial agents, indiscriminate use will likely increase the frequency of isolation of organisms resistant to mupirocin and may decrease its utility. Groups that may be candidates for eradication of colonization include those responsible for nosocomial transmission of S. aureus, especially MRSA, and those groups that have been shown to have fewer infections when the carrier state is eliminated, as has been previously reported for patients receiving hemodialysis or peritoneal dialysis (4). Further definition of the epidemiology of nasal S. aureus carriage and of subpopulations which may benefit from nasal eradication is warranted. The association between clearance of S. aureus from the nose and hands is an important finding of our study. We did not investigate the mechanism of this association, and we did not ask volunteers to wear gloves during application of mupirocin on a swab to the nares. Our data support the previous findings of Luzar and colleagues (4) and of others that the nares are the primary site of colonization. Several studies have shown that recovery from other sites, such as the groin, rectum, or wrists is much less common (4, 5). Our finding of a significant decrease in the frequency of hand carriage of S. aureus after nasal treatment, while controlling for baseline hand carriage, is both unique and noteworthy. Regardless of the mechanism involved, we consider clearance of hand carriage to be a potentially significant factor in limiting autoinoculation and nosocomial spread of S. aureus. Last, follow-up nasal cultures showed a decrease in all categories of bacteria, including gram-negative rods. This observation is consistent with previous findings (5). However, con-

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tinued observation of the nasal flora of treated patients is warranted.

these patients than in patients without lupus. Further work is needed to identify the reasons for these differences.

David R. Reagan, MD, PhD East Tennessee State University Johnson City, TN 37614

Daniel C. Cattran, MD Marie Aprile, PhD For the Toronto Multiple Organ Retrieval and Exchange Program University of Toronto and Toronto Hospital Toronto, Ontario M5G 1L7

Bradley N. Doebbeling, MD, MS Richard P. Wenzel, MD, MSc University of Iowa College of Medicine Iowa City, IA 52242 References 1. Reagan DR, Doebbeling BN, Pfaller MA, et al. Elimination of coincident Staphylococcus aureus nasal and hand carriage with intranasal application of mupirocin calcium ointment. Ann Intern Med. 1991; 114:101-6. 2. Davies EA, Emmerson AM, Hogg GM, Patterson MF, Shields MD. An outbreak of infection with a methicillin-resistant Staphylococcus aureus in a special care baby unit. J Hosp Infect. 1987;10:120-8. 3. Weinstein HJ. The relation between the nasal staphylococcal carrier state and the incidence of postoperative complications. N Engl J Med. 1959;260:1303-8. 4. Luzar MA, Coles GA, Faller B, et al. Staphylococcus aureus nasal carriage and infection in patients on continuous ambulatory peritoneal dialysis. N Engl J Med. 1990;322:505-9. 5. Casewell MW, Hill RL. Elimination of nasal carriage of Staphylococcus aureus with mupirocin ("pseudomonic acid")—a controlled trial. J Antimicrob Chemother. 1986;17:365-72.

