Restrictive cardiomyopathy

C O R R E S P O N D E N C E
the study. I concur that allergy shots may be more usefulin patients in the real world who tend to have lower levelsof compliance with pharmacotherapy.
American College of Allergy, Asthma and Immunology 1. Adkinson NF Jr, Eggleston PA, Eney D, et al. A controlled trial of im-
munotherapy for asthma in allergic children. N Engl J Med 1997;336:324-
31.
Immunotherapy for Asthma
2. Abramson MJ, Puy RM, Weiner JM. Is allergen immunotherapy effec-
tive in asthma? A meta-analysis of randomized controlled trials. Am J Res-
To the Editor: The failure of the study by Adkinson et al.
(Jan. 30 issue)1 to demonstrate a significant benefit of im-munotherapy with a few allergens to a particular group ofchildren with asthma does not negate the positive benefit To the Editor: In the study by Adkinson et al. the pa- demonstrated in numerous other studies. The meta-analy- tients differed from people with asthma in the real world sis by Abramson et al.2 suggests that 33 negative studies in two respects. All the patients, and their parents, volun- would be necessary to overturn the results that demon- teered for the study. Volunteers are generally far more in- strated significant odds of symptomatic improvement, de- terested in their disease and in adhering to lifestyle alter- creased medication use, reduction in bronchial hyperreac- ations likely to help it than are most patients with asthma.
tivity, and improvement in forced expiratory volume in These volunteers were uncommonly likely to comply with prescribed management and also received unusually in- Some of the patients may have been sensitive to aller- tense follow-up by the clinical research team. The compli- gens not included in treatment (or presumably in testing).
ance rate with medication was 93 percent.
These might include cockroach, other molds, and other tree The clinical improvement reported by Adkinson et al. in and fall-weed pollens. Most allergist-immunologists are fa- both the immunotherapy and placebo groups is similar to miliar with the wide variety of pollens at different seasons that achievable in less strongly motivated patients, followed in their areas, and they test and treat with all the major less intensively, but with immunotherapy to supplement en- pollens that have positive results on skin-prick testing. They vironmental controls and medications.
would not expect improvement if they treated with only Might it be most appropriate to conclude that for un- one type of allergen for the season. Adkinson et al. chose commonly motivated patients, coached and monitored by to limit the number of allergens in order to reach very an allergy research team that checks closely for compliance high doses and perhaps threw out the baby with the bath with medications, adding immunotherapy probably will not The authors themselves suggest caution in interpreting their results. The patients received maintenance treatment with free medications with close follow-up, and any partic- ipating children who did not comply were dropped from Letters to the Editor are considered for publication (subject to editing and abridgment) provided they do not contain material that has been submitted or published elsewhere. Please note the following: •Your letter must be typewritten and triple-spaced. •Its text, not including references, must not exceed 400 words (please include a word count). •It must have no more than five references and one figure or table.
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Downloaded from nejm.org on December 4, 2012. For personal use only. No other uses without permission. Copyright 1997 Massachusetts Medical Society. All rights reserved. T h e New E n g l a n d Jo u r n a l o f Me d i c i n e 1. Coifman RE. Dynamic approach to asthma. J Asthma 1983;20:45-
these aspects of the study and should be considered in in- To the Editor: The study by Adkinson et al. has impor- tant flaws. The placebo group received injections of hista- mine. Histamine is not an inert agent and is thus inappro-priate for use in a placebo. Histamine has physiologic activity on the immune system, even at low doses,1 and has been used for therapy for several conditions.2 Therefore,failure to demonstrate a difference between the histamine Centre Hospitalier de l’Université de Montréal group and the immunotherapy group could indicate that both treatments were active. In fact, this possibility is sug-gested by the observed decreases in medication-use scoresand in methacholine sensitivity that occurred in both To the Editor: In the study by Adkinson et al. the pa- tients received mixtures of allergens, but mixing induces Each patient in the immunotherapy group was treated rapid degradation of allergens.1 Although changes in skin- with only two to six inhalant allergens. The omission of test results and levels of specific IgG were observed, such many important perennial allergens from treatment, includ- changes do not preclude an effect of the composition of ing animal danders, cockroach, penicillium, helminthospo- the allergen extract. If some allergens essential to the pa- rium, and others, may have resulted in treatment with in- tient’s sensitivity are degraded, immunotherapy is less ef- sufficient numbers of allergens to reduce the total allergy fective. This comment is substantiated by the study itself, load significantly. Both the history and clinical testing fre- since when patients were receiving more than five aller- quently incriminate multiple allergic triggers of asthma in gens, there was strictly no effect of immunotherapy. . . .
a single patient, and failure to treat enough of these trig-gers adequately is a very possible reason for the failure of This study shows a large effort and commendable at- tention to detail, but unfortunately, the methods used do not exclude several large possible sources of error. There-fore, I believe that the authors’ conclusion that immuno-therapy was of no benefit in this study group may be in- 1. Nelson HS, Ikle D, Buchmeier A. Studies of allergen extract stability:
the effects of dilution and mixing. J Allergy Clin Immunol 1996;98:382- 1. Brune M, Hellstrand K. Remission maintenance therapy with histamine
and interleukin-2 in acute myelogenous leukaemia. Br J Haematol 1996;
92:620-6.
