LETTERS

Letters submitted for publication must be typed double-spaced. Text length must not exceed 500 words, and no more than five references may be used. Complete references must be furnished, as specified in "Information for Authors" (page 1-6). Specific permission to publish should be appended as a postscript. Publication depends on availability of space: We give preference to comment on recent content and to new information. Letters for this section should be concise—the Editor reserves the right to shorten them and make changes that accord with our style. Hypothermia

it the potential for harm. A s well, the changes in pH during hypothermia, as reflected in the correction factors, interface with decisions on advisability of bicarbonate administration. For example, a patient with a core temperature of 27 °C and a pH of 7.10 and Po 2 of 20 mm Hg would have, with correction for temperature, a tissue-level pH of 7.25 and a Po 2 of 20 mm Hg. Therefore, not to use correction factors for arterial blood gases in dealing with the hypothermic patient, as some authors have advocated (2), is to ignore major pathophysiologic changes that may have significant impact on management and lead to unnecessary and potentially dangerous therapy in a rapidly changing metabolic milieu. J A M E S B. R E U L E R , M . D .

T o THE EDITOR: In the excellent review of hypothermia in the October issue (Ann Intern Med 89:519-527, 1978), Dr. Reuler states that "arterial blood gases must be corrected for body temperature'* and that "because these values are standardly measured at 37 °C, direct communication to the laboratory is necessary in order to obtain results that can be rationally interpreted and applied to management." Does Dr. Reuler intend that the laboratory measure the sample at the patient's core temperature, or simply to supply an arbitrary correction retrievable from the literature? The first possibility presents an enormous logistical problem in a busy blood gas laboratory, for to bring one or more blood gas analyzer down to the patient's core temperature would take excessive time, and each succeeding sample would be similarly delayed in analysis if the patient's temperature is being raised (which presumably is the case). If the intent is simply to apply a correction, then I have to ask whether Dr. Reuler recommends that this correction be applied equally to hypothermic and febrile patients alike. I question the need for this because everything else we do is referred to 37 °C, and if we apply this correction, this neglects the decreased oxygen requirements that the hypothermia engenders and might lead to unnecessary oxygen administration with potential harm to the patient. Surely if the mixed venous Po, is maintained, auxiliary oxygen is superfluous. To me, it seems more reasonable to have all of the relevant information—arterial blood gases, mixed venous blood gases, and cardiac output—than to insist on a correction for only one of the variables. H. H . ROTMAN, M.D. University of Michigan Medical Center; Ann Arbor, MI 48109 In comment: Dr. Rotman raises several excellent points on blood gas measurements in hypothermia. It is unrealistic due to technical and logistical limitations to recalibrate the blood gas analyzer to the patient's core temperature. The provided correction factors obviate the need for recalibration and should be applied to febrile as well as hypothermic patients, as is done routinely in some respiratory care units. Because mixed venous Po 2 and cardiac output measurements are difficult to obtain readily and may be altered due to regional changes in perfusion and the effect of the lowered core temperature on cardiac performance, the arterial blood gases remain an important variable in evaluating the hypothermic patient. Although oxygen requirements are decreased in hypothermia, inadequate tissue perfusion can more than offset the benefit derived from lowered tissue demands for oxygen (1). The adequacy of tissue perfusion during hypothermia depends on many factors, including cardiac output, peripheral resistance, and blood viscosity. The oxyhemoglobin dissociation curve is also shifted to the left, causing increased affinity for oxygen. This, combined with problems with mucous plugging and ventilation-perfusion inequalities, makes it quite unlikely that oxygen administration carries with

Portland Veterans Administration Hospital; Portland, OR 97201 REFERENCES 1. MACLEAN

D,

EMSLIE-SMITH

D: Accidental

Hypothermia.

Oxford,

Blackwell Scientific Publications, 1977, pp. 116-122 2. PATTERSON RH, SONDHEIMER HM: Assessing acid-base metabolism

with samples of arterial blood obtained from hypothermic subjects. / Surg Res 6:19-23, 1966

T o T H E EDITOR: I wish to comment on an additional method of treatment of hypothermia. This may supplement the suggestions made by Dr. Reuler in his very thorough review (Ann Intern Med 89:519-527, 1978). When weather and terrain combine to force treatment of hypothermia in the place where the victim is found, adequate equipment has always been a definite problem to rescuers. Since 1970, the Bellingham Mountain Rescue Council has successfully used a lightweight rewarming blanket on several patients with severe hypothermia. This device, which has acquired the nickname "hydraulic sarong," is capable of delivering 2.5 kcal/min. It is a manifold of Teflon® tubing sewn into a light cloth blanket. Water, heated by a "backpacker's" stove, is circulated through it by means of a small hand pump. Inhaled air can also be heated by wide-bore tubing traversing the blanket. We believe, however, that in situations where the blanket is useful, the heated air that prevents additional cooling is not in itself adequate. This equipment has recently been described (1). J O H N W. A R N O L D , M . D .

Consultants in Internal Medicine, Inc. P.S.; Bellingham, WA 98225 REFERENCE 1. A R N O L D JW, EICHENBERGER CH: The hydraulic sarong: emergency

treatment device for accidental hypothermia. J Am Coll Emergency Physicians 4:438-439, 1975

T o THE EDITOR: In his article "Hypothermia: Pathophysiology, Clinical Settings, and Management" (Ann Intern Med 89:519527, 1978), Reuler discusses susceptibility of the elderly to accidental hypothermia. This subject is of great interest not only for clinicians but for the general public and politicians. Politicians are looking for scientific data on the need of the aged for adequate means of heating and cooling their homes and on the particular hazard that shortage of energy for such purposes poses to their health (1). There are studies supporting Reuler's view that the elderly are more prone to hypothermia due to several specific aging factors; however, one should be cautious with generalizations regarding the entire aged population. Studies have shown that

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there is a group of elderly persons at high risk of developing hypothermia, but most older persons have a capacity of normal temperature regulation (2). The study of Macmillan and colleagues (3) showed that normal subjects aged 84 to 93 years had normal thermoregulatory responses on cooling as opposed to a group of survivors of accidental hypothermia aged 66 to 89. More investigations are needed to clarify the mysterious relation between hypothermia and the aging process. For practical reasons, conditions common to the elderly such as chronic diseases that limit their mobility, myxedema, and drug influences (phenothiazine, barbiturates) should be recognized as triggers for development of hypothermia.