Renal Transplantation in Lupus Erythematosus To the Editors: We have just finished reviewing our singlecenter experience with renal transplantation in patients who have systemic lupus erythematosus and would like to comment on the article by Nossent and colleagues (1). Although the authors suggest that patients with lupus are * 'excellent candidates for renal transplantation/' there are data to suggest such patients constitute a special group. When we compared our nonlupus (n = 555) and lupus (n = 11) groups regarding outcome over the past 5 years, patient survival was similar in both groups and was equal to that seen in the Dutch group (90% at both I and 3 years); however, graft survival was significantly lower in the lupus group at both 6 months (63% compared with 84%) and 18 months (53% compared with 81%) (P < 0.01). These survival rates are consistent with recently reported data from the North American Transplant Registry (2), which show that the renal allograft survival rate is higher at 1 year in patients with primary glomerulonephritis (non-lupus) than in patients with lupus (80% compared with 67%, P < 0.05). Patients with lupus were also the only group whose graft outcome was influenced by the primary disease. This finding is compatible with the recent finding that the higher the mean panel reactive antibody percentage, the lower is the graft survival rate (3): For example, patients with peak panel reactivity of more than 50% had a 1-year graft survival that was, on average, 8% lower compared with unsensitized patients regardless of their primary renal disease. Seventy-three percent of our patients with lupus had a peak panel reactivity of more than 50% compared with only 13.5% of our patients without lupus. Recent single-center multivariate analysis indicates that this sensitization interacts strongly with recipient gender; graft outcome is particularly low in women with a high peak panel reactivity (4). In both our study and the one done by Nossent and colleagues (1), the female sex dominated the lupus disease category (85% and 72%, respectively). Whether the decreased graft survival is due to the effects of humoral anti-HLA antibodies that are not detected by our current cross-match procedures or whether presensitization is an index for an augmented T-cell-mediated immunoresponsiveness is unknown. Our data support those of Nossent and colleagues that other standard characteristics of both donor and recipient, such as mean age, ABO blood group, warm and cold ischemic time, and the degree of HLA tissue match are not different in patients without lupus and therefore are not an explanation for a lower 1-year graft survival. However, regarding renal transplantation, patients with lupus appear to be a special problem group; graft survival is substantially worse in

References 1. Nossent HC, Swaak TJ, Berden JH, et al. Systemic lupus erythematosus after renal transplantation: patient and graft survival and disease activity. Ann Intern Med. 1991;114:183-8. 2. Terashita GY, Cook DJ. Original disease of the recipient. In: Terasaki P, ed. Clinical Transplants. Los Angeles, California: UCLA Tissue Typing Laboratory; 1987:373-79. 3. Cecka JM, Cho L. Sensitization. In: Terasaki P, ed. Clinical Transplants. Los Angeles, California: UCLA Tissue Typing Laboratory; 1988:365-73. 4. Cardella CJ, Rochon J, Shoker A, et al. The sensitized patient: a single center study. In: Terasaki P, ed. Clinical Transplants. Los Angeles, California: UCLA Tissue Typing Laboratory; 1988:171-9. In response: Drs. Cattran and Aprile disagree with our conclusion that patients with lupus are excellent candidates for renal transplantation. Their main arguments are based on their own single-center data which show a similar patient survival in patients with and without lupus but a lower graft survival in patients with lupus. One can wonder, however, at the validity of comparing survival in 555 patients with that in 11 patients. They also support their view with data from the North American Transplant Registry, which, however, show a patient and a graft survival that are similar to ours. The fact that graft survival is better in patients with non-lupus glomerulonephritis does not directly imply that patients with lupus do badly after transplantation. Nonetheless, it is worth considering why the patients without lupus do better. Drs. Cattran and Aprile suggest that high panel reactivity before transplantation is a major factor. However, we found no difference in graft survival between patients with low-panel reactivity (< 50%) (n = 10) and those with high-panel reactivity (> 50%) (n = 18). Lymphocytopenia due to anti-T-cell autoantibodies is one of the most common manifestations of systemic lupus erythematosus and usually follows the pattern of disease activity (1). However, we did not find any influence of disease activity (which might reflect lymphocytopenia and thereby autoreactive anti-T-cell antibodies) on graft survival. Thus, we doubt whether such high panel reactivity is of major importance in determining graft outcome in patients with lupus. However, the fact that patients with non-lupus glomerulonephritis do even better after transplantation should indeed be an incentive for further work in this area. Hans C. Nossent, MD Tom J. G. Swaak, MD, PhD Jo H. M. Berden, MD, PhD Dr. Daniel den Hoed Clinic Rotterdam, The Netherlands Reference 1. Harley JB, Gaither KK. Autoantibodies. Rheum Dis Clin North Am. 1988;14:43-56.