To the Editor: Figure 1 of the article by Adkinson et 2. Fischer AJ. Histamine in the treatment of vertigo. Acta Otolaryngol
al. shows the medication scores for the immunotherapy group and the placebo group at randomization and at the 3. Ohman JL Jr. Allergen immunotherapy: review of efficacy and current
last follow-up visit. The text states that Table 3 shows the practice. Med Clin North Am 1992;76:977-91.
mean change in scores between base line and the last fol-low-up visit. If base line is the time of randomization,there seems to be a discrepancy. Figure 1 shows the score To the Editor: The study by Adkinson et al. found that for the immunotherapy group to be greater than that treatment with multiple-allergen immunotherapy in poly- of the placebo group, and both appear to be greater than sensitized children with asthma is not efficient. These re- 5. Table 3 shows the base-line score for the placebo sults are very interesting. However, the panel of allergens group to be 5, and the score for the immunotherapy for which children were tested was not reported, nor the group is only 4.9. Are the figure and table showing differ- prevalence of some perennial allergens such as cockroach.
Cockroach is an important perennial allergen in the pedi-atric population of North America. Because eviction of this allergen is difficult to obtain and no extract is avail-able for immunotherapy, continuous exposure to it could maintain bronchial inflammation and explain the lack ofefficacy of immunotherapy in these polysensitized pa-tients. Moreover, one benefit of participation in this pro-tocol was free asthma medications, and this could have led To the Editor: The report by Adkinson et al. concludes to a selection bias toward children of low socioeconomic that immunotherapy may be of limited value in the man- status and thus more exposure to cockroach allergen. For agement of asthma in allergic children, a position many al- all these reasons, more details would be appreciated on lergists can accept on the basis of experience. But it is very Downloaded from nejm.org on December 4, 2012. For personal use only. No other uses without permission. Copyright 1997 Massachusetts Medical Society. All rights reserved. C O R R E S P O N D E N C E
important to point out that the study does not indicate and altered skin-test reactivity, suggesting that, at least that accurate diagnosis of the child’s allergies is unimpor- for most allergens, substantial biologic potency remained.
tant. Children can be much better protected from house The work of Litwin et al.5 shows that enzyme degrada- dust, a moldy environment, or a cat when their reactivity tion of ragweed may actually convey advantages for im- is documented and the physician can focus the parents’ attention on appropriate environmental-control measures.
The apparent discrepancy in base-line medication scores These avoidance techniques are very important in treating between Table 3 and Figure 1 reflects the fact that median childhood asthma and were used in both the treated and levels are shown in Figure 1, whereas the scores in Table 3 the control groups in this study with excellent results. Spe- cific diagnosis of allergy is an essential component of the We heartily agree with Dr. Marinkovich’s assertion that successful treatment of children with asthma. Radioaller- accurate diagnosis of allergy in children with allergic asth- gosorbent tests or skin tests can provide accurate assess- ma is indispensable to proper environmental control and patient education. Irrespective of the issue of immuno-therapy, we believe that every child with asthma deserves and will benefit from comprehensive allergy evaluation and Johns Hopkins University School of Medicine To the Editor: Dr. Wray suggests that the meta-analysis of 20 asthma-immunotherapy studies by Abramson et al.
1. Abramson MJ, Puy RM, Weiner JM. Is allergen immunotherapy effec-
demonstrated efficacy that outweighs our negative results.
tive in asthma? A meta-analysis of randomized controlled trials. Am J Res-pir Crit Care Med 1995;151:969-74.
Most of the trials Abramson et al. analyzed dealt with sin- 2. Sarpong SB, Hamilton RC, Eggleston PA, Adkinson NF Jr. Socioeco-
gle allergens, seasonal disease models, or both.1 We do not nomic status and race as risk factors for cockroach allergen exposure and dispute the protective benefit of immunotherapy in select- sensitization in children with asthma. J Allergy Clin Immunol 1996;97: ed cases, but our study demonstrates that it is not clinically 1393-401.
3. Van Metre TE Jr, Adkinson NF Jr, Amodio FJ, et al. A comparison of
indicated in children with well-managed moderate to se- immunotherapy schedules for injection treatment of ragweed pollen hay fe- ver. J Allergy Clin Immunol 1982;69:181-93.
