Comments submitted for publication must be typed doublespaced, and text length must not exceed 500 words. 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. Lupus Erythematosus and Brain Scanning TO THE EDITOR: We were concerned to read the paper in the December 1974 issue on the interpretation of a positive brain scan in patients with systemic lupus erythematosus and localising neurologic signs ( 1 ) . While not disputing that the patients described may have had cerebral vasculitis, we believe that opportunistic infection of the central nervous system is an equally likely cause of this clinical feature when such patients are receiving immunosuppressive therapy. This is exemplified by three cases, (two with cerebral toxoplasmosis, one with brain abscesses due to nocardial infection) described below and shown in Figure 1. We believe that delay in diagnosis of infection may result from the belief that cerebral lupus is by far the most likely cause of an abnormal brain scan in a patient with systemic lupus erythematosus and neurologic deficits. We fear that the paper referred to above may strengthen that belief. We propose that if the patient is clearly immunosuppressed and the disease well controlled clinically, serologically, and on spinal fluid testing, then exclusion of infection must be carried out urgently. Depression of cellmediated immune function should particularly be noted, as the great majority of the ubiquitous opportunistic organisms require cell-mediated immunity for their eradication. If the presence of cerebral infection is determined, the need for withdrawal of all immunosuppressive therapy contrasts strongly with the treatment for cerebral vasculitis. In a subsequent letter ( 2 ) , the need to consider cerebral lymphoma was pointed out. Although this extremely rare complication must be kept in mind, its diagnosis does not require the urgency inherent in the therapeutic dilemma of infection versus vasculitis. A 13-year-old girl with biopsy-proved lupus nephritis in 1970 was treated for 2 years with prednisone, 15 to 30 mg, on alternate days plus azathioprine, 50 to 100 mg/day. Despite this, the disease process remained active. Azathioprine was therefore replaced with chlorambucil, 4 mg/day, which resulted in dramatic improvement in laboratory indices. 18 months later she was admitted to hospital with severe frontal headache and vomiting. A brain scan showed a midline area of increased uptake anteriorly that involved both frontal lobes. A presumptive diagnosis of cerebral lupus was made and dosage of immunosuppressive agents increased. Despite this, she continued to deteriorate and died a month after admission. At autopsy, necrotic lesions containing Toxoplasma gondii were found in both cerebral hemispheres, the thalamus on the right, and the cerebellum.

Figure 1A. Case 1: technetium-99 pertechnetate brain scan, anterior view showing a midline area of increased uptake extending into both hemispheres. Lateral view showed its anterior position in the frontal lobe region. B. Case 2: anterior view of scan showing abnormal activity inferiorly on the right side. Right lateral view confirmed its presence in the temporal lobe region. C. Case 3: right lateral scan showing large area of increased uptake in the parietal lobe region. D. Case 3: anterior view of skull X ray after aspiration of abscess cavities and instillation of steri-paque contrast medium.

A 25-year-old woman with systemic lupus erythematosus was treated for 5 years with prednisone, azathioprine, and plaquenil In 1974 she was admitted with a 4-day history of drowsiness and right-sided hemiparesis. Apart from an antinuclear factor titre of 1:100, there was no serologic or spinal fluid evidence of disease activity. A lesion in the right temporal region was seen on brain scan that was considered to be consistent with cerebral lupus, and the dose of prednisone was increased. Although a brain biopsy was done, no organisms were identified, and, despite the addition of ampicillin, she died a few days later. Autopsy examination showed extensive cerebritis containing Toxoplasma gondii. A 31-year-old man presented in 1969 with severe skin, joint, and pleural manifestations of lupus erythematosus. Prednisone and azathioprine were required for adequate control of clinical and laboratory indices of disease activity. After development of nephritis in 1973, azathioprine was replaced by chlorambucil. In July 1974 he presented with widespread herpes zoster, followed by grand mal fits. Brain scan showed an abnormality in the right parietal region, which was shown on aspiration to be two abscesses due to Nocardia asteroides. Despite intensive antibiotic therapy and repeated drainage, coupled with reduction in dosage of immunosuppressive agents, he died 3 months later. GRAEME STEWART, M.B., M.R.A.C.P. ANTONY BASTEN, M.B., M.R.C.P.

Department of Clinical Immunology Royal Prince Alfred Hospital Camperdonn, N.S.W. 2050, Australia REFERENCES

1. BENNAHUM DA, MESSNER RP, SHOOP JD: Brain scanfindingsin

central nervous system involvement by lupus erythematosus. Ann Comments and Correction

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Intern Med 81:763-765, 1974 2. KRAAG G, RICHARDS AJ, GORDON DA: Brain scanning in lupus erythematosus. Ann Intern Med 82:594, 1975