Clarifying Confusion To the Editors: By developing the new confusion assessment method (CAM), Inouye and colleagues (1) contributed a muchneeded tool for clinicians and clinical epidemiologists who work with elderly patients. However, we are concerned that their conclusion that "because the CAM is highly sensitive, rapid, and simple, it may be useful for widespread, daily assessment of delirium in persons in high risk settings" may be premature. Although the CAM may take only 5 minutes to administer, it was based on at least a 20-minute assessment, including the Mini-Mental State Examination, the immediate story recall, an

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interview with another observer, and, at one site, the digit span forward. As validated, therefore, the CAM incorporates these other tests. In addition, the CAM was administered by academic geriatricians who were involved in the development of the method. The excellent concurrent validity is unlikely to be generalizable to other physicians and nurses. In particular, the criteria for defining positivity for each of the four features of delirium (acute onset and fluctuating course, inattention, disorganized thinking, and altered consciousness) are not clearly stated, which may result in an inconsistent interpretation of the CAM. The other validation procedures used by the authors also tend to overestimate what can be expected in practice. Face validity was assessed by the same investigators who developed the CAM, not by outside experts. The interobserver reliability was based on the observation of the same clinical encounter by two specialists, not on independent appraisals. Another issue is the selection of study subjects. The value of the CAM would be to distinguish among various altered mental states, such as delirium and dementia, not between an altered and a normal mental state. The inclusion in the study of patients without mental alterations results in an optimistic picture of the specificity and sensitivity of the CAM. These remarks are intended to encourage further development and field testing of the CAM before its widespread use. The work by Inouye and colleagues (1) provides an excellent basis for such endeavors. Thomas Perneger, MD, MPH Michael J. Klag, MD, MPH The Johns Hopkins Medical Institutions Baltimore, MD 21205 Reference 1. Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Intern Med. 1990;113:941-8.

In response: We appreciate the letter from Drs. Perneger and Klag, which raises several important points and allows us to clarify aspects of the CAM validation study (1). We agree that the CAM should be validated using alternative methods of assessment, such as routine clinical care or informal cognitive evaluation. As stated in our discussion section, the proficiency and thoroughness of the primary observations may well influence the performance of the CAM. We are in the process of validating the CAM as applied by trained lay interviewers and have found that comparable results are achieved (unpublished data). As stated in the discussion, training is required for optimal use of the CAM. Because of limitations of space, detailed standardization and coding information was not included in our article (1). A training manual is available on request (Dr. Inouye, Yale-New Haven Hospital, 20 York Street, Tompkins Basement 15, New Haven 06504). Standardized training will particularly address Drs. Perneger and Klag's concern about consistent interpretation of the CAM. The CAM questionnaire and criteria were developed by one author (Dr. Inouye), and face validity was determined by an independent expert panel. Thus, face validity was not determined by the same investigators who developed the CAM. We agree with Drs. Perneger and Klag that test-retest reliability ideally should have been determined. However, we found insurmountable problems in accomplishing this because of the rapidly fluctuating nature of delirium. In fact, temporal separation between interviews accounted for some of the discrepancies found between the geriatrician's and psychiatrist's evaluations in the concurrent validation. Thus, of necessity, interobserver reliability was based on observations of the same clinical encounter rated blindly and independently by two observers. In the future, videotaped observations with independent ratings may be used as an alternative method of assessment. As noted in the patient selection section, great efforts were made to include subjects with "altered mental status" (for 992

example, dementia and other organic brain syndromes) to adequately challenge the CAM. In contrast to the argument raised by Drs. Perneger and Klag, only three patients (Site I) in the entire study had "normal mental status," and these were included only to verify the specificity of the CAM in this group. All other patients were chosen to include subjects with a broad range of ailments that could potentially lead to falsepositive results. At Site II, all patients had suspected "altered mental status" identified by the nursing staff. We agree with Drs. Perneger and Klag that further validation studies are needed and would welcome future studies of the CAM using alternative methods of assessment, broader patient samples, and larger sample sizes. Sharon K. Inouye, MD, MPH Yale University School of Medicine New Haven, CT 06510 Cathy A. Alessi, MD University of California, Los Angeles Los Angeles, CA 90024 Sepulveda VAMC GRECC Sepulveda, CA 91343 Reference 1. Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Intern Med. 1990;113:941-8.