Drs. Wray and Coifman express concern that the pa- 4. Sundin B, Lilja G, Graff-Lonnevig V, et al. Immunotherapy with par-
tients selected for our study were highly compliant and tially purified and standardized animal dander extracts. I. Clinical results from a double-blind study on patients with animal dander asthma. J Aller- therefore not representative of typical immunotherapy pa- tients. Although this may be true, we do not believe it ex- 5. Litwin A, Pesce AJ, Fischer T, Michael M, Michael JG. Regulation of
plains our negative results, since there was still much symp- the human immune response to ragweed pollen by immunotherapy: a con- tomatic disease after stabilization at base line and multiple trolled trial comparing the effect of immunosuppressive peptic fragments of short ragweed with standard treatment. Clin Exp Allergy 1991;21:457- disease markers improved significantly in both groups dur- ing the study. If immunotherapy had been effective inthese subjects, the study design was sufficient to haveshown it.
Another concern expressed is that there were critical A Prediction Rule for Community-Acquired
omissions of important aeroallergens, especially cockroach.
Pneumonia
In mid-study we performed cockroach skin testing andhome-dust analysis for cockroach allergens for 87 of the To the Editor: Fine and colleagues (Jan. 23 issue)1 pre- 121 subjects.2 Only 20 children had positive cockroach sent a detailed analysis of community-acquired pneumo- skin tests and bedroom Bla g I levels Ͼ1 unit per gram. If nia. An important complicating factor not specifically ad- the omission of cockroach or any other locally important dressed in their prediction rule is pregnancy. Pneumonia is allergen is essential for a successful outcome of immuno- one of the most common and serious nonobstetrical infec- therapy, then much of the immunotherapy currently ad- tions during pregnancy. Before 1940, maternal mortality ministered for asthma in the United States must be con- from pneumonia was as high as 30 percent. Substantial maternal and perinatal morbidity and mortality still result Dr. Gordon objects that histamine has biologic effects and should not have been used in our placebo solutions.
The risk-scoring system derived by Fine and colleagues Diluents containing 1 to 10 mg of histamine per milliliter favors outpatient therapy for young, otherwise healthy have been used in numerous controlled studies of immu- women. In the two maternal–fetal deaths in our series at notherapy with positive outcomes.3,4 It would be surpris- Parkland Hospital,4 both women would have been in risk ing if small doses of histamine injected intradermally weeks class II and could have been assigned to outpatient man- apart ameliorated asthma symptoms, and we would wel- come any evidence that this is the case.
We support the development of standardized treatment Dr. Bousquet and colleagues point to evidence that al- plans for the management of pneumonia in pregnant lergen mixtures may lead to autodegradation of impor- women. Until this scheme is evaluated prospectively, how- tant allergens, thereby rendering them impotent. In our ever, we continue our policy of promptly hospitalizing all study we observed pronounced IgG-antibody responses pregnant women with radiographically confirmed pneu- Downloaded from nejm.org on December 4, 2012. For personal use only. No other uses without permission. Copyright 1997 Massachusetts Medical Society. All rights reserved. T h e New E n g l a n d Jo u r n a l o f Me d i c i n e TABLE 1. MATERNAL AND PERINATAL OUTCOMES IN PREGNANCIES
PREGNANCIES
MATERNAL OUTCOMES
PERINATAL OUTCOMES
monia in order to ensure that optimal respiratory support is provided and to determine the responsiveness of the in-fection to therapy.
To the Editor: On the basis of anecdotal clinical experi- ence and five published articles on the maternal and fetal outcomes of pneumonia during pregnancy, Bloom and colleagues recommended hospitalization for all pregnant women with community-acquired pneumonia. However, the studies they cite differed from ours in that they fo- cused exclusively on hospitalized pregnant women, poten- tially biasing the study populations toward more severely Among the 2287 patients enrolled in the Pneumonia 1. Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-
Patient Outcomes Research Team (Pneumonia PORT) risk patients with community-acquired pneumonia. N Engl J Med 1997;336:243-50.
study, there were only five pregnant women. Three were 2. Madinger NE, Greenspoon JS, Ellrodt AG. Pneumonia during pregnan-
classified as being in risk class I and two as being in risk cy: has modern technology improved maternal and fetal outcome? Am J class II. Two patients in risk class I and one in risk class II were treated as outpatients. None of the five patients 3. Berkowitz K, LaSala A. Risk factors associated with the increasing prev-
alence of pneumonia during pregnancy. Am J Obstet Gynecol 1990;163:
died or were admitted to intensive care units because of respiratory failure or hemodynamic compromise. Howev- 4. Richey SD, Roberts SW, Ramin KD, Ramin SM, Cunningham FG.
er, the low prevalence of pregnant women in our study Pneumonia complicating pregnancy. Obstet Gynecol 1994;84:525-8.
precluded the assessment of pregnancy as a predictor of 5. Briggs RG, Mabie WC, Sibai BM. Community-acquired pneumonia in
pregnancy. Am J Obstet Gynecol 1996;174:389. abstract.
short-term mortality or of the implications of our pro- 6. Munn MB, Groome LJ, Baker SL, Atterbury JL, Hoff C. Pneumonia as
posed hospitalization strategy for this patient population.