Alternate-Day Steroid Therapy TO THE EDITOR: The study of Hunder and colleagues (Ann Intern Med 82:613-618, 1975) showed daily administration of corticosteroids to be superior to an alternate-day regimen in the initial management of giant cell arteritis. However, it may be premature to totally discard the concept of alternate-day steroid therapy in this disease, for two reasons. First, some patients in the alternate-day nonresponder group apparently derived significant benefit on the days that they received steroids, since "typically, the patients receiving alternate-day therapy who did not respond completely felt reasonably well during some portion of the day on which 90 mg of prednisone was given. . . ." Seybold and Drachman (1) noticed an increase in weakness on the "off" day in patients with myasthenia gravis treated with alternate-day prednisone, who responded to a dose of 5 to 10 mg on that day. This included "several patients in whom the alteration was marked." While 4 of their 12 patients did develop side effects, it was not necessary to withdraw the steroids in any case. It is possible that a small dose (5 to 10 mg) of prednisone on the "off" day might reduce the loss of control and enable eventual suppression in patients with giant cell arteritis without an increase in side effects. Second, it has been shown that relapse can occur in this disease either during rapid decrease or after withdrawal of steroids, even after 2 years of treatment ( 2 ) . Consequently, treatment with 7.5 to 12.5 mg daily for at least 2 years has been recommended ( 2 ) . Perhaps, alternate-day steroids, even if not effective in obtaining initial suppression of this disease, might prove to be as effective a means of preventing relapses as prolonged daily therapy without its attendant risks. Therefore, one might consider switching patients to an alternate-day regimen after the disease has been controlled and then reducing their doses during the 2 years. This would not seem unreasonable, since the authors did not present evidence that any patient actually deteriorated on alternate-day treatment. JEFFREY T. KESSLER, M.D.

Department of Neurosciences College of Medicine and Dentistry of New Jersey New Jersey Medical School Newark, New Jersey 07103 REFERENCES 1. SEYBOLD ME, DRACHMAN DB: Gradually increasing doses of prednisone in myasthenia gravis. N Engl J Med 290:81-84, 1974 2. FAUCHALD P, RYGVOLD O, 0YSTESE B: Temporal arteritis and polymyalgia rheumatica. Clinical and biopsy findings. Ann Intern Med 77:845-852, 1972

In comment: Our study, referred to by Dr. Kessler, showed rather clearly that at commonly used corticosteroid doses, alternate-day therapy cannot be relied on to control the inflammatory process associated with giant cell arteritis. But it did not answer the specific question raised by him. 734

We have tried both methods that he has suggested with several patients who had giant cell arteritis and have not found them to be generally helpful. However, the questions posed would be answered most convincingly by additional carefully controlled observations. Regarding his first suggestion, it is not fair to compare myasthenia gravis to giant cell arteritis. Besides being vastly different diseases, the aims of treatment are different. In myasthenia gravis, the aim is to control reversible symptoms, while in giant cell arteritis the major aim is to prevent arterial occlusions or ruptures, which usually cause irreversible tissue damage. Treatment of giant cell arteritis is made more difficult by the fact that these vascular complications do not always develop when the patient's symptoms are worst. But the complications seem to be prevented by suppressing the inflammatory process, as reflected best by an elevation of the erythrocyte sedimentation rate and alpha 2 globulins. These factors should be kept in mind when considering criteria for therapeutic effectiveness of a drug regimen and the risks of investigating the regimen. Even though none of our patients on alternate-day drug therapy seemed to have suffered permanent vascular complications due to inadequate control of the disease, one had transient blindness and another developed inflammation and dilation of a carotid artery. Regarding the second question, we found no evidence to suggest that alternate-day therapy was more effective in milder cases of giant cell arteritis, and several patients "late" in the course of the disease were switched to daily corticosteroid treatment at equivalent total doses to control more successfully musculoskeletal symptoms. Although our experience might sound somewhat discouraging, we urge Dr. Kessler to carefully pursue his questions further in order to more fully define the advantages and limitations of alternate-day therapy. G E N E G. HUNDER, SHELDON G. SHEPS, GEORGE L. ALLEN, JOHN W. JOYCE,

Mayo Clinic Rochester, Minnesota Steroid Therapy in Goodpasture's Syndrome TO THE EDITOR: The recent paper by de Torrente and associates ("Serious Pulmonary Hemorrhage, Glomerulonephritis, and Massive Steroid Therapy," Ann Intern Med 83:218-219, 1975) indicates that massive steroid therapy may provide an alternative to bilateral nephrectomy as therapy for life-threatening pulmonary hemorrhage in patients with Goodpasture's syndrome. We wish to report a second case of lung hemorrhage in Goodpasture's syndrome successfully treated with massive steroid therapy. A 32-year-old Eskimo woman was admitted to the hospital because of cough, hemoptysis, and progressive shortness of breath of 5 days' duration. She gave a history of right upper lobectomy for therapy of tuberculosis 13 years before admission. One year before admission, therapy with isoniazide and ethambutol was started because of radiographic recurrence of her tuberculosis. She had remained asymptomatic with a normal exercise tolerance until the onset of the acute illness 5 days before hospitalization. Her hematocrit was 21% and her prothrombin time, partial thromboplastin time, and platelet count were within normal limits. Urinalysis was recorded as within normal limits. Chest

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M.D. M.D. M.D. M.D.