Delirium with Sepsis To the Editors: In his recent editorial, Bone (1) makes the long overdue suggestion that the terminology related to bloodborne infection be clarified and standardized. I have often bristled at the indiscriminate use by both students and fully trained physicians of the word *4 septic'' to describe patients with transient asymptomatic bacteremia as well as seriously ill septic patients, and I want to applaud Dr. Bone for clarifying such matters. I was, however, struck to see no mention whatsoever of delirium (that is, acute central nervous system failure) in his delineation of indicators of the more serious end of the spectrum of blood-borne infection. Lipowski (2) and others (3, 4) have collected and reviewed the data on delirium in the acute medical-surgical setting. Particularly in the elderly and others with pre-existing clinical or subclinical central nervous system dysfunction, these data lead us to believe that delirium, or acute change in mentation, may be the earliest and most sensitive sign of impending life-threatening systemic medical illness. And as the prospective study of Francis and colleagues (4) shows, clinically severe infection is foremost among illnesses causing delirium. I fully agree with Dr. Bone (1) that "early recognition of impending circulatory compromise" via 44readily available noninvasive clinical criteria" is essential to * improve clinical outcomes." I completely disagree with him when he implies that only laboratory tests, (for example, arterial blood gas, blood lactate, and quantified urinary output) and not appropriate elements of the clinical history and physical examination fill the bill. Bedside examination for delirium is clearly a central element in early noninvasive patient monitoring. In their routine clinical interactions, nurses, housestaff, and attending physicians should look at patients with a critical eye for evidence of delirium: 44memory gaps, inconsistencies, distractability, disorganized thinking, and impaired orientation" (2), as well as 4 'restlessness or irritability, insomnia or vivid frightening dreams" (3). Periodically, these efforts should be supplemented with a brief cognitive screen, such as the quantitative and well-validated Folstein Mini-Mental State Examination (5) that particularly targets arousal, orientation, attention and concentration, and short-term memory. Charles E. Schwartz, MD North Central Bronx Hospital/Montefiore Medical Center Bronx, New York 10467

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References 1. Bone RC. Sepsis, the sepsis syndrome, multi-organ failure: a plea for comparable definitions. Ann Intern Med. 1991;114:332-3. 2. Lipowski ZJ. Delirium (acute confusional states). JAMA. 1987;258: 1789-92. 3. McEvoy JP. Organic brain syndromes. Ann Intern Med. 1981 ;95:21220. 4. Francis J, Martin D, Kapoor WN. A prospective study of delirium in hospitalized elderly. JAMA. 1990;263:1097-101. 5. Folstein MF, Folstein SE, McHugh PR. Mini-Mental State: a practical method for grading the cognitive state of patients for clinicians. J Psychiatric Res. 1975;12:189-98. The Hemophagocytic Syndrome To the Editors: The article on the acute lupus hemophagocytic syndrome (1) implies that the mechanism underlying the cytopenias is phagocytosis of the blood cells by macrophages. This in turn raises the question of whether there are antibodies to the blood cells in the plasma, because macrophages have surface receptors for immunoglobulins. Did the authors test these patients for antibodies that react in vitro to erythrocytes (Coombs test), neutrophils, or platelets? Histiocytes with phagocytosed neutrophils have been described in the bone marrow and spleen of patients with autoimmune neutropenia (2) who do have serum antibodies to neutrophils. The dosage of prednisone reported by Wong and colleagues (1) is 1 to 2 g/kg body weight. Is this correct? A more usual dose would be 1 to 2 mg/kg body weight. Mortimer S. Greenberg, MD Mount Auburn Hospital Cambridge, MA 02238 References 1. Wong K, Hui P, Chan JKC, Chan YW, Ha SY. The acute lupus hemophagocytic syndrome. Ann Intern Med. 1991;114:387-90. 2. Boxer LA, Greenberg MS, Boxer GJ, et al. Autoimmune neutropenia N Engl J Med. 1975;293:748-53. In response: We agree that autoimmune destruction of blood cells may be considered a possible pathogenetic mechanism for the cytopenia in patients with systemic lupus erythematosus. However, the Coombs test was uniformly negative in all our patients except one (Patient 1) who exhibited a weak positive reaction (1). This finding, coupled with a low reticulocyte count, renders the possibility that autoimmune hemolysis contributed to the anemia unlikely. We have not done serologic tests for autoantibodies to neutrophils, but our cases differ clinically and pathologically from the cases of autoimmune neutropenia as previously reported by Dr. Greenberg (2). A careful scrutiny of his article (2) shows that there was no mention of increased hemophagocytic histiocytes in the bone marrow at all, and it was further stated that "bone marrow morphology was not helpful in predicting the presence of antineutrophil antibody in our patients." Because all our patients showed strong evidence of immune-complex-mediated tissue damage, we postulated this as being the most likely pathogenetic mechanism of acute lupus hemophagocytic syndrome. It will certainly be valuable to demonstrate the presence of circulating immune complexes in this group of patients in future study. We thank Dr. Greenberg for drawing our attention to the typographic error. The dosage of prednisone used in our patients was 1 to 2 mg/kg, not 1 to 2 g/kg. K. F. Wong, MBBS J. K. C. Chan, MBBS P. K. Hui, MD Queen Elizabeth Hospital and Kwong Wah Hospital Kowloon, Hong Kong References 1. Wong KF, Hui PK, Chan JKC, Chan YW, Ha SY. The acute lupus hemophagocytic syndrome. Ann Intern Med. 1991;114:387-90.