on 30 March 1978 was treated to 5 May 1978 with cloxacillin 12 g/day. The development of severe oesophagitis prompted an increase of cimetidine dosage to 1000 mg/day from 14 April to 3 May with a return then to 400 m g / day until interruption of the drug on 9 May. Although the signs of septicemia had already subsided, leukopenia (down to 1700 leukocytes/ml with 16% neutrophils) and thrombocytopenia (down to 2000 platelets/ul) developed, anemia became more severe, and the reticulocyte count fell to 0 (Figure 1). Interruption of cimetidine and cloxacillin therapy was followed by hematologic recovery, the reticulocytosis reaching 7.6% 13 days after cimetidine withdrawal despite maintenance of all other medication. Six weeks later the bone marrow was cultured on soft agar with control serum, the patient's serum, and two different concentrations of cimetidine. No growth inhibition of the colony-forming units was noticed (courtesy Dr. Symann).

V A L E R Y A. P O R T N O I , M . D .

George Washington University Medical Center; Washington, D C 20037 REFERENCES

1. BUTLER RN: Energy and aging. The impact of rising energy costs on older Americans, in Testimony Before the U.S. Senate Special Committee on Aging, 5 April 1977. Washington, D.C., U.S. Department of Health, Education, and Welfare, 1977 2. WOLLNER L, SPALDING JMK: Temperature regulation, in Textbook

of

Geriatric Medicine and Gerontology, edited by BROCKLEHURST JC. New York, Churchill Livingstone, 1973, pp. 235-244 3. MACMILLAN AL, CORBETT JL, JOHNSON RH, CRAMPTON SMITH A, SPALDING JMK, WOLLNER L: Temperature regulation in survivors of

accidental hypothermia of the elderly. Lancet 2:165-169, 1967

Pancytopenia with Cimetidine T o T H E EDITOR: Cimetidine has been recently implicated in the

development of five cases of agranulocytosis and in one case of pancytopenia (1-6). We have seen an additional case in which the development of severe pancytopenia was apparently related to cimetidine treatment. A 45-year-old diabetic man had been dialysed since 1973 for terminal renal failure due to diabetic glomerulosclerosis. A duodenal ulcer had been diagnosed in 1970, with relapses in 1972 and 1973. In 1974 an abortive attempt to transplant a cadaver kidney was complicated by gastrointestinal hemorrhage, without documented recurrence of the ulcer. Cimetidine, 400 mg/day was started on 15 February 1978 to alleviate later postprandial epigastric pain. A Staphylococcus aureus bacteremia diagnosed

Pancytopenia developed in this patient coincidentally with the introduction of cloxacillin treatment and an increase in cimetidine dosage. It proved reversible upon withdrawal of both drugs. We have not found any report of pancytopenia associated with cloxacillin. By contrast, several recent case reports have suggested that cimetidine induces agranulocytosis (1-5) and, in one case, pancytopenia (6). The mechanism of cimetidine-induced blood disorders remains to be ascertained. The fact that in our patient as well as in a previous case (2) cimetidine failed to inhibit bone marrow culture argues against the hypothesis that bone marrow toxicity resulted from histamine H2 receptor blockade of stem cells (7). Our observation underlines the need to watch blood counts during cimetidine treatment. C. DE GALOCSY, M.D. C. VAN YPERSELE DE STRIHOU, M.D. Cliniques Universitaires St-Luc; 1200 Brussels, Belgium REFERENCES

1. CRAVEN ER, WHITTINGTON JM: Agranulocytosis four months after cimetidine therapy (letter). Lancet 2:294-295, 1977 2. JOHNSON NM, BLACK AE, H U G H E S ASB, CLARKE SW: Leucopenia

with cimetidine (letter). Lancet 2:1226, 1977 3. UFBERG MH, BROOKS CM, BOSANAC PR, KINTZEL JE: Transient neu-

tropenia in a patient receiving cimetidine. Gastroenterology 1977

73:635-638,

4. L 6 P E Z - L U Q U E A, RODRIGUEZ-CUARTERO A, PEREZ-GALVEZ N, P O MARES-MORA J, P E N A - Y A N E Z A: Cimetidine and bone-marrow toxicity

(letter). Lancet 1:444, 1978 5. KLOTZ SA, KAY BF: Cimetidine and agranulocytosis (letter). Ann Intern Med 88:579-580, 1978 6. JAMES C, PROUT BJ: Marrow suppression and intravenous cimetidine (letter). Lancet 1:987, 1978 7. BYRON JW: Cimetidine and bone-marrow toxicity (letter). Lancet 2:555556, 1977

Aspirin and Renal Function T o T H E EDITOR: We read with some concern the article by

Figure 1 . Hematologic changes during and after cloxacillin and cimetidine therapy. Hb = hemoglobin; WBC = leukocyte count. 2 7 4

Kimberly and colleagues (1) stating that true glomerular filtration rate was depressed in patients with systemic lupus erythematosus taking aspirin. The article may be misleading in several respects. The most striking inconsistency appears when one analyzes the measurements of glomerular filtration rate. Although the mean value for inulin and creatinine clearance is only slightly different in the control period, impressive differences are evident when these measurements are compared in three of the six patients. Firm evidence exists supporting the good correlation between endogenous creatinine clearance and inulin clearance over a wide range of glomerular filtration rate (2, 3). The ratio of creatinine to inulin clearance is near unity when clearances are measured simultaneously. There may be as much as a 20% change, however, when either measurement is made successively (2). If this spontaneous variability of filtration rate is not recognized, erroneous conclusions may be drawn. We must assume from the discrepancy that the clearance measurements are erroneous or were not done simultaneously, making the results uninterpretable. In addition to baseline variability of clearance measurements, analysis of the inulin clearance in the recovery period fails to

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show the trend suggested by the authors. In Patients 1 and 2 there is a significant rise in the glomerular filtration rate from the control period. (One might as effectively argue that this represents a therapeutic effect of aspirin.) Patient 3 shows no significant change in inulin clearance in either the control, treatment, or recovery period, and Patient 4 had a further decrease in inulin clearance after aspirin therapy was discontinued. In only one of the six patients did inulin clearance fall with and return to baseline after aspirin therapy, a pattern the authors suggest is characteristic of the group as a whole. Further, the p-aminohippurate clearances are more suspect. As p-aminohippurate is actively secreted by the renal tubule, the very presence of aspirin, a drug well known to effect tublar secretion, makes evaluation of p-aminohippurate clearance measurements difficult at best. The measurement of a p-aminohippurate extraction ratio by renal arterial and venous sampling is mandatory for a precise estimate of renal blood flow in this setting. From the data presented it is difficult to draw any conclusion about the effects of aspirin on glomerular filtration rate. Before a drug with known therapeutic benefit such as aspirin (4) is withheld from patients with systemic lupus erythematosus, a further evaluation of its effects on glomerular filtration is needed. R I C H A R D S. M U T H E R , M . D . G E O R G E A. P O R T E R , M . D .