X ray showed an alveolar infiltrate involving the entire left lung and the right lower lung. Sputum stains were negative for acid-fast bacilli. Because of the large quantity of pulmonary hemorrhage, a pulmonary angiogram was done in an attempt to localize a bleeding site. None was found. During the first 36 hours pulmonary hemorrhage continued, and her arterial Po2 decreased to 37 mm Hg, despite intubation and positive end-expiratory pressure using 80% inspired oxygen. A repeat urinalysis showed a profusion of erythrocyte casts and coarse granular casts with 4+ protein. An open renal biopsy was done under local anesthesia. A proliferative glomerulonephritis with focal capillary tuft necrosis was seen by light microscopy. Crescents were present on 18 of 26 glomeruli examined. Immunofluorescent microscopy showed a linear pattern of immunoglobulin G with a broken pattern for the third component of complement. Heavy fibrin deposition was noted in the crescents and locally in several glomerular tufts. On the basis of clinical and pathologic data, a diagnosis of Goodpasture's syndrome was made. At the time of renal biopsy, the patient's creatinine clearance was approximately 75 ml/min. Despite this, bilateral nephrectomy was considered as a possible means to treat her lifethreatening pulmonary hemorrhage. On the basis of anecdotal data, methyl prednisolone was begun with a dose of 1 g every 8 hours in an attempt to ameliorate her pulmonary hemorrhage. Other medications included the antituberculous drugs: streptomycin, isoniazide, and rifampin. Within 24 hours of beginning methyl prednisolone, the patient's pulmonary hemorrhage ceased and did not recur. Artificial respiration with positive end-expiratory pressure was necessary for the next 5 days, and her respiratory function slowly improved. During this time her methyl prednisolone dose was tapered and replaced with oral prednisone in a dose of 80 mg/day. Her creatinine clearance stabilized at 60 ml/ min until discharge on her 15th hospital day. Serum samples assayed for the presence of antiglomerular basement membrane antibodies by Dr. Curtis Wilson (Scripps Clinic and Research Foundation) were negative on the first, third, and seventh hospital day. Since discharge, the patient has been seen in the outpatient department, and her steroid dose has been tapered to 60 mg orally every other day. Her glomerular filtration rate has remained stable at 60 to 70 ml/min, although her urinary sediment remains abnormal, showing many granular casts, and she loses 3 to 5 g of protein in urine per day. Her chest film is clear except for the evidence of previous tuberculosis. As in the case reported by de Torrente and colleagues, this patient had only mild renal impairment, but lifethreatening pulmonary hemorrhage that ceased within 24 hours of starting massive steroid therapy. In case reports of this type one cannot be certain of the effect of a given therapeutic maneuver. Yet this case provides the second instance where massive steroid therapy seemed to provide a successful alternative to bilateral nephrectomy, which was being considered. It is reasonable to consider this form of therapy in future Goodpasture's syndrome patients who present with life-threatening pulmonary hemorrhage and relatively intact renal function. ROBERT KOPELMAN, M.D. PHILLIP H O F F S T E N , M.D. SAULO KLAHR, M.D., F.A.C.P.

Department of Medicine Renal Division Washington University School of Medicine St. Louis, Missouri 63110

Asbestos Pleural Effusion? TO THE EDITOR: I read with interest the paper by Galen

and associates (1) on hemorrhagic pleural effusion in patients undergoing chronic hemodialysis. When pleural effusion is found in a uremic case, one must rule out other causes. My main interest was in the patient who initially, before the administration of heparin, had a clear yellow pleural fluid, a chest X ray confirming the effusion, and "bilateral pleural thickening with pleural calcification on the right." My inquiry is whether this was a benign persistent pleural effusion associated with asbestosis. Pleural plaques and calcifications from asbestos exposure may occur without parenchymal asbestosis. As in this patient, asbestos pleural effusion is a sterile exudate, usually bilateral, and may be clear fluid or blood tinged ( 2 ) . The exposure to asbestos dust could have been urban or occupational. Recent unpublished data have shown that a good occupational history is not often obtained, and 3.3 histories are taken before past exposure to asbestos is discovered ( 3 ) . FAYSAL M. HASAN, M.D.

Department of Medicine American University Hospital Beirut, Lebanon REFERENCES

1. GALEN MA, STEINBERG SM, LOWRIE EG, et al: Hemorrhagic

pleural effusion in patients undergoing chronic hemodialysis. Ann Intern Med 82:359-361, 1975 2. GAENSLER EA, KAPLAN Al: Asbestos pleural effusion. Ann Intern Med 74:178-191, 1971 3. HASAN FM, NASH G, KAZEMI H: Epidemiological significance of

asbestos-induced and non-asbestos-induced mesothelioma. Unpublished In comment: Doctor Hasan has raised an interesting point. While parenchymal disease was absent and we were unable to elicit an occupational history, we, of course, cannot state with certainty that the patient did not in fact have asbestosis. She worked as a bookkeeper her entire life and did a substantial fraction of her work within her own home. She had eight admissions to this hospital and related between two and three histories with each. N o history of asbestos exposure is recorded in the chart. Unfortunately, the patient has died and postmortem examination was denied by the family. Even if, in fact, the effusion were benign and due to some cause such as asbestosis, its conversion from nonhemorrhagic to hemorrhagic is well documented. One could conclude, then, that an otherwise benign effusion may add to the risks of hemodialysis therapy by mechanisms reviewed in the discussion in the paper. EDMUND G. LOWRIE, M.D.