a complication of pregnancy. Am J Obstet Gynecol 1997;176:S186. ab- Given the potential risk to both mother and fetus, the threshold for hospitalization of pregnant women withpneumonia may need to be lowered. Future studies are re-quired to assess maternal and fetal outcomes in the full To the Editor: . . . The elderly nursing home residents spectrum of pregnant women with community-acquired whom we are called to admit with the diagnosis of pneu- monia usually have underlying disorders such as congestive Our data support the point of Drs. Tsiodras and Mal- heart failure, stroke, and renal dysfunction. These patients hotra that most nursing home patients with community- easily meet the criteria for class IV and, according to the acquired pneumonia who are referred for hospitalization prediction rule of Fine et al., should be admitted. Many of are elderly and have multiple coexisting illnesses. There these patients are clinically stable enough to be treated were a total of 195 Pneumonia PORT study patients who with intravenous antibiotics in the monitored environment resided in nursing homes (8.5 percent), of whom 86 per- of the long-term care facility. Would there be a way to pre- cent were older than 70, 95 percent had one or more co- vent unnecessary admissions in this patient population? existing illnesses, and 91 percent were in risk class IV orV. Thirty-day mortality was 16 percent in class IV nursing home patients and 36 percent in class V.
Although our findings demonstrate that nursing home residents with community-acquired pneumonia who are referred for hospital admission have a high risk of short- Downloaded from nejm.org on December 4, 2012. For personal use only. No other uses without permission. Copyright 1997 Massachusetts Medical Society. All rights reserved. C O R R E S P O N D E N C E
term mortality, our proposed threshold for hospitalization based on the prediction rule may require modification. The nursing home environment permits both clinical observa- tion and many of the treatments (e.g., oxygen therapy and intravenous antimicrobial therapy) that often dictate the need for hospitalization among noninstitutionalized pa- tients.1 Furthermore, for some nursing home residents with terminal illnesses, palliative care is desired by both thepatients and their families.2 Our study did not address the prognosis or outcomes of patients with pneumonia diagnosed and treated at nursing homes without subsequent hospital referral, so the validity of our prediction rule in this patient population still needs 1. Fine MJ, Hough LJ, Medsger AR, et al. The hospital admission decision
for patients with community-acquired pneumonia: results from the Pneu-monia Patient Outcomes Research Team cohort study. Arch Intern Med 1997;157:36-44.
2. Mehr DR. Nursing-home-acquired pneumonia: how and where to
treat? J Am Board Fam Pract 1997;10:168-70.
The Epidemic of Cardiovascular Disease
in Eastern Europe
Figure 1. Trends in Premature Cardiovascular Mortality (Stand-
To the Editor: Mortality from cardiovascular disease in ardized Mortality Rates for Men and Women 64 Years of Age Eastern Europe was low at the beginning of the 1960s, or Younger) in Europe. (Data are from the World Health Organ- but a serious increase has occurred and in 1990 mortality was substantially higher than in Western Europe and theUnited States.1 The political changes in Eastern Europeafter 1990 caused serious economic problems and si-multaneously led to a further increase in mortality fromcardiovascular disease (Fig. 1). Premature mortality from tries of Central Europe that had a lifestyle similar to that cardiovascular disease among men in the Russian Federa- of Western Europe, but also the former Soviet republics tion is now almost four times as high as in the United of Central Asia that have cultures influenced by Islam.
The World Health Organization’s Monitoring Trends The causes of the epidemic of cardiovascular disease in and Determinants in Cardiovascular Disease (MONICA) Eastern Europe are not known. The affected area has 400 project2 found a higher prevalence of smoking and hyper- million inhabitants and is almost 2.5 times as large as the tension in men living in Eastern Europe than in Western United States. Mortality from cardiovascular disease in Europe, but the prevalence of hypercholesterolemia was Eastern Europe has substantially overtaken the previous lower. In women, the prevalence of hypertension was maximum rate, reached in the 1960s in the United States higher than in Western Europe, but the number of female and Finland. Currently, nearly 500 in 100,000 men in smokers and the level of cholesterol were lower,2 because the Russian Federation die prematurely from cardiovascu- economic problems in this area limited consumption of lar disease. Such a level has never before been observed meat and dairy products. In the United States, epidemi- anywhere in the world and is twice as high as the maxi- ologic studies have quantified the effects of smoking, mum reached in the United States in the 1960s. The ep- hypertension, and hypercholesterolemia on coronary mor- idemic is concentrated in the countries that were gov- tality.3 Similar studies are not possible in Eastern Europe- erned by Communist regimes; if one passes through the an countries for economic reasons, so the help of the in- former Iron Curtain from west to east, mortality from ternational scientific community is necessary. Such help cardiovascular disease increases by two to six times. The would not only be humanitarian, but research on the ep- epidemic affected not only the post-Communist coun- idemic of cardiovascular disease in Eastern Europe could Downloaded from nejm.org on December 4, 2012. For personal use only. No other uses without permission. Copyright 1997 Massachusetts Medical Society. All rights reserved. T h e New E n g l a n d Jo u r n a l o f Me d i c i n e also broaden our knowledge of nontraditional cardiovas- was observed both in patients with and in those without preexisting coronary heart disease at base line.1 Pharmacologic treatment of hypertension plays a crucial part in the risk of long-term morbidity and mortality due Institute of Preventive and Clinical Medicine to cerebrovascular accidents.2 In agreement with a recent study in a similar setting,3 the authors report that at thetime of randomization approximately 40 percent of pa-tients were receiving calcium-channel blockers and 35 per- 1. Health for All. Statistical database 1996. Copenhagen, Denmark: World
Health Organization Regional Office for Europe, 1996.