The importance of recognizing aspirin's effect on renal function lies not in the removal of aspirin and other nonsteroidal anti-inflammatory drugs from our therapeutic armamentarium; rather, we must consider the potential for this reversible phenomenon when assessing renal function and include it among drug-related renal effects in clinical medicine. R O B E R T P. K I M B E R L Y , M . D .

Cornell University Medical Center; New York, N Y 10021 J O H N R. G I L L , J R . , M . D .

National Heart, Lung, and Blood Institute; Bethesda, M D 20014 P A U L H. P L O T Z , M . D .

National Institute of Arthritis, Metabolism, and Digestive Diseases; Bethesda, M D 20014 REFERENCES 1. DONKER AJM, ARISZ L, BRENTJENS JRH, V A N DER H E M GK, HOLLE-

MANS HJG: The effect of indomethacin on kidney function and plasma renin activity in man. Nephron 17:288-296, 1976 2. ARISZ L, DONKER AJM, BRENTJENS JRH, V A N DER H E M GK: The

effect of indomethacin on proteinuria and kidney function in the nephrotic syndrome. Acta Med Scand 199:121-125, 1976 3. ROSE G: Medical Research Council trials, in Glomerulonephritis, edited by K L U T H E R, VOGT A, BATSFORD SR. New York, John Wiley and

Sons, 1977, pp. 174-182 4. BERG KJ, BERG AN A: Effects of different doses of acetylsalicylic acid on renal function in the dog. Scand J Clin Lab Invest 36:779-786, 1976

W I L L I A M M. B E N N E T T , M . D .

University of Oregon Health Sciences Center; Portland, OR 97201 REFERENCES 1. KIMBERLY RP, G I L L JR JR, B O W D E N RE, KEISER HR, PLOTZ PH:

Elevated urinary prostaglandins and the effects of aspirin on renal function in lupus erythematosus. Ann Intern Med 89:336-341, 1978 2. BENNETT WM, PORTER GA: Endogenous creatinine clearance as a clinical measure of glomerular filtration rate. Br Med J 2:84-86, 1971 3. DOOLAN PD, A L P E N EL, THEIL GB: A clinical appraisal of the plasma

concentration and endogenous clearance of creatinine. Am J Med 32:6579, 1962 4. ROPES MW: Systemic Lupus Erythematosus. Cambridge, Massachusetts, Harvard University Press, 1976, p. 103

In comment: We agree that aspirin or other nonsteroidal antiinflammatory drugs ought not to be withheld in clinically important situations because of potential changes in the serum creatinine. Neither we nor others who have observed effects on glomerular filtration have found the changes to be irreversible (1-3). We do not believe that our data presented are uninterpretable. Aspirin clearly reduced glomerular filtration, as measured by a reduced endogenous creatinine clearance in seven of seven patients and a reduced inulin clearance in six of six patients, with a return towards normal after drug withdrawal (creatinine, six of six patients; inulin, four of five patients). Variability in a set of observations requires the use of statistical analysis. Although statistics cannot assess clinical significance of the observations, it can assess the probability that a phenomenon is due to random variability alone. The statistical analysis of our data indicates a very high probability that the reduction in clearance of creatinine and inulin is associated with aspirin effect. The variability that we observed and that Drs. Muther, Porter, and Bennett noted does not erase the clear pattern of the data. Further, although the reduction of renal blood flow is, as we pointed out, overestimated because of aspirin's effect on the tubular secretion of P-aminohippurate, there is a true reduction in renal blood flow (4). The association of a fall in clearance of p-aminohippurate with a fall in creatinine and inulin clearance supports the intrepretation that a change in renal hemodynamics underlies the change in glomerular filtration rate and consequently the change in serum creatinine and blood urea nitrogen. The reduction in elevated urinary immunoreactive prostaglandin E levels induced by aspirin correlates with the observed hemodynamic changes.

Drugs and Pregnancy T o THE EDITOR: In their article "Safety of Therapy for Allergic Symptoms During Pregnancy" in the August issue, Greenberger and Patterson (1) cited, with permission, data in their Tables 2 and 3 that were originally published by us (our Tables 23.1 and 25.1) (2). The numbers, as presented, are accurate, but the authors do not point out the limited interpretability of our findings, a matter that we emphasized repeatedly throughout our book. We conducted, quite literally, thousands of comparisons between drug exposures in early pregnancy and various categories of malformations. According to statistical principles, one would expect to find, by chance, associations significant at the 5% level in five of 100 comparisons. Thus any associations in our data should be considered to be, at most, hypotheses requiring independent confirmation. Inferences of causality based solely on our data are not appropriate. To cite an isolated association having a P value of less than 0.05 between antenatal exposure to brompheniramine and malformations (Table 2), out of context, is to assign to it undeserved importance. The same principles would also apply in interpreting the associations between malformations and exposure to either phenylephrine or epinephrine (Table 3). Moreover, all three associations, even though statistically significant, were relatively unstable in terms of interval estimation (that is, the magnitude of the relative risks and their confidence limits) because of modest numbers. With brompheniramine, in particular, there were 65 exposed gravidae who gave birth to 10 malformed children. Few epidemiologists would draw conclusions from such scanty data. We also stressed that the data presented in our Tables 23.1 and 25.1 were not controlled for the influence of bias due to confounding (other than that attributable to hospital variability). More than one half of our book was devoted to a detailed consideration of the problem of confounding bias in this complicated study. Our presentation of comprehensive tables, in which only hospital variability was controlled, was simply intended to provide a bird's-eye view of the overall data before proceeding to more detailed analysis. We used this strategy in considering a wide range of drug groups. We stressed that in the absence of the fullest possible control for confounding, the preliminary estimates of statistical significance were to be interpreted cautiously. If fact, when we shifted from the preliminary analysis, which was quoted in the article, and considered only Letters