Department of Medicine Peter Bent Brigham Hospital Boston, Massachusetts

Fluphenazine and Inappropriate Secretion of Antidiuretic Hormone TO THE EDITOR: A recent case of inappropriate secretion of antidiuretic hormone ( A D H ) secondary to the use of fluphenazine was reported in the June issue. The patient that was reported suffered two convulsive seizures ( 1 ) . Comments and Correction

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Although we have observed a case of inappropriate ADH secretion in one of our patients treated with fluphenazine ( 2 ) , convulsive seizures can in themselves produce the syndrome "by virtue of an irritable focus that promotes the secretion of the hormone" (3-5). The case reported by Dr. de Rivera does not provide sufficient causeeffect relationship between the use of fluphenazine and inappropriate ADH secretion, particularly when an already proved causative factor of the syndrome is present. JORGE S. ZUNIGA, M.D. TOBY HAZAN, M.D.

Crises Intervention Center Department of Psychiatry Sinai Hospital of Detroit 6767 West Outer Drive Detroit, Michigan 48235

observation of a temporal association, with exclusion beyond reasonable doubt of well-known causes of the syndrome, including intracranial lesions. There is, however, a wide array of obscure conditions that may produce this syndrome, including exacerbated psychosis ( 3 ) . My case report is only suggestive of a possible relationship between fluphenazine (and perhaps other phenothiazines) and inappropriate secretion of ADH, a relationship that awaits further elucidation. This may come from Drs. Zuniga and Hazan, if they report their case; it would be particularly interesting if they have been able to study the fluid-electrolyte metabolism of their patient, with and without medication. J. L. G. DE RIVERA, M.D.

Psychiatric Consultation Service Montreal General Hospital Montreal, PQ H3A 1A1, Canada


1. DE RIVERA JLG: Inappropriate secretion of antidiuretic hormone from fluphenazine therapy. Ann Intern Med 82:811-812, 1975


3. DILLON RS: Handbook of Endocrinology. Philadelphia, Lea and Febiger, 1973, pp. 201-202

1. WELT LG: Disorders of fluids and electrolytes, in Harrison's Principles of Internal Medicine, 7th ed., edited by WINTROBE MM et al. New York, McGraw Hill, 1974, p. 1347 2. ADAMS R: The convulsive state. See Reference 1, p. 135

4. WELT LG, DINGMAN J, THORN G: in Harrison's Principles of

3. DUBOVSKY SL, GRABON S, BERL T, et al: Syndrome of inappro-

2. SHAW R, LQRETTI L: Unpublished

Internal Medicine, 7th ed., edited by WINTROBE MM et al. New York, McGraw Hill, 1974, chapters 84 and 264 5. SCHWARTZ WB: in Cecil-Loeb Textbook of Medicine, 14th ed.,

priate secretion of antidiuretic hormone with exacerbated psychosis. Ann Intern Med 79:551-554, 1973

edited by BEESON PB, MCDERMOTT W. Philadelphia, W. B.

Saunders, 1975, p. 1582

In comment: After my report on inappropriate secretion of antidiuretic hormone ( A D H ) from fluphenazine therapy, Drs. Zuniga and Hazan mention having observed a second case, possibly similar. It would be of interest to know more details about their case, unreported until now. They comment that "convulsive seizures can in themselves produce the syndrome [of inappropriate secretion of ADH]." Although this may possibly happen, there are no pertinent data in the literature to support their statement. There is, however, strong evidence on the opposite relationship, namely, that the syndrome of inappropriate secretion of ADH may produce, through hyponatremia, convulsive seizures ( 1 ) . The authors quoted by Drs. Zuniga and Hazan do not refer to convulsions as causative of inappropriate A D H secretion but to intracranial lesions (infection, trauma, or tumor), which, independently of their ability to induce seizures, may produce inappropriate secretion of A D H "by partial destruction of the posterior [lobe] of the pituitary gland, with escape of hormone; or by virtue of an irritative focus that promotes the secretion of the hormone" ( 1 ) . There was no evidence in my reported case of any such intracranial lesion. Brain scan, skull X ray, and spinal examination were normal; the electroencephalogram showed nonspecific abnormalities, compatible with the metabolic state, not indicative of intracranial lesion and certainly not of "irritative focus." There was no neurologic abnormality after recovery from the acute episode. However, there was strong evidence of water intoxication and hyponatremia, conditions known to be occasionally complicated by generalized motor seizures ( 2 ) , as was the case in our patient. I agree that the evidence of a cause-effect relationship between fluphenazine and the syndrome of inappropriate secretion of A D H is merely circumstantial, based on an 736

The report by Dr. de Rivera on the possible association between fluphenazine therapy and the syndrome of inappropriate secretion of antidiuretic hormone is an important observation and adds a further cause of this syndrome to the list applying to psychiatric patients. This list now includes schizophrenia itself ( 1 ) , thiothixene ( 2 ) , amitriptyline ( 3 ) , promethazine ( 4 ) , carbamazepine ( 5 ) , emotional stress, pain, nicotine, barbiturates, morphine, chronic alcoholism, hypofunction of the adrenal, thyroid, and pituitary glands, acute intermittent porphyria, many tumors, and miscellaneous nervous system and thoracic disorders ( 6 ) . The syndrome may be mimicked by psychogenic polydipsia, by syndromes where A D H secretion is appropriate (for example, heart failure and liver disease), by renal impairment (which can be intrinsic or due to diuretic therapy or metabolic disorders), and by a wide range of other medications (for example, sulphonylureas, acetaminophen, clofibrate, and antineoplastic and antihypertensive drugs [7]). Two important considerations derive from this ever expanding list. First, reports that incriminate factors associated with this syndrome should be as completely documented as possible, since one must make the difficult positive diagnosis of the syndrome and identify the agent responsible by methodically excluding all other known possibilities. In this regard the report incriminating fluphenazine warrants further investigation. If fluphenazine had been responsible for the hypoosmolality, one would expect osmolality to have fallen again when water restriction was stopped 8 days before the end of the pharmacologic action of fluphenazine, which continues for 14 days after parenteral administration. Second, since the manifestations of hypoosmolality syndrome are protean, there may be a place for more frequent measurement of serum osmolality (or sodium concentration) in neuropsychiatric patients.