cent were receiving beta-blockers. Both agents modulate 2. Ginter E. Cardiovascular risk factors in the former communist coun-
blood pressure, but they have different prognostic value.
tries: analysis of 40 European MONICA populations. Eur J Epidemiol Whereas a reduced risk of stroke in hypertensive patients treated with beta-blockers has been documented,2 calci- 3. Stamler J, Wentworth D, Neaton JD. Is relationship between serum
cholesterol and risk of premature death from coronary heart disease con-
um-channel blockers seem to increase overall mortality.3,4 tinuous and graded? Findings in 356,222 primary screenees of the Multi- Interestingly, calcium-channel blockers exert an antiplate- ple Risk Factor Intervention Trial. JAMA 1986;256:2823-8.
let effect, which might have been protective against em-bolic strokes. We believe that cardiovascular medicationstaken by the patients at randomization should have been Risk of Stroke after Myocardial Infarction
To the Editor: The report by Loh et al. (Jan. 23 issue),1 evaluating the association between left ventricular dys- function and the risk of stroke in patients enrolled in the Survival and Ventricular Enlargement (SAVE) trial, raisesimportant questions regarding the care of patients who have had myocardial infarctions. Two of the most impor- tant predictors of stroke are a history of stroke and tran- sient ischemic attacks.2,3 Although the authors document the effect of a history of smoking, diabetes, and hyperten-sion and of previous myocardial infarction, they do not 1. Prospective Studies Collaboration. Cholesterol, diastolic blood pressure,
comment on those two well-documented risk factors. I am and stroke: 13 000 strokes in 450 000 people in 45 prospective cohorts. curious whether their conclusions regarding the associa- tion of ventricular dysfunction and stroke would still hold 2. Dahlof B, Lindholm LH, Hansson L, Schersten B, Ekbom T, Wester
PO. Morbidity and mortality in the Swedish Trial in Old Patients with Hy-
if their analysis had controlled for a history of stroke and pertension (STOP-Hypertension). Lancet 1991;338:1281-5.
3. Soumerai SB, McLaughlin TJ, Spiegelman D, Hertzmark E, Thibault
G, Goldman L. Adverse outcomes of underuse of b-blockers in elderly sur-
vivors of acute myocardial infarction. JAMA 1997;277:115-21.
4. Pahor M, Guralnik JM, Corti M-C, Foley DJ, Carbonin P, Havlik RJ.
University of California, San Francisco, Medical Center Long-term survival and use of antihypertensive medications in older per- sons. J Am Geriatr Soc 1995;43:1191-7.
1. Loh E, St John Sutton M, Wun C-CC, et al. Ventricular dysfunction
and the risk of stroke after myocardial infarction. N Engl J Med 1997;336:
251-7.
2. Manolio TA, Kronmal RA, Burke GL, O’Leary DH, Price TR. Short-
To the Editor: We agree with Dr. Michaels that a history term predictors of incident stroke in older adults. Stroke 1996;27:1479-86.
of stroke or transient ischemic attacks is a risk factor for 3. Aronow WS. Risk factors for geriatric stroke: identification and follow-
subsequent stroke after myocardial infarction. Unfortu- nately, in the SAVE trial, prerandomization data-base formsdid not include this information. Accordingly, these vari-ables could not be considered in the multivariate analysis.