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malformations whose diagnosis was not dependent to any appreciable degree on the subjective judgment of the observers, there were no significant associations with antenatal exposure to any antihistamine or sympathomimetic drug (Tables 23.2 and 25.2). Finally, Drs. Greenberger and Patterson were in error on two points. 1. The statement that "brompheniramine was statistically different from the 1.10 relative risk for all antihistamines and antinauseants at the 0.05 level of confidence" is incorrect. The relative risk from brompheniramine was significantly different from 1.0, and the reference group comprised all nonexposed mother-child pairs in the cohort. 2. In Tables 2 and 3, although the authors gave the correct numbers, they changed the titles. In so doing, they changed the meaning of our original tables. Whereas our language was chosen to be nonjudgmental and descriptive ("Children with Any Malformation in Relation to Exposure to . . ."), they labelled the tables as "Data on Teratogenic Effects of. . . .** These labels carry unwarranted implications of causality that may consciously or unconsciously bias the reader. D E N N I S S L O N E , M.D. S A M U E L SHAPIRO, M.B.

Boston University Medical Center; Boston, MA 02138 REFERENCES 1. GREENBERGER P, PATTERSON R: Safety of therapy for allergic symptoms during pregnancy. Ann Intern Med 89:234-237, 1978 2. HEINONEN OP, SLONE D, SHAPIRO S: Birth Defects and Drugs in Pregnancy. Littleton, Massachusetts, Publishing Sciences Group, Inc., 1977

pointing and perhaps misleading. Though there has been a decline in the medicinal use of marijuana in some areas, there has been a resurgence in others. Of particular importance is the role of cannabis in treating nausea and vomiting in patients receiving cancer chemotherapy. Sallan, Zinberg, and Frei (1) have documented the effectiveness of oral tetrahydrocannabinol over placebo in reducing vomiting of central origin caused by chemotherapeutic agents. This ongoing research has significant clinical implications for the quality of the lifestyle of some cancer patients and for the quantification of central cerebral effects of cannabis. S U S A N N A E. B E D E L L , M . D .

Beth Israel Hospital; Boston, MA 02215 REFERENCE 1. SALLAN SE, ZINBERG NE, F R E I E: Antiemetic effect of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy. N Engl J Med 293:795-797, 1975

In comment: The UCLA Conference on cannabis was not intended to be broad in scope but rather focused on certain aspects of recent cannabis research that engaged the interest of investigators at the UCLA School of Medicine. Dr. Bedell's letter suggests to us that the choice of title for the conference, "Cannabis, 1977," was unfortunate because it has the misleading connotation of a comprehensive review. Dr. Bedell is quite correct in pointing out that one of the more promising therapeutic applications of delta 4 -tetrahydrocannabinol and related compounds is in reducing the vomiting caused by cancer chemotherapy. D O N A L D P. T A S H K I N , M . D .

In comment: Our article attempted to clarify the situation for the practicing physician. The letter of Drs. Slone and Shapiro adds significant information about the safety of antihistamines and sympathomimetic drugs. It also points out difficulties in trying to interpret the risk to the infant of medications taken by the mother during pregnancy. We think that the titles of the tables in our paper were neutral, although we can see where they could be interpreted otherwise. The problem of controlling symptoms in pregnancy and the problem of risk of drugs in pregnant patients is of significant concern to physicians and patients. We believe Drs. Heinonen, Slone, and Shapiro (1) have made valuable contributions in this difficult area. We were attempting to provide guidelines for safety in the pregnant allergic patient and believe this was partially accomplished. If brompheniramine, phenylephrine, or epinephrine were inappropriately overemphasized in our article as higher risk drugs, we are glad that this has been corrected. ROY PATTERSON, M.D. PAUL GREENBERGER, M.D.

Northwestern University Medical School; Chicago, IL 60611 REFERENCE 1. HEINONEN OP, SLONE D, SHAPIRO S: Birth Defects and Drugs in Pregnancy. Littleton, Massachusetts, Publishing Sciences Group, Inc., 1977

Cannabis and Cancer Chemotherapy T o T H E EDITOR: Delta 9 -tetrahydrocannabinol, commonly known as marijuana, has been extensively mystified, mythologized, and politicized during the 20th century. The scientific review by Dr. Tashkin and co-authors {Ann Intern Med 89:539-549, 1978) offers hope for a more rigorous, cautious, and clinically relevant use for cannabis. Although this excellent discussion is optimistic in its anticipation of the future for cannabis in clinical medicine, it is flawed by its limited appreciation of the research already showing delta'-tetrahydrocannabinol to be beneficial for some groups of human subjects. Dr. Tashkin's statement that the "potential therapeutic properties [of cannabis] were gradually forgotten" during the 20th century is disap276

UCLA School of Medicine; Los Angeles, CA 90024

Lymphoma and Rifampin T o T H E EDITOR: The immunosuppressive effects of rifampin have been well established (1-3). Long-term complications, however, have not yet been reported. We wish to report the case of a patient who developed nasopharyngeal lymphoma after treatment with rifampin for Pott's disease. A 41-year-old Navajo man presented in June 1974 with a large right paraspinal mass and T6,T7,TK destruction. He had been taking isoniazid for 2 months because of a positive P P D test (5 TU). His initial treatment was with isoniazid, ethambutol, and streptomycin but was subsequently changed to isoniazid, ethambutol, and rifampin because of the possibility of isoniazid-resistant organisms. He then underwent surgical drainage of the abscess. He was continued on isoniazid, ethambutol, and rifampin therapy for 24 months (January 1975 to January 1977). He took his medicine somewhat sporadically. Complete healing with fusion of the involved vertebrae occurred. In November 1977 he complained of hoarseness, and a routine ear, nose, and throat examination found a nasal polypoid mass. Biopsy of this mass revealed non-Hodgkin lymphoma, diffuse histiocytic type.