2. Boxer LA, Greenberg MS, Boxer GJ, Stossel TP. Autoimmune neutropenia. N Engl J Med. 1975;293:748-53. Requiem for Digoxin? To the Editors: Falk and Leavitt (1) would like to sound the death knell for digoxin as therapy for atrial fibrillation. They cannot understand why the drug has been popular for 200 years and conclude that it must be because of mythology and not science. Although aware of the beneficial effects of digoxin in patients with atrial fibrillation, they choose to emphasize its questionable use for prevention of atrial fibrillation in patients who have reverted to sinus rhythm, the possibility that digoxin makes recurrences of atrial fibrillation worse, and the questionable significance of tachycardia during exercise if it occurs. They cite the availability of other drugs such as calciumchannel and beta blockers but insist on their judicious and selective use to avoid complications. New drugs have been touted as replacements for digoxin, the most recent being propafenone (2) and flecainide (3). However, both these drugs were associated with adverse effects, propafenone in 9 of 10 patients and flecainide in 32 of 43 patients. Increased mortality has also been found with the long-used and ever-popular quinidine (4). It is for these reasons that the time has come not to bid adieu to digoxin but rather to use it properly. In patients with atrial fibrillation, digoxin is given in that dosage which is needed to attain specific objectives, including elimination of pulse deficit, attainment of appropriate ventricular rate at rest, reigning in of an undue increment of ventricular rate on effort or excitement, the avoidance of toxicity, and the abolition of any precipitating factor if present. If in this process of titration, sinus rhythm reappears, it is an end point for the use of digoxin unless use of the drug is indicated for other reasons such as systolic dysfunction. Although the search continues for drugs to prevent recurrences of atrial fibrillation, digoxin for atrial fibrillation has not yet been surpassed. Jacob Zatuchni, MD Pennsylvania Hospital Philadelphia, PA 19139 References 1. Falk RH, Leavitt JI. Digoxin for atrial fibrillation: a drug whose time has gone? Ann Intern Med. 1991;114:573-5. 2. Pritchett EL, McCarthy EA, Wilkinson WE. Propafenone treatment of symptomatic paroxysmal supraventricular arrhythmias. Ann Intern Med. 1991;114:539-44. 3. Pietersen AH, Hellemann H. Usefulness of flecainide for prevention of paroxysmal atrial fibrillation and flutter. Am J Cardiol. 1991 ;67: 713-7. 4. Coplen SE, Antman EM, Berlin J A, Hewitt P, Chalmers TC. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion. Circulation. 1990;82:1106-16. Requiem for Gold? To the Editors: The time has come to stop the use of injectable (or any other) gold in the treatment of adult rheumatoid arthritis. The recent report by Epstein and colleagues (1) on the apparent ineffectiveness of parenteral chrysotherapy is highly significant. Since the first reports of the use of gold therapy in rheumatoid arthritis, 64 years ago, its efficacy has been hotly debated and its toxicity has been amply documented. A recent study (2) found that of six commonly used second-line drugs for the treatment of rheumatoid arthritis (methotrexate, injectable gold, D-penicillamine, sulfasalazine, auranofin, and antimalarials), injectable gold had the highest toxicity. In 1946, almost 20 years after the use of parenteral gold in rheumatoid arthritis was popularized, three eminent students of the disease concluded in a review article (3) that if the benefits of gold therapy were established, the risks of its toxicity could be justified in a potentially crippling disease, but this not being the case " . . . the hazard of this form of therapy should furnish the decisive argument against its general u s e . "