To the Editor: Loh et al. report that a decreased ejection We also agree with the comments of Gambassi et al., fraction and older age are both independent predictors of which emphasize the important role of antihypertensive an increased long-term risk of stroke after myocardial in- agents such as beta-blockers in reducing the risk of stroke farction. Besides the role of chronic atrial fibrillation as a in patients with hypertension, regardless of the presence or known risk factor, which the authors address, a potential absence of coronary heart disease. In our population of pa- role of blood pressure should also be considered. Al- tients with left ventricular dysfunction after myocardial in- though the authors report that the proportion of patients farction and a mean prerandomization blood pressure of with a history of hypertension did not differ significantly 113/70 mm Hg, we were not able to demonstrate that between the two groups, blood-pressure measurements the nonrandomized use of beta-blockers, nitrates, or cal- would have been helpful in clarifying the role of this factor.
cium-channel blockers affected the risk of subsequent In a review of 45 prospective observational studies, the stroke. Furthermore, in this blood-pressure range, even risk of stroke was strongly related to diastolic blood pres- the randomly assigned use of the angiotensin-converting– sure.1 The relation did not tend to flatten out at levels be- enzyme inhibitor captopril did not reduce the risk of low 80 mm Hg, and there was no threshold below which stroke. However, the nonrandomized use of beta-blockers diastolic blood pressure was not positively associated with was associated with an improvement in clinical outcomes the risk of stroke. Most important, this positive relation (decreased risk of death from cardiovascular causes and of Downloaded from nejm.org on December 4, 2012. For personal use only. No other uses without permission. Copyright 1997 Massachusetts Medical Society. All rights reserved. C O R R E S P O N D E N C E
heart failure), to which the effect of angiotensin-convert- failure due to amyloid cardiomyopathy supervenes, the prognosis is very poor regardless of the degree of left ven-tricular thickening.
Finally, it should be mentioned that dose-intensive mel- Hospital of the University of Pennsylvania phalan with autologous-blood stem-cell support for the treatment of AL amyloidosis is currently undergoing in-tensive evaluation.5 Initial data suggest a good response of the plasma-cell dyscrasia, but the tolerability and effective- University of Texas Health Science Center ness of this treatment in patients with cardiac amyloidosis 1. Vantrimpont P, Rouleau JL, Wun CC, et al. Additive beneficial effects
of beta-blockers to angiotensin-converting enzyme inhibitors in the Sur-vival and Ventricular Enlargement (SAVE) Study. J Am Coll Cardiol 1997; 1. Kushwaha SS, Fallon JT, Fuster V. Restrictive cardiomyopathy. N Engl
J Med 1997;336:267-76.
2. WHO-IUIS Nomenclature Sub-Committee. Nomenclature of amyloid
and amyloidosis. Bull World Health Organ 1993;71:105-12.
Restrictive Cardiomyopathy
3. Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and labora-
tory features in 474 cases. Semin Hematol 1995;32:45-59.
4. Cueto-Garcia L, Reeder GS, Kyle RA, et al. Echocardiographic findings
To the Editor: We wish to raise some points of disagree- in systemic amyloidosis: spectrum of cardiac involvement and relation to ment with the description of cardiac amyloidosis by Kush- survival. J Am Coll Cardiol 1985;6:737-43.
waha et al. (Jan. 23 issue)1 in their article on restrictive 5. Comenzo RL, Vosburgh E, Simms RW, et al. Dose-intensive melphalan
cardiomyopathy. The internationally accepted classifica- with blood stem cell support for the treatment of AL amyloidosis: one-year follow-up in five patients. Blood 1996;88:2801-6.
tion of the amyloidosis is based on the chemical nature ofthe deposited protein fibrils.2 Secondary amyloidosis refersexclusively to the reactive form characterized by deposition To the Editor: The excellent review of restrictive cardio- of a nonimmunoglobulin, amyloid A (AA), in association myopathy by Kushwaha et al. requires some clarification of with chronic infection and inflammation (e.g., rheumatoid the often difficult problem of differentiating restrictive arthritis, inflammatory bowel disease, osteomyelitis, tuber- cardiomyopathy from constrictive pericarditis. Apart from culosis, or leprosy). The familial and senile amyloidoses are the fact that constrictive pericarditis can be associated with distinct entities that have never been classified as second- an S gallop, the contrast of S in restrictive cardiomyopa- ary and that have unique biochemical and clinical features.
thy and pericardial knock in constrictive pericarditis is er- The majority of patients with primary (now known as AL) roneous. The abnormal third heart sound of constrictive amyloidosis do not have multiple myeloma.3 This is im- pericarditis has the same dynamics as any abnormal third portant, because the clinician must consider AL amyloido- heart sound (perhaps with an added element of diastolic sis if features of a restrictive cardiomyopathy are present, suction). A truly “knocking” third heart sound is extreme- despite the absence of signs of myeloma.
ly uncommon today and characterizes a bygone era when We disagree with several of the authors’ clinical state- diagnosis was delayed and the chronic constrictive peri- ments about cardiac amyloidosis. They state that the ven- carditis developed in the fortunate survivor. Acute and tricular cavities are often moderately dilated, that cardio- subacute constriction are more common today, mainly be- megaly is uncommon, and that atrial dilatation is a function cause of rapid recognition. Conceptually, the phenome- of atrioventricular valvular regurgitation. In our own data non is a third heart sound that both in constrictive peri- base of more than 200 patients with cardiac amyloidosis carditis and restrictive cardiomyopathy tends to be earlier (unpublished data), echocardiographic left ventricular dil- than other abnormal third heart sounds. Also, the pericar- atation was seen in only 3 percent of the patients and dium itself does not generate the abnormal third heart when present was frequently associated with coexisting sound, except to the extent that the constricting pericar- coronary artery disease or substantial mitral regurgitation.
dium contributes to the degree of myocardial restriction.