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P. J. PHILLIPS, M.B., B.S., M.A. ( O X O N ) , M.R.A.CP R W. PAIN, M.B., B.S., F.R.C.P.A.

Division of Clinical Chemistry, Institute of Medical and Veterinary Science Frome Road Adelaide, South Australia 5000 r Australia REFERENCES 1. HOBSON J A, ENGLISH JT: Self-induced water intoxication. Ann

Intern Med 58:324-332, 1963 2. AJLOUNI K, KERN MW, TURES JF, et al: Thiothixene-induced

hyponatremia. Arch lnterm Med 134:1103-1105, 1974 3. LUZECKY MH, BURMAN KD, SCHULTZ ER: The syndrome of in-

appropriate secretion of antidiuretic hormone associated with amitriptyline administration. South Med J 67:495-497, 1974 4. DYBALL REJ: The effect of drugs on the release of vasopressin. Br J Pharmacol Chemother 33:329-341, 1968 5. KIMURA T, MATSUI K, SATO T, et al: Mechanism of carbamaz-

epine (Tegretol) induced antidiuresis: evidence for release of antidiuretic hormone and impaired excretion of a water load. J Clin Endocrinol Metab 38:356-362, 1974 6. MAXWELL MH, KLEEMAN CR: Clinical Disorders of Fluid and

Electrolyte Metabolism, 2nd ed., New York, McGraw Hill, 1972, chapter 7 7. SCHRIER RW, BERL T: Non-osmolar factors affecting water excretion. N Engl J Med 292:141-145, 1975

paper "Laxative-Induced Hypokalemia, Sodium Depletion and Hyperreninemia" in the July "Annals." We agree that a shift of intracellular sodium to the extra cellular space could have occurred when potassium depletion was specifically corrected. This shift, however, may not occur in the sodium-deprived subject, as suggested by Cannon, Frazier, and Hughes (1) on the basis of histologic data but without the intracellular and extracellular electrolyte determinations to confirm it. In the experimental human studies of potassium depletion and repletion effects on plasma renin ( 2 ) , no direct measurements of plasma volume were recorded, and unfortunately none are available in our patient. Bull and coworkers ( 3 ) , in studies of potassium repletion after diureticinduced hypokalemia in sodium deprived subjects, noted no change in blood volume and a slight increase in plasma volume, but they did not find any significant alteration in plasma renin activity. Thus, Dr. Butkus' suggestion can only be tested in future cases similarly studied with the addition of appropriate fluid volume measurements.

Renin Suppression


TO THE EDITOR: The paper by Fleming and associates in the July issue (Ann Intern Med 83:60-62, 1975) understates the possible role of volume repletion in contributing to the suppression of serum renin levels noted during the early period of potassium repletion in their patient (Figures 1 and 2, p. 61). During the initial period of potassium repletion, although external sodium balance was maintained, a positive balance of over 300 meq of potassium was attained with an increase in body weight of 1 kg. Potassium depleted states are accompanied by a reciprocal increase in intracellular sodium (1-3). Repletion of the potassium deficit results in a decrease in intracellular sodium with a shift of sodium to the extracellular space. In the patient described by the authors, although external sodium balance was maintained, it is likely that internal shifts of sodium as a result of potassium repletion resulted in at least mild extracellular fluid volume expansion, which could, in part, explain the observed reduction in serum renin. That volume expansion was only partial (as documented later in their report) would explain the continued exaggerated response of serum renin to upright posture. Concomitant measurements of plasma volume might have served to distinguish between the direct effect of potassium repletion and the indirect effect of internal sodium shifts on the observed reduction in serum renin level in this interesting report. DONALD E. BUTKUS, M.D., LTC, MC

Nephrology Service Fitzsimons Army Medical Center Denver, Colorado 80240 REFERENCES 1. COTLOVE E, HOLLIDAY MA, SCHWARTZ R, et al: Effects of elec-

trolyte depletion and acid-base disturbance on muscle cations. Am J Physiol 167:665-675, 1951 2. LEAF A, SANTOS RF: Physiologic mechanisms in potassium deficiency. N Engl J Med 264:335-341, 1961 3. FLEAR CTG, FLORENCE T: Muscle biopsy in man: an index of

cellular potassium? Nature (Lond) 199:156-158, 1963

In comment: We note with interest the comments of Dr. Butkus on our

Division of Medicine The Mt. Sinai Hospital of Cleveland Cleveland, Ohio 44106 REFERENCES 1. CANNON PR, FRAZIER LE, HUGHES HR: Sodium as a toxic ion in

potassium deficiency. Metabolism 2:297:313, 1953 2. BRUNNER HR, BAER L, SEALEY JE, et al: The influence of potas-

sium administration and of potassium deprivation on plasma renin in normal and hypertensive subjects. J Clin Invest 49:21282138, 1970 3. BULL MB, HILLMAN RS, CANNON PJ, et al: Renin and aldoster-

one secretion in man as influenced by changes in electrolyte balance and blood volume. Circ Res 27:953-960, 1970