As estimated by the New Mexico Cancer Control Program (personal communication), lymphoma occurs in about 50 Navajo men per 100 000 Navajo population. Our service unit treats about 20 000 Navajo patients per year, at five clinic visits per year per patient, yielding about two cases of lymphoma per year. This patient had our only case of lymphoma in the past 4 years. This may very well be just a chance occurrence, but considering the well-established immunosuppressive effects of rifampin one wonders whether this patient's "immune surveillance system" was compromised and allowed this malignancy to develop. We welcome other comments in order to establish whether prolonged rifampin therapy can be implicated in the subsequent development of malignancy. ROBERT RATE, M.D. CAROL C H E R V E N A K , R.PH. G A R Y PAVINICH, R.PH.

Keams Canyon U.S. Public Health Service; Keams Canyon, AZ 86034

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REFERENCES

1. SANDERS WE JR: Rifampin. Ann Intern Med 85:82-86, 1976 2. G R A B E R CD, JEBAILY J, G A L P H I N RL, D O E R I N G E: Light chain pro-

teinuria and humoral immunoincompetence in tuberculous patients treated with rifampin. Am Rev Respir Dis 107:713-717, 1973 3. M U K E R J E E P, S C H U L D T S, KASIK JE: EfTect of rifampin on cutaneous

hypersensitivity to purified protein derivative in humans. Agents Chemother 4:607-611, 1973

Antimicrob

Oxacillin and the Liver T o THE EDITOR: In a recent article (1) hepatitis from intravenous oxacillin therapy was reported in eight patients. When we received that issue of the Annals we were treating a 62-year-old woman for Staphylococcus aureus endocarditis with intravenous oxacillin and gentamicin. Symptoms of nausea, malaise, and anorexia with hepatic enlargement and tenderness began after 4 days of oxacillin (total dose of 60 g). After 8 days of oxacillin, the drug was discontinued. The patient was known to have hepatic congestion secondary to tricuspid insufficiency with baseline serum glutamic-oxalacetic transaminase (SOOT) levels of 60 to 100 m U / m l (normal, 5 to 40 mU/ml). The following are her SGOT levels: before oxacillin, 66 mU/ml; seventh day on oxacillin, 1445 mU/ml; first day off oxacillin, 2545 mU/ml; third day off oxacillin, 848 mU/ml; sixth day off oxacillin, 188 mU/ml; tenth day off oxacillin, 65 m U / m l . One week earlier, she had completed a 2-week course of intravenous oxacillin (total dose, 144 g) for Staphylococcus aureus bacteremia without evidence of endocarditis. Our case is evidence for a hypersensitivity reaction mechanism on re-exposure to the drug, suggests a more marked rise in abnormal liver functions in a chronically congested liver (highest reported SGOT in the eight-patient series was 373 mU/ml), and underlines the timeliness of your journal. AILEEN DENNY, M.D. JAMES ADAMS, M.D. T. C. M I L L E R , M . D .

University of Minnesota Unit for Teaching and Research in Internal Medicine, Northwestern Hospital; Minneapolis, M N 55407 REFERENCE

1. ONORATO IM, A X E L R O D JL: Hepatitis from intravenous high-dose oxacillin therapy. Findings in an adult inpatient population. Ann Intern Med 89:497-500, 1978.

Treatment of Staphylococcal Infection T o THE EDITOR: Wheat, Kohler, and White (1) have provided us with some important data regarding solid-phase radioimmunoassay (RIA) for Staphylococcus aureus antibody and its application to the problem of serious staphylococcal infection. Specifically, they have suggested that the RIA technique may be helpful in differentiating patients with "complicated" from those with "uncomplicated" bacteremia. Included in the group with "complicated" bacteremia, however, are a number of patients whose treatment remains controversial—namely those with a primary focus that is not removed or drained, but without evidence of endocarditis or metastatic abscess. Because the antibody levels in this group of patients, measured by both agar-gel diffusion and RIA, overlapped with those of the endocarditis patients, the obvious implication is that these patients should be treated with antibiotics for 4 to 6 weeks. Indeed, the authors state that "81% of patients with complicated bacteremia were cured by 4 to 6 weeks of antibiotic therapy," suggesting that the patients in this subgroup did, in fact, receive extended therapy. However, in their discussion the authors recommend that patients with "primary sites of infection but without evidence of secondary areas of infection be treated for 14 to 21 days with

parenteral antimicrobial therapy." This advice appears inconsistent, yet there is no question that some patients who fit this description recover after brief courses of therapy despite the fact that the primary focus is not removed or drained (2) (experience at the U.N.M. Affiliated Hospitals). The question still remains, how long must we treat these patients? The trend in the recent staphylococcal antibody literature has been to correlate serologic findings with such clinical categories as "endocarditis," "metastatic abscess," and "uncomplicated bacteremia." If serologic tests are to become useful in the management of staphylococcal bacteremia, perhaps there should be greater emphasis on their correlation with the duration of successful antibiotic therapy. J O N A T H A N E. K A P L A N , M . D .

Bernalillo County Medical Center; Albuquerque, N M 87106 REFERENCES 1. W H E A T LJ, K O H L E R RB, W H I T E A: Solid-phase radioimmunoassay for

immunoglobulin G Staphylococcus aureus antibody in serious staphylococcal infection. Ann Intern Med 89:467-472, 1978 2. N O L A N CM, BEATTY H N : Staphylococcus aureus bacteremia. Current clinical patterns. Am J Med 60:495-500, 1976

In reply: Dr. Kaplan asks the question, how long must we treat patients with staphylococcal bacteremia and primary sites of infection that were not drained or removed promptly? The answer to that question is not known. Prospective studies comparing a short course of therapy with a long course of therapy are needed. Although the majority of our patients in this group received prolonged therapy, we cannot say that they would not have responded to short-course therapy. Three patients in this group were indeed cured by short-course therapy. Admitting that the optimal duration of therapy is not known, one should recognize that a positive antibody result might be caused by an undrained primary site (10 patients) or a primary site representing a chronic infection (two patients) rather than by the presence of endocarditis or secondary foci of infection. If endocarditis or secondary foci were not present clinically, one should look for an undrained primary site; the duration of therapy should be decided on an individual basis. Dr. Kaplan also suggests that studies should correlate the antibody result with the duration of successful therapy. Obviously, these questions cannot be resolved by retrospective studies. Prospective studies addressing both the duration of therapy and the role of tests for staphylococcal antibodies are in the planning stage. JOSEPH W H E A T , M.D.