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Now, 45 years later, significant evidence of the ineffectiveness and toxicity of gold therapy is again presented. Surely the time has come to leave this empirical, ineffective, and toxic therapy for rheumatoid arthritis in the hands of medical historians. Luis Fernandez-Herlihy, MD 91 Lenox Street West Newton, MA 02165.

References 1. Epstein WV, Henke CJ, Yelin EH, Katz PP. Effect of parenterally administered gold therapy on the course of adult rheumatoid arthritis. Ann Intern Med. 1991;114:437-44. 2. Felson DT, Anderson JJ, Meenan RF. The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Results of two metaanalyses. Arth Rheum. 1990;33:1449-61. 3. Short CL, Beckman WW, Bauer W. Gold therapy in rheumatoid arthritis. N Engl J Med. 1946;235:362-8.

Seizures after Mefloquine To the Editors: Mefloquine, 250 mg weekly starting 1 week before travel and ending 4 weeks after departure from areas in which malaria is endemic, has been recommended in the United States for prophylaxis in travelers to areas where chloroquine-resistant falciparum malaria has been reported (1). Although minor side effects, such as dizziness and vomiting, were commonly reported in a placebo-controlled, doubleblinded trial in U.S. soldiers deployed to Thailand, weekly mefloquine was generally well tolerated (2). A study of 3386 European tourists returning from Africa who received mefloquine indicated only one possibly drug-related reaction (depression), and there were no reports of seizures or acute brain syndromes (3). Rarely, acute psychosis has been linked to prophylactic mefloquine (4). We report the case of a French traveler to Thailand who developed seizures while taking prophylactic mefloquine. A 57-year-old male French tourist was admitted to a hospital in Bangkok, Thailand, in December 1990 after experiencing his first grand mal seizure. He had been receiving weekly mefloquine (Lariam, Hoffmann La Roche), 250 mg, for malaria chemoprophylaxis. He had taken a total of three doses of mefloquine. The last dose was 3 days before the seizure. He had no history of other medication ingestion or recreational drug use. He regularly drank alcohol, typically two glasses of wine at meals. The physical examination was within normal limits 12 hours after his tonic-clonic seizure with loss of consciousness. Laboratory tests showed normal values for serum electrolytes, blood urea nitrogen, creatinine, calcium, and phosphorus. The serum mefloquine concentration on the day after the seizure was 491 ng/mL. The mean serum mefloquine concentration in U.S. soldiers in Thailand on the same prophylaxis regimen was 450 ng/mL (2). A chest roentgenogram, an electroencephalogram, and a computed axial tomographic scan of the brain showed no abnormalities. The patient recovered and was discharged after 6 days to return under medical escort to France. There are reports of three other French travelers to Thailand who developed seizure for the first time in their lives 1 to 3 days after the second or third dose of prophylactic mefloquine (Harinasuta T, Bunnag D. Unpublished data). Although seizures in French patients after treatment with mefloquine have been described (5), it is unclear whether there is another cause for seizures in French tourists to Thailand or whether this represents a reporting bias. Medical authorities at the French Embassy in Bangkok report that no other French nationals have been evacuated from Thailand recently because of any form of seizure disorder (Nauleau G. Personal communication). Post-marketing surveillance is critical for assessing the risk/ benefit ratio of any newly introduced pharmaceutical, particularly when it is given to healthy persons for prophylaxis. We appeal to the readership to report adverse effects of malaria chemoprophylactic drugs to the Malaria Action Program of the 994