Factor VIII Nomenclature TO THE EDITOR: A task force has recommended to the International Committee on Thrombosis and Haemostasis the adoption of a new nomenclature for the "factor-VIII-related-activities." An "on-the-line" system of nomenclature has been recommended for the three major classes of activities related to blood coagulation factor VIII, that is VIII:C (for the coagulant activity), VIIIR:AG (for the antigenic activities related to factor VIII), and VIIIR:WF (for the "von Willebrand factor" activities related to factor VIII). Adoption of these recommendations, which are at present before the International Committee, will be deferred for at least 1 year while the task force receives and considers suggestions of modification. Anyone who wishes a copy of the full report or wishes to make suggestions to the task force should contact its chairman: Professor John B. Graham, Department of Pathology, School of Medicine, University of North Carolina, Chapel Hill, NC 27514, USA. JOHN B. GRAHAM, M.D.

Department of Pathology School of Medicine University of North Carolina Chapel Hill, North Carolina 27514 Comments and Correction

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Antiplatelet Antibody

Pulmonary Radiation Reactions

TO THE EDITOR: In their recent paper (Ann Intern Med 83: 190-196, 1975) Lackner and Karpatkin reported that many patients with the "easy bruising" syndrome have abnormal platelet function, increased percentages of megathrombocytes, and an elevated prevalence of antiplatelet antibody. I agree that the easy bruising in these patients reflects a qualitative platelet defect, but I question whether the defect is the result of an autoimmune process. Most of the patients studied were women of child-bearing age and, unless the target platelets used for platelet antibody testing were autologous, the increased frequency of platelet antibody activity could be explained by the presence of pregnancy-induced (or transfusion-induced) isoantibody. I also question whether the increased percentage of megathrombocytes in these patients is evidence for a compensated thrombocytolytic state. This would be more convincingly shown by platelet survival measurements, since megathrombocytes may be seen in normal persons, (1, 2) and, as the authors note, their presence in excess may not always reflect shortened platelet survival ( 3 ) .

TO THE EDITOR: I have recently described the appearance of increased clinically symptomatic pulmonary radiation reactions with adjuvant chemotherapy (1), specifically a combination of nitrogen mustard, procarbazine, and vincristine. My comments in that paper suggested that "increased reactions be looked for in all organ systems that are irradiated during combination studies." Further evidence in support of this statement is given by the recent report of synergistic cardiotoxicity with adriamycin and radiation in your journal by Merrill and associates (Ann Intern Med 82:122-123, 1975), and another article by Cassady and associates (2) on treatment of Wilms tumor with combined modality therapy. To expand on my original articles citing increased pulmonary radiation reactions with adjuvant chemotherapy (1, 3), I later observed similar symptomatic pulmonary reactions in patients who received radiotherapy after cyclic chemotherapy with adriamycin, vincristine, and cyclophosphamide. Evaluation of my data collected while at the National Cancer Institute, plus preliminary evaluation of patients recently treated here (present address), indicates that the degree of symptomatic reaction is related to a number of factors, including the number of cycles of chemotherapy before radiotherapy, the size of the radiation field, whether the radiation is given during or after completion of chemotherapy, and presumably the drug itself. The main reason for my two papers was to point out that the big danger in increased symptomatic reactions is that making an incorrect diagnosis could lead to improper and perhaps even dangerous therapy. However, it is becoming more obvious that increased reactions should be looked for in all organ systems that are irradiated during combination studies, and this possibility should be considered when protocols are planned.


Division of Hematology University of Texas Medical School Houston, Texas 77025 REFERENCES 1. O'BRIEN JR, JAMIESON S: A relationship between platelet volume and platelet number. Thromb Diath Haemorrh 31:363-365, 1974 2. VON BEHRENS WE: Mediterranean macrothrombocytopenia. Blood 46:199-208, 1975 3. MURPHY S: Hereditary thrombocytopenia. Clin Haematol 1:359368, 1972

In comment: It is unlikely that the presence of antiplatelet antibody could be due to isoantibody induced by pregnancy for two reasons: [1] 7 of our 19 patients (Types I and II) with positive antiplatelet antibody were childless or unmarried, or both, and two were men; and [2] we have tested several normal women with multiple pregnancies and have not found positive antiplatelet antibody titers. The presence of increased megathrombocytes does not prove the existence of a compensated thrombocytolytic state, and its presence in excess may not reflect shortened platelet survival in some rare conditions. Nevertheless, we consider the presence of increased megathrombocytes as highly suggestive of a compensated thrombocytolytic state, since the 8 patients whom we studied with this finding had shortened platelet survival ( 1 , 2 ) . HENRIETTE LACKNER, M.D., M.R.C.P. SIMON KARPATKIN, M.D.