Wishard Memorial Hospital, 1001 West 10th Street, OP317; Indianapolis, I N 46202

Valve Resection for Endocarditis T o THE EDITOR: The report by Chandraratna and colleagues (1) states that "surgical resection of a vegetation, without valve replacement, has not been previously reported.*' A s a medical intern I helped care for a patient with antibiotic-refractory Serratia marcescens endocarditis who was cured by debridement of vegetations without resection of her tricuspid valve. This case was reported by Alexander, Holloway, and Honsinger (2). Moreover, Parrott and colleagues (3) have reviewed the role of valve debridement without excision in a series of patients who required surgical management for bacterial endocarditis. Thus, earlier reports (2, 3), and now another (1), describe debridement of an infected, but functionally intact valve as a possible surgical procedure in patients with endocarditis who respond poorly to antimicrobial therapy. L. B A R T H R E L L E R , M . D .

University of Colorado Medical Center; Denver, CO 80262 REFERENCES 1. C H A N D R A R A T N A PAN, R E A G A N RB, IMAIZUMI T, L A N G E V I N E, E L Letters

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KINS RC: Infective endocarditis cured by resection of a tricuspid valve vegetation. Ann Intern Med 89:517-518, 1978 2. A L E X A N D E R R, HOLLOWAY A JR, HONSINGER RW JR: Surgical de-

bridement for resistant bacterial endocarditis: a case of antibiotic-refractory Serratia marcescens infection on the tricuspid valve cured by operative excision. JAMA 210:1757-1759, 1969 3. PARROTT JCW, HILL JD, KERTH WJ, GERBODE F: The surgical man-

agement of bacterial endocarditis: a review. Ann Surg 183:289-292, 1976

In comment: I thank Dr. Reller for pointing out the reference cited in his letter. I regret the oversight. P. A . N . C H A N D R A R A T N A , M . D .

Noninvasive Laboratory, Long Beach Veterans Administration Hospital; Long Beach, CA 90822

Intestinal Bypass and Zinc T o THE EDITOR: The recent observations of decreased zinc and copper levels in patients after intestinal bypass procedures in the absence of skin lesions seems, at first glance, to be an observation in search of a disease (1). However, the finding strengthens a suspicion that low zinc levels in these patients may add to the protein deficiency that develops in the postoperative period. Because zinc deficiency may alter the senses of taste and smell, it seems likely that, in some cases, dysosmia (perverted smell) and dysgeusia (perverted taste) may develop, leading to avoidance of certain foods with subsequent protein deficiency (2). Some patients whose postoperative jejunoileal bypass nutrition status was poor, with abnormal liver chemical tests but without skin lesions, complain of a constant unpleasant smell, especially for food. Consequently dietary intake may be quite limited. Zinc deficiency may be the cause. The article by Atkinson and associates (1) suggests that zinc deficiency may be a common finding in patients after intestinal bypass procedures and should be sought in those patients who have markedly decreased appetite, especially when associated with dysgeusia. Until more definitive studies are done to characterize the nature of this defect, zinc sulfate supplements should be considered in affected patients. The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the Department of Defense or the Department of the Air Force. GEORGE MEYER, M.D.

Department of Medicine, Uniformed Services School of Medicine; Bethesda, M D 20014

University

REFERENCES 1. ATKINSON RL, D A H M S WT, BRAY GA, JACOB R, SANDSTEAD HH:

Plasma zinc and copper in obesity and after intestinal bypass. Ann Intern Med 89:491-493, 1978 2. HENKIN RI, SCHECHTER PJ, HOYE R, MATTERN CFT: Idiopathic hypo-

geusia with dysgeusia, hyposmia, and dysosmia. JAMA 1971

217:434-440,

Hemolytic Transfusion Reaction

Aside from considerations of the effect of such a suggestion, I must still, based on the data in their case report, take issue with its justification. The titer of anti-A in the donor plasma they transfused was 1:8192, well above the 95% confidence limits for anti-A titers in group O sera. A s pointed out by Mollison (2), "95% of sera has anti-A titers in the range 32-2048 . . . the commonest anti-A titer was 256." It should be fairly clear, then, just how rare such a situation as described by Inwood and Zuliani must be. In addition, because in the worst-case analysis, which their patient represents, "the patient made an uneventful recovery," the potential for harm and a serious waste of a valuable resource is greater if one follows the suggestion to eschew any but group specific blood than it would be if one were to continue transfusing compatible units when the exigency of the situation so dictated. I suggest that the reportability of the patient of Inwood and Zuliani reminds us of the extreme rarity of an untoward reaction associated with the use of compatible erythrocytes and should serve to encourage, rather than discourage, the use of such blood. While no one could disagree with the principle of removing plasma from erythrocytes via a saline wash, the urgency of the clinical situation often precludes such a fastidious approach. It is critical in such a setting that the patient not suffer the consequences of a delay in transfusion while group O cells are washed, the donor blood tested for the presence of high-titer immune anti-A or anti-B, or—even worse—group specific blood insisted on. A R T H U R J. S I L V E R G L E I D , M . D .

Blood Bank of San Bernardino and Riverside Counties; Riverside, CA 92503 REFERENCES

1. INWOOD MJ, ZULIANI BA: Anti-A hemolytic transfusion with packed 0 cells. Ann Intern Med 89:515-516, 1978 2. MOLLISON PL: Blood Transfusion in Clinical Medicine, 4th ed. Philadelphia, J.B. Lippincott Company, 1967, p. 247

In comment: We thank Dr. Silvergleid for his comments regarding this unusual but very real complication of group O packed cell transfusion. The major reason for reporting this event was to emphasize again to clinicians that the use of group O packed cell transfusions to persons with group A, B, or A B blood is not without risk. In the case with which we were associated we were fortunate that the intravascular hemolysis of the recipient's cells did not cause major complications. However, if this person had been in hypovolemic shock, the subsequent clinical course would not have been so optimistic. The recognition that national and local shortages of homologous ABO blood can occur nevertheless does not mitigate the fact that non-ABO homologous transfusions constitute an added risk to the patient. We would still recommend that those blood banks who must use such practices would have group O blood available that had been pretested for high titre anti-A and anti-B antibodies. The donor of the offending unit finally has been located and was found to have participated in a plasmapheresis programme, where donors were stimulated for the production of ABO antibodies for subsequent reagent production. The donor neglected to inform the blood transfusion service that he was involved in such a process, and this explains the high anti-A titre. M A R T I N J. I N W O O D , M . D .