World Health Organization or to the Malaria Branch of the Centers for Disease Control. Kanwar Singh, MD Bangkok General Hospital Bangkok, Thailand 10400 G. Dennis Shanks, MD Armed Forces Research Institute Medical Sciences Bangkok, Thailand 10400 Henry Wilde, MD Chulalongkorn University Bangkok, Thailand 10400 References 1. Change of dosing regimen for malaria prophylaxis with mefloquine. MMWR. 1991;40:72-3. 2. Arthur JD, Shanks GD, Echeverria P. Mefloquine prophylaxis. Lancet. 1990; 1:972. 3. Steffen R, Heusser R, Machler R, et al. Malaria chemoprophylaxis among European tourists in tropical Africa: use, adverse reactions, and efficacy. Bull WHO. 1990;68:313-22. 4. Bjorkmann A. Acute psychosis following mefloquine prophylaxis. Lancet. 1989;2:865. 5. Rouveix B, Bricaire F, Michon C, et al. Mefloquine and an acute brain syndrome. Ann Intern Med 1989;110:577-8. Nuclear Venography The article by Kelley and colleagues (1) reviewed a large body of data on the diagnosis of pulmonary embolism and deep venous thrombosis of the lower extremities. The authors failed to mention, however, a useful and readily available technique for diagnosing deep venous thrombosis of the lower extremity, namely, nuclear venography. Because lung perfusion scanning can be done by injecting macroaggregated albumin through any peripheral vein, one can inject the tracer through veins in the feet and image the deep venous system as the tracer travels to the lungs. The technique requires only a few extra minutes and entails no additional radiation exposure. There is a better than 90% correlation between findings in radionuclide venography and those in contrast venography (see Hayt and colleagues [2] for review). Thus, patients who have a low- or intermediateprobability lung scan and a positive nuclear venogram would require anticoagulation and would not need to have pulmonary angiography. Jerry V. Glowniak, MD Veterans Affairs Medical Center Portland, OR 97207 References 1. Kelley MA, Carson JF, Palevsky HI, Schwartz S. Diagnosing pulmonary embolism: new facts and strategies. Ann Intern Med. 1991;! 14: 300-6. 2. Hayt DB, Blatt JC, Freeman LM. Radionuclide venography: its place as a modality for the investigation of thromboembolic phenomena. Semin Nucl Med. 1977;7:263-81. Teenage Pregnancy To the Editors: Because the results of teenage pregnancy, either delivery or abortion, fall within the province of health care, it is generally assumed that teenage pregnancy must therefore be a disease. Bolstered by the recommendations of our government that a healthy society requires the reduction of the incidence of teenage pregnancy, we accept the challenge to fix the problem without commenting on either the necessity or sufficiency of our role. We have once again acquiesced to the medicalization of a social ill and are once again getting prepared to accept blame when we fail, as we inevitably will. Drs. Fielding and Williams (1) suggest that primary care providers have important roles in the prevention of unintended pregnancy. Preying on the long-recognized inability of primary