New York University Medical Center 550 First Avenue New York, New York 10016 REFERENCES 1. GARG SK, AMOROSI EL, KARPATKIN S: Use of the mega thrombocyte as an index of megakaryocyte number. N Engl J Med 284: 11-17, 1971 2. KARPATKIN S, GARG SK, SISKIND GW: Autoimmune thrombocytopenic purpura and the compensated thrombocytolytic state. Am J Med 51:1-4, 1971 738


Department of Radiation Therapy Arnot-Ogden Memorial Hospital Roe Avenue Elmira, New York 14901 REFERENCES 1. LAMOUREUX KB: Increased clinically symptomatic pulmonary rediation reactions with adjuvant chemotherapy. Cancer Chem Rep 58:705-708, 1974 2. CASSADY JR, MEYER G, JAFFE N, et al: Fever, lethargy and rash complicating treatment for Wilms' tumor—a new syndrome? Radiology 115:171-174, 1975 3. LAMOUREUX KB: Diagnostic problems after radiotherapy involving the lung. South Med J 66:1388-1392, 1973

BCG Therapy and Urticaria TO THE EDITOR: We are presently treating a patient who developed recurrent urticarial eruptions that were temporally related to the administration of BCG. This systemic reaction is not described in the recent article by Aungst, Sokal, and Jager (1) nor in other extensive reviews of the complications of BCG therapy (2-4). The patient is a 49-year-old man who was referred to the New England Medical Center Hospital in November 1974 with pancytopenia and shortness of breath. He had petechiae, ecchymoses, and splenomegaly. The leukocyte count was 5000 with

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67% myeloblasts, and the bone marrow was diagnostic of acute myelomonocytic leukemia. Complete remission was induced with cytosine arabinoside and 6-thioguanine. His course from aplasia to remission was complicated by sepsis, candidal esophagitis, jaundice, and a perirectal abscess with fistula requiring a colostomy. He received a good deal of blood component support, including granulocytes, and experienced a single episode of urticaria concomitant with the administration of a unit of packed erythrocytes. After it was shown that he was not anergic, he was started on a maintenance regimen consisting of cyclical courses of BCG and 6-mercaptopurine. BCG, 300 mg, was administered by scarification on Days 1 and 8. On Days 15 to 20, he received 500 mg/m2 body surface of 6-mercaptopurine orally. He received five and a half courses with two omissions of 6-mercaptopurine because of cytopenias or a transient increase in serum concentrations of hepatic enzymes. Several days after the fourth BCG injection, he noted mild urticaria over his extremities and back that subsided rapidly and spontaneously. With each subsequent injection the urticaria appeared more rapidly and was more intense and diffusely distributed. An episode of mild angioneurotic edema occurred in the mouth after the final dose. These lesions were only minimally responsive to diphenhydramine, were unresponsive to hydroxyzine and chlortrimeton, and gradually resolved within a week. At no time did he experience any fever or chills after BCG administration. A local inflammatory response occurred only after the final dose. Eosinophilia (up to 10%) was noted for the first time a few days before the initial episode of urticaria and was also seen once more during his course. The patient's leukemia has recently relapsed. Since BCG and 6-mercaptopurine have been withdrawn, urticaria has not recurred. This supports our impression that the urticaria was an allergic phenomenon related to the BCG. BRUCE D. CHESON, M.D.

Department of Hematology New England Medical Center Hospital Boston, Massachusetts 02111 REFERENCES

to increase the proportion of animals that died in the convulsive phase. Prophylactic sodium thiosulfate (1 g/kg, 15 minutes before azide) also had no effect on mortality. Two additional human cases of azide poisoning from the accidental ingestion of a hematologic laboratory regent (4) further emphasize the need for an effective antidote. We will continue to recommend the induction of methemoglobinemia by nitrite for acute poisoning by hydrogen sulfide or its salts. To our knowledge it has not yet been tried in acute human sulfide intoxication. As evaluated in animals, an equivalent methemoglobinemia afforded a much greater degree of protection against sulfide than against azide ( 5 ) . Moreover, antidotal effects of nitrite in sulfide poisoning have also been determined in animals ( 6 ) . Oxygen and thiosulfate can do no harm, but they had only marginal effects at best, whether used alone or in combination with nitrite. ROGER P. SMITH, PH.D. ROBERT E. GOSSELIN, M.D., PH.D. ROBERT KRUSZYNA, M . S .

Department of Pharmacology and Toxicology Dartmouth Medical School Hanover, New Hampshire 03755 REFERENCES 1. ABBANAT RA, SMITH RP: The influence of methemoglobinemia

on the lethality of some toxic anions. I. Azide. Toxicol Pharmacol 6:576-583, 1969


2. GLEASON MN, GOSSELIN RE, HODGE HC, et al: Clinical Toxic-

ology of Commercial Products, 3rd ed. Baltimore, Williams & Wilkins, 1969, pp. 11-20, 111-122 3. EMMETT EA, RICKING JA: Fatal self-administration of sodium

azide. Ann Intern Med 83:224-226, 1975 4. RICHARDSON SGN, GILES C, SWAN CHJ: TWO cases of solium

azide poisoning by accidental ingestion of Isoton. / Clin Pathol 28:350-351, 1975 5. SMITH RP, GOSSELIN RE: On the mechanism of sulfide inactiva-

tion by methemoglobin. Toxicol Appl Pharmacol 8:159-172, 1966 6. SMITH RP, KRUSZYNA R, KRUSZYNA H: Management of acute

sulfide poisoning: effects of oxygen, thiosulfate and nitrite. Arch Environ Health, in press