Although atrial enlargement was common, it was generallyunrelated to atrioventricular valvular regurgitation — rath- er, it was a function of high atrial-filling pressures. In ourexperience, mild-to-moderate cardiomegaly is frequently apparent on chest films once heart failure occurs. This mayreflect either atrial enlargement and ventricular thickeningor right ventricular dilatation, since the left ventricular While left-ventricular-wall thickness is a prognostic de- To the Editor: Dr. Reisinger and colleagues correctly terminant in amyloidosis, the paper cited4 does not deal point out that the classification of amyloidosis is based on exclusively with cardiac amyloidosis. Indeed, most patients the chemical nature of the amyloid fibrils, and we agree with normal wall thickness (median survival, 2.4 years) that the majority of patients with primary amyloidosis do had no evidence of cardiomyopathy. Once severe heart not have multiple myeloma. In fact, we stated in the article Downloaded from nejm.org on December 4, 2012. For personal use only. No other uses without permission. Copyright 1997 Massachusetts Medical Society. All rights reserved. T h e New E n g l a n d Jo u r n a l o f Me d i c i n e that primary amyloidosis is often due to multiple myeloma, which does not necessarily suggest that multiple myelomaoccurs in the majority of patients who present with pri- mary amyloidosis. The intention of the paper was not to discuss the classification of amyloidosis but to review itsrelevance to restrictive cardiomyopathy. We acknowledgethat familial and senile amyloidoses have unique biochem- ical and clinical features, which are discussed in the article,and that those diseases are best not classified as secondaryforms of amyloidosis.
The unpublished observations of Reisinger and colleagues are interesting, and we agree that gross cardiomegaly isuncommon. In fact, as the review states, the ventricularcavities are often normal in this condition. Atrial enlarge- ment may indeed be secondary to high atrial-filling pres-sures, but it is our observation that it tends to be more common in the presence of atrioventricular valvular regur-gitation, which is also correlated with the development of heart failure. We agree that once cardiac failure due to car- diomyopathy supervenes, the prognosis is poor; however, this tends to be correlated with increased wall thickness —although this may not always be the case.
We thank Reisinger and colleagues for bringing to our attention the therapy with dose-intensive melphalan and autologous-blood stem-cell support, and it will be inter-esting to see what effect this therapy may have on the We recognize the expertise of Dr. Spodick on the peri- cardium and its physiology and would like to thank himfor his insightful remarks and clarification regarding the third heart sound and the pericardial knock. We agree thatthis sound may be uncommon but contend that when itdoes occur, it is diagnostic. And we acknowledge that an S gallop can also occur in constrictive pericarditis.
Olfactory Dysfunction in Multiple Sclerosis
Figure 1. Relation between UPSIT Scores and the Numbers of
Multiple-Sclerosis–Related Plaques in Olfactory (Panel A) and
To the Editor: Multiple sclerosis, the most common neu- Nonolfactory (Panel B) Brain Regions.
rologic disease in young adults, is accompanied by focal The olfactory brain region is defined as the inferior frontal demyelinating plaques within the central nervous system, lobes (inferior and anterior to the body and genu of the corpus which can be quantified in vivo by using high-resolution callosum, respectively) and the inferior temporal lobes (bound- magnetic resonance imaging (MRI). Thus, multiple scle- ed by the plane of the sylvian fissure superiorly). These areas rosis may be an excellent model for the study of the influ- contain the major zones of known central-olfactory connec- ences of focal lesions on some forms of sensory function.