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care providers to say "no" to any well-written litany of needs, they encourage us to talk empathetically, confidentially, and directly with any at risk, while readily acknowledging that none of these efforts have yet been shown to have any effect. Even if marginally effective, how many of these women have seen a doctor or school nurse at a propitious time in their young lives? I rather suspect that we make the problem worse. Teenage pregnancy is a social malady, not a disease. Causes are as basic as the procreative urge and as complex as the webs of economic and social privation and the failure of the family unit. Because the problem is complicated, we are moved by the rallying cry of the need for everyone to do his or her part to win this desperate enterprise. However, when we permit the medicalization of this malady, we encourage the complacency of others. "Don't worry, the medical profession has a plan. We're going to talk them into celibacy or condoms." John W. Burnside, MD University of Texas Southwestern Medical School Dallas, TX 75235-9005 Reference 1. Fielding J, Williams C. Unintended pregnancy among teenagers: important roles for primary care providers. Ann Intern Med. 1991;! 14: 599-601. Surgery or Assisted Suicide? To the Editors: A bright, alert, elderly man with several different life-threatening illnesses sought counseling for what he hoped would be an approach to euthanasia. He had long since thoroughly informed himself about the "Hemlock Society." Several months of nondirective discussion sessions resulted in his postponing active intervention. A "new" symptom precipitated the possibility of major surgery, albeit with an awareness on all sides of the poor prognosis. Nonetheless, the patient pushed for the surgery, which resulted in his death. The patient achieved his wish by seducing his medical caregivers to unwittingly expedite his demise. This letter was of necessity cryptic in order to protect the identities of those concerned. I present the case not to be pejorative, but rather as a matter of clinical concern. Nathan Schnaper, MD University of Maryland Cancer Center University of Maryland Hospital Baltimore, MD 21201

only organization within internal medicine with the authority, responsibility, and accountability to serve as an effective agent of change. It should be noted that the APM has begun to work towards positive change on several fronts. The APM has undertaken the major project for examining the curriculum for internal medicine residency training by appointing a curriculum committee that is being chaired by Dr. Harold Fallon, Chairman of the Department of Medicine at the Medical College of Virginia. Dr. Fallon and his committee have already established broad guidelines and are in the process of organizing a major retreat under the co-sponsorship of the APM and the Association of American Medical Colleges (AAMC), which should lead to important curricular changes in residency training programs. In the public policy arena, the APM has full-time representation in Washington and plays an active role in many issues important to academic internal medicine. These include biomedical research, the Veterans Affairs medical school enterprise, and graduate medical education funding. The APM committee on governmental relations expresses its opinions directly and frequently to Congress in order to influence the enactment of key legislation. The APM currently has a committee that is developing a policy for the APM regarding the funding for graduate medical education. We intend to take a proactive stand on this issue because it is of vital importance to our teaching hospitals and to the individual departments of medicine. Finally, a special committee has been charged with the difficult task of establishing the appropriate proportion of generalists and subspecialists to be trained in our training programs, providing a model by which reasonable manpower planning can be done. Dr. Reitemeier, and your readers, should also be aware that when Dr. Alvin Tarlov created the National Study of Internal Medicine Manpower in 1976, it was a direct outgrowth of the APM Manpower Task Force. Thanks to this APM effort, internal medicine is the only specialty to develop precise manpower information useful not only to our specialty but also to Congress. The APM is an organization that relies primarily on membership dues for support, and thus, our resources are not large. Although it is our goal to continue to grow and mature as an organization, at the present time the APM must prioritize the key issues we wish to target for special emphasis, many of which are included in the broad agenda listed by Dr. Reitemeier. It is a pleasure for us to inform Dr. Reitemeier and your readership of the active role the APM is playing to meet most, if not all, of the challenges he enumerated.

Leadership in Internal Medicine; APM Responds

Gerald S. Levey, MD President, Association of Professors of Medicine Washington, DC 20036

To the Editors: The members of the Association of Professors of Medicine (APM) have read with great interest the article by Dr. Reitemeier (1) on the leadership crisis in internal medicine. We agree with Dr. Reitemeier that the APM is the

Reference 1. Reitemeier R. The leadership crisis in internal medicine: what can be done? Ann Intern Med. 1991;114:69-75.

1 June 1991 • Annals of Internal Medicine • Volume 114 • Number 11 Downloaded from https://annals.org by University of Otago user on 01/19/2019

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