T o THE EDITOR: The recent case report by In wood and Zuliani (1) represents an interesting, and obviously quite rare, occurrence that apparently has prompted the authors to make a misleading, and potentially dangerous, suggestion. On the basis of mild intravascular hemolysis that developed in their patient as a result of the transfusion with extremely high-titered anti-A present in the residual plasma accompanying a unit of group O erythrocytes they suggest "that if this complication is to be avoided, the clinician must rigidly accept the principle that only ABO homologous blood should be transfused to patients." Considering the nationwide chronic shortage of blood products and the often more acute local shortages, following this suggestion would dangerously impede, if not reverse, our efforts to educate physicians in the use of compatible blood in situations where group specific blood is not available. 2 7 8

Department of Blood Transfusion, St. Joseph's Hospital, The University of Western Ontario; London, Ontario, Canada B R U C E H.

Lymph Node Biopsy in Thrombotic Thrombocytopenic Purpura T o THE EDITOR: In the article by Goodman and colleagues (1) on the use of gingival biopsy in the diagnosis of thrombotic thrombocytopenic purpura, the authors mention the use of

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ZULIANI

Canadian Red Cross Blood Transfusion Service; London, Ontario, Canada

lymph node biopsy in passing but make no further reference. The article by Amorosi and Ultmann (2) references five reports in which lymph node biopsy was used in making the diagnosis of thrombotic thrombocytopenic purpura during life. Four of the five cases had positive lymph node biopsies. Although this is a small sampling, it does represent a positive biopsy rate of 80%. In addition to a positive lymph node biopsy during life in one of the above cases, 15 postmortem lymph nodes, all grossly normal, were positive for the typical thrombotic lesion (3). The frequent involvement by thrombotic thrombocytopenic purpura in lymph nodes at autopsy has been previously reported (4) and, in fact, probably prompted the first use of antemortem lymph node biopsy for diagnosis in this syndrome (5). Lymph node biopsy during life for the diagnosis of thrombotic thrombocytopenic purpura appears to be useful and possibly has a greater yield than gingival biopsy. Did the authors examine lymph nodes in their 16 patients? If so, we would be interested in their findings. The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of Defense or of the Department of the Navy. W I L L I A M M. M I L L E R , M . D . S A N F O R D A. STASS, M . D . H A R O L D R. SCHUMACHER, M . D .

Division of Hematopathology, Department of Laboratory Medicine, National Naval Medical Center; Bethesda, M D 20014 REFERENCES 1. GOODMAN A, RAMOS R, PETRELLI M, HIRSCH SA, BUKOWSKI R, H A R -

RIS JW: Gingival biopsy in thrombotic thrombocytopenic purpura. Ann Intern Med 89:501-504, 1978 2. AMOROSI EL, U L T M A N N JE: Thrombotic thrombocytopenic purpura:

report of 16 cases and review of the literature. Medicine (Baltimore) 45:139-159, 1966 3. SHARNOFF JG: Thrombotic thrombocytopenic purpura. Am J Med 23:740-747, 1957 4. ADELSON E, HEITZMAN EJ, FENNESSEY JF: Thrombohemolytic throm-

bocytopenic purpura. Arch Intern Med 94:42-60, 1954 5. MOREY DAJ, W H I T E JB, D A I L Y WM: Thrombotic thrombocytopenic

purpura diagnosed by random lymph node biopsy. Arch Intern Med 98:821-823, 1956

In reply: In response to the question of Drs. Miller, Stass, and Schumacher, we did not do lymph node biopsies on any of our 16 patients with thrombotic thrombocytopenic purpura. In two instances in which autopsy results were available, thrombotic lesions were reported in sectioned lymph nodes (although the number of nodes examined is not known exactly to us). Overall frequency of lymph node involvement in thrombotic thrombocytopenic purpura is often expressed in qualitative terms, which may reach opposite conclusions (1, 2): The 1954 article (1) cited by Drs. Miller, Stass, and Schumacher reviewed clinical manifestations in 52 cases and states that "The organs most extensively affected are the heart, brain, adrenal cortex, lymph nodes, kidney, liver, and spleen." N o exact figures for individual tissue involvement are given, however. In contrast is the review of Symmers (2), who surveyed 85 published and 30 unpublished cases of thrombotic thrombocytopenic purpura, concluding that "the blood-vessels in lymph-nodes and tonsils may be heavily involved but this seems to be quite unusual." Once again, however, exact numbers of specimens reviewed are not available. The case reports of positive antemortem lymph node biopsy cited by Amorosi and Ultmann (3) were single case reports only. To the best of my knowledge, no subsequent reports of consecutive pre- or postmortem lymph node examinations in thrombotic thrombocytopenic purpura have been published. In addition, lymphadenopathy is uncommon in thrombotic thrombocytopenic purpura (2) and, therefore, the selection of which node(s) to biopsy becomes arbitrary. Furthermore, lymph node biopsy is not a bedside procedure (as both gingival and bone marrow biopsies may be) and can be technically difficult in a patient with a bleeding diathesis.

For these reasons, we believe that gingival biopsy and, possibly, bilateral bone marrow biopsies should have priority in the efforts made to obtain antemortem histologic confirmation of the diagnosis of thrombotic thrombocytopenic purpura. A N I T A GOODMAN, M.D.

Cleveland 44109

Metropolitan

General

Hospital; Cleveland, OH

REFERENCES 1. ADELSON E, HEITZMAN EJ, FENNESSEY JF: Thrombohemolytic throm-

bocytopenic purpura. Arch Intern Med 94:42-60, 1954 2. SYMMERS W S T C: Thrombotic microangiopathy: histologic diagnosis during life. Lancet 1:592-596, 1956 3. AMOROSI EL, U L T M A N N JE: Thrombotic thrombocytopenic purpura:

report of 16 cases and review of the literature. Medicine 45:139-159, 1966

(Baltimore)

Pericardial Echocardiography T o THE EDITOR: I wish to make the following comments on the published echocardiogram (Figure 1A) in the brief report of Orlando, Moyer, and Barnett (1). They state that "Pericardiocentesis was attempted because of her compromised state. N o pericardial fluid was obtained, and thoracotomy was done. At thoracotomy the pericardium was thickened with dense fibrotic tissue occupying the space between it and epicardium." How do the authors explain absence of thickening in the epicardium and pericardium shown in Figure 1A after damping? To exclude a false positive effusion (2), was a scan obtained from the left ventricle to the left atrium? The marked epicardial and pericardial echoes are about 20 mm apart posteriorly. Were the adhesions 2 cm thick? The anterior echo-free space measures about 10 mm. Were the adhesions 10 mm thick anteriorly at thoracotomy? This wide separation between epicardium and pericardium shown in Figure 1A would roughly indicate about 1009 ml of pericardial fluid (3). (The distances between the anterior and posterior epicardium and pericardium are 11.5 cm and 8.0 cm, respectively.) When such large effusions are possible, but the posterior leaflet of mitral valve is not seen in the echocardiogram (Figure 1A), a false-positive effusion due to the medial angulation of the transducer becomes a strong possibility. The posterior left ventricular wall is too close to the mitral valve and further supports the above possibility. RAVI PRAKASH, M.D.