tions. UPSIT denotes University of Pennsylvania Smell Identifi- Since multiple-sclerosis–related plaques vary in number over time, differ considerably from patient to patient, andoften occur in regions of the brain associated with theability to smell,1 we determined whether the number ofmultiple-sclerosis–related plaques in olfactory regions cor- ing a 1.5-T Signa scanner (General Electric, Milwaukee) relates with scores on the University of Pennsylvania Smell employing a standard head coil. Plaques were counted Identification Test (UPSIT), a standardized 40-odorant without knowledge of the patients’ UPSIT scores. quantitative test of olfactory function.2 We found a strong negative relation (Spearman r ϭ Ϫ0.94, Nine men and 17 women (mean [ϮSD] age, 42.2Ϯ7.2 PϽ0.001) between the UPSIT scores and the number of years) with confirmed multiple sclerosis were tested. Thin- demyelinating plaques within the inferior frontal- and section MRIs of the brain with gadolinium enhancement temporal-lobe regions, which are involved in olfaction were performed on the same day as olfactory testing by us- (Fig. 1A). No such relation was found between the scores Downloaded from nejm.org on December 4, 2012. For personal use only. No other uses without permission. Copyright 1997 Massachusetts Medical Society. All rights reserved. C O R R E S P O N D E N C E
and the numbers of plaques in brain regions not related to Insomnia
olfaction (rϭϪ0.08, P not significant) (Fig. 1B), implyingthat the relation was restricted to brain structures directly To the Editor: In the excellent review of the management of insomnia by Kupfer and Reynolds (Jan. 30 issue),1 we Relative to normative data based on nearly 4000 sub- read that “zolpidem may be less likely than benzodiaz- jects,3 38.5 percent of the patients had demonstrable ol- epines . . . to cause cognitive and psychomotor side ef- factory loss; 7.7 percent had severe bilateral microsmia, fects (and may have fewer withdrawal effects).” It is clear 19.2 percent moderate bilateral microsmia, and 11.5 per- that many clinicians believe this to be true, since zolpidem cent mild bilateral microsmia. None had anosmia. No sex is the most commonly prescribed hypnotic agent in the differences or meaningful left–right asymmetries in UPSIT United States.2 However, the authors cite only three stud- scores or numbers of plaques were found.
ies in support of this idea, two of which did not even com- These findings clarify the ongoing controversy over the pare zolpidem with a benzodiazepine.
presence of olfactory dysfunction in multiple sclerosis and The study that did compare these drugs with respect to invalidate claims of normal olfactory function in patients rebound insomnia and withdrawal used a dose of triazo- with the disease.4 Notably, they support the concept that lam that is now considered excessive, with twice the hyp- multiple sclerosis, with its relatively discrete focal regions notic potency of the zolpidem dose (0.5 mg of triazolam of inflammation, demyelination, and gliosis, can serve as a vs. 10 mg of zolpidem).3 Nonetheless, little or no clinically useful model for the study of the influences of lesions of significant difference was observed between the drugs in the central nervous system on sensory perception. Al- this study, and rebound insomnia occurred only after the though numerous studies have reported olfactory dysfunc- first night of triazolam withdrawal.
tion in several neurodegenerative disorders, including Alz- Several well-designed studies have directly compared heimer’s disease and idiopathic Parkinson’s disease,5 our zolpidem and triazolam and have failed to show a differ- findings provide a clear physiologic explanation for de- ence in cognitive and psychomotor effects between the two creased olfactory function in patients with any major neu- drugs. The authors generally conclude that the cognitive rologic disease. Given that olfaction influences the quality and performance-impairing effects are remarkably similar, of life and provides a basic means for detecting smoke, that they are linked directly to hypnotic potency, and that leaking natural gas, and other environmental hazards, per- no clinically significant difference exists at the usually rec- sons involved in the care of patients with multiple sclerosis ommended, equipotent doses of these agents. Our con- should be aware of the potential for olfactory losses and clusion from the available data is that zolpidem has no clinically important advantage over benzodiazepines (spe-cifically, triazolam) with respect to the potential to cause cognitive, psychomotor, or withdrawal effects.
University of Pennsylvania Medical Center 1. Kupfer DJ, Reynolds CF III. Management of insomnia. N Engl J Med
1. Young IR, Hall AS, Pallis CA, Legg NJ, Bydder GM, Steiner RE. Nu-
clear magnetic resonance imaging of the brain in multiple sclerosis. Lancet 2. Top 200 drugs of 1995. Pharmacy Times. April 1996:27-36.
3. Monti JM, Attali P, Monti D, Zipfel A, de la Giclais B, Morselli PL.
2. Doty RL, Shaman P, Dann M. Development of the University of Penn-
Zolpidem and rebound insomnia — a double-blind, controlled polysom- sylvania Smell Identification Test: a standardized microencapsulated test of nographic study in chronic insomniac patients. Pharmacopsychiatry 1994; olfactory function. Physiol Behav 1984;32:489-502.
3. Doty RL. The Smell Identification Test administration manual. Haddon
4. Greenblatt DJ, Harmatz JS, Wright CE, Harrel L, Shader RI. Does
zolpidem have unique clinical properties? A pharmacodynamic comparison 4. Lumsden CE. The neuropathology of multiple sclerosis. In: Vinken
with triazolam and placebo. Clin Pharmacol Ther 1996;59:178. abstract.
PJ, Bruyn GW, eds. Multiple sclerosis and other demyelinating diseases. 5. Wesensten NJ, Balkin TJ, Belenky GL. Effects of daytime administration
Handbook of clinical neurology. Vol. 9. New York: Elsevier, 1970:217- of zolpidem and triazolam on performance. Aviat Space Environ Med 5. Doty RL. Olfactory dysfunction in neurodegenerative disorders. In:
Getchell TV, Doty RL, Bartoshuk LM, Snow JB Jr, eds. Smell and taste in
health and disease. New York: Raven Press, 1991:735-51.
1997, Massachusetts Medical Society.
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