California College of Medicine, University of California Irvine Medical Center; Orange, C A 92668 REFERENCES 1. ORLANDO RC, MOYER P, BARNETT TB: Methysergide therapy and con-

strictive pericarditis. Ann Intern Med 88:213-214, 1978 2. PRAKASH R, KING J, ARONOW WS: Enlarged left atrium causing possible false positive echocardiography diagnosis of pericardial effusion. Angiology 27:219-222, 1976 3. PRAKASH R, MOORTHY K, D E L VICARIO M, A R O N O W WS: Reliability

of echocardiography in quantitating pericardial effusion: a prospective study. J Clin Ultrasound 5:398-403, 1977

In reply: The published echocardiogram in our report demonstrates the presence of an echo-free space between the epicardium and pericardium after damping. This finding coupled with a scan from left ventricle to left atrium showing disappearance of the echo-free space was consistent with the diagnosis of pericardial effusion. At thoracotomy, no pericardial effusion was found, but instead dense fibrosis between pericardium and epicardium was noted. Because no detailed measurements of this fibrosis were made at surgery, precise correlation with echocardiographic measurements could not be done. However, thoracotomy by demonstrating dense fibrosis between epicardium and pericardium was definitive in documenting that the echofree space was not a technical artifact due to medial angulation of the transducer. Other investigators have documented that an Letters

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abnormal echocardiogram consistent with effusion can result from fibrosis or tumor (1).

REFERENCES 1. BIRD TD, TURNER JL, SUMI SM, BIERMAN EL: Abnormal function of

R O Y C. O R L A N D O , M . D .

University of North Carolina School of Medicine; Chapel Hill, N C 27514 REFERENCE

1. MlLLMAN A, MELLER J, MOTRO M, BLANK HS, HOROWITZ I, HERMAN MV, TEICHHOLZ LE: Pericardial tumor or fibrosis mimicking pericardial effusion by echocardiography. Ann Intern Med 86:434-436, 1977

2.

3. 4.

5.

Endocrinopathy and Spastic Paraplegia T o THE EDITOR: I read with interest "Abnormal Function of Endocrine Pancreas and Anterior Pituitary in Friedreich's Ataxia'* (1). The neurodegenerative system disorders are occasionally accompanied by endocrinopathies (2, 3), but the participation of hypothalamus had not been established clearly. Recently, we studied another example of the association of motor disturbance and endocrinopathies. Our patients were three siblings 30, 28, and 25 years old with dwarfism, hypogonadism, spastic paraplegia, atypical retinal degeneration, and mental retardation. They were not obese and had no digital anomaly. These physical abnormalities are consistent with the Laurence-Moon syndrome (4) or Laurence-Moon-Hutchinson syndrome (5). The sella turcica was small in each case, and endocrinologic examinations showed impaired production of growth hormone, thyroid-stimulating hormone, and gonadotropins. Repeated administrations of thyrotropin-releasing hormone and luteinizing hormone-releasing hormone resulted in lower levels of thyrotropin-releasing hormone test and luteinizing hormone-releasing hormone test. This syndrome seems to be the association of the familial small sella turcica (6) and the spinocerebellar atrophy with pigmentary retinopathy. When we see the patient with motor disturbance and endocrinopathy, we are apt to think of the participation of hypothalamus, but our case study shows that the presence of hypothalamic lesion is not inevitable. FUMITOSHI SHIOMI, M.D. Department of Medicine, KOchi-kenritsu Central Hospital; KOchi-city, Japan

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6.

Skin Color as a Clinical Datum T o THE EDITOR: Mansbach and colleagues (1) in a brief report mention the patient's skin color twice within two paragraphs but give little other sociologic, economic, or genetic information. Skin color as a designation of race is an arbitrary sociologic classification and rarely, if ever, adds to our diagnostic, pathogenic, or therapeutic knowledge. Some journals now remove references to race in articles to be published, except of course, where race has, or may have, implications for the acquisition, course, or treatment of a disease. Our knowledge of a patient's history would be better served if his race, when pertinent, were mentioned only once and relegated to the social history in the case presentation. H E N R Y ROTHSCHILD, M . D . , P H . D . F R E D M. H U N T E R , M . D . L o u i s i a n a State U n i v e r s i t y M e d i c a l Center; N e w O r l e a n s , L A 70112

REFERENCE 1. MANSBACH CM II, SHELBURNE JD, STEVENS RD, DOBBINS WO III:

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endocrine pancreas and anterior pituitary in Friedreich's ataxia. Studies in a family. Ann Intern Med 88:478-481, 1978 LAURENCE JZ, MOON RC: Four cases of "retinitis pigmentosa" occurring in the same family, and accompanied by general imperfections of development. Ophthalmol Rev 2:32-41, 1966 KAPUSCINSKI W: Ueber familiare Adelhautentartung mit ataktischen Storungen. Ber Dtsch Ophthalmol Ges 50:13-19, 1934 MCKUSICK VA: Mendelian Inheritance in Man. Catalogs of Autosomal Dominant, Autosomal Recessive, and X-Linked Phenotypes. Baltimore and London, the Johns Hopkins University Press, 1975 FRANCESCHETTI A, KLEIN D: Les manifestations tapetoretiniennes et leur importance clinique et genetique. Rev Otoneuroophtalmol 20:109128, 1948 FERRIER PE, STONE EF JR: Familial pituitary dwarfism. Pediatrics 43:858-865, 1969

Lymph-node bacilliform bodies resembling those of Whipple's disease in a patient without intestinal involvement. Ann Intern Med 89:64-66, 1978