1. AUNGST CW, SOKAL JE, JAGER BV: Complications of BCG vac-

cination in neoplastic diseases. Ann Intern Med 82:666-669, 1975 2. SPARKS FC, SILVERSTEIN MJ, HUNT JS, et al: Complications of

BCG vaccination in patients with cancer. N Engl J Med 289: 827-830, 1973 3. BAST RC JR, ZBAR B, BORSOS T, et al: BCG and cancer. N Engl

J Med 290:1413-1420, 1458, 1974 4. NATHANSON L: Use of BCG in the treatment of human neoplasms: a review. Semin Oncol 1:337, 1974

Sodium Azide Poisoning TO THE EDITOR: Since we (RS, R G ) were responsible for the suggestion that the therapeutic induction of methemoglobinemia might be of value in acute azide poisoning ( 1 , 2), we are naturally disappointed that it was not effective in its first human trial ( 3 ) . That recommendation will not appear in the fourth edition of our reference manual, which is now in press ( 2 ) . Recent observations by one of us ( R K ) suggest that there are two distinctive mechanisms of death in mice acutely poisoned by sodium azide. If death in convulsions does not occur within 10 minutes, survivors may die during the phase of collapse an hour or more after azide administration. Although the prophylactic and therapeutic administration of oxygen (100% at 1 atmosphere) had no effect on the overall mortality of azide-poisoned mice, it seemed

Furosemide Screening Test and Pheochromocytoma TO THE EDITOR: It was recently suggested in this journal that the measurement of peripheral plasma renin activity after the administration of oral furosemide is a reliable screening test in hypertension to rule out a surgically correctable lesion ( 1 ) . Plasma renin activity above 5 ng/ml • h was associated with a renovascular cause of hypertension in five patients. We wish to report on two additional patients who had markedly elevated plasma renin activity in the furosemide screening test and no evidence of any renovascular abnormalities. Patient 1 was a 54-year-old white woman who had hypertension and superimposed hypertensive paroxysms responsive to intravenous phentolamine. The hypertension was unresponsive to all conventional medications except phenoxybenzamine. Urinary vanillylmandelic acid was elevated between crises (16.3 mg/g creatinine), as well as during the paroxysms (69.2 mg/0.2 g creatinine). The norepinephrine and epinephrine were within normal limits. Arteriography did not show evidence of any adrenal or renovascular lesion. A laporotomy did not identify an abdominal chromaffin tumor, and postoperatively the patient continued to save the same hypertensive episodes. Preoperatively and postoperatively, the plasma volume was constricted at 31.08 ml/kg (ideal, 47.43). Plasma Comments and Correction

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renin activity postfurosemide was 11.1 ng/ml • hr, clearly elevated in the renovascular range. Patient 2 was a 28-year-old black woman who presented with pulmonary edema and normotension. During hospitalization, she had several hypertensive crises. Urinary vanillymandelic acid, norepinephrine, and epinephrine were elevated at 116 mg/g creatinine, 210.6 /xg/24 h, and 82.2 fig/24 h, and 82.2 /xg/24 h, respectively. Laporotomy showed a solitary pheochromocytoma and no evidence of a renovascular lesion. Preoperatively, the plasma volume was diminished at 36.47 ml/kg (ideal, 47.43). Plasma renin activity postfurosemide was 13.6 ng/ml • h. Postoperatively, the plasma volume returned to normal, the patient was normotensive, and plasma renin activity returned to a normal value of 1.2 ng/ml • h. From these data it becomes obvious that elevated plasma renin activity postfurosemide not only may implicate renovascular hypertension (1) but also pheochromocytoma. The plasma volume is obviously a major determinant ( 2 ) , and the circulating catecholamines play a role as well (2, 3 ) . We believe that in the presence of elevated plasma renin activity postfurosemide, a pheochromocytoma should be given special consideration, since radiologic procedures used in the delineation of renovascular hypertension are potentially dangerous in patients with chromaffin tumors ( 4 ) . ZEV M. M U N K , M.D.C.M. GEORGE TOLIS, M.D., M . S C , C.S.P.Q. ( C )

Douglass would be much greater than in the cooked (and presumably processed) diet taken previously by those two patients. We suggest that the insulin requirement of both these patients fell because the postprandial rises of blood sugar were not as great after raw food as after processed and cooked food. ANTHONY R. LEEDS, DAVID J. A. JENKINS, MIGUEL A. GASSULL, BERNARD COCHET, LAWRENCE M. BLENDIS,

M.D. M.D. M.D. M.D. M.D.

Medical Research Council Gastroenterology Unit Central Middlesex Hospital London N.W.10 7 N.S., England REFERENCES

1. DOUGLASS JM: Raw diet and insulin requirements. Ann Intern Med 82:61-62, 1975 2. HORWITZ DL, SLOWIE L: Raw diet in diabetes mellitus. Ann Intern Med 82:853-854, 1975 3. JENKINS DJA, LEEDS AR, GASSULL MA, et al: Reduction in

postprandial glycaemia by guar and pectin. Unpublished

Fever, Flashbulbs, Humps, and Spikes

TO THE EDITOR: A letter {Ann Intern Med 83:84, 1975) adds a new phrase to medical jargon in addition to "fever spike." In its accompanying figure, the depicted febrile bout resembles a dagger more than a goalpost or a spike REFERENCES (daggerfever?). A spike is a large untapered nail. It is doubtful if fever ever rises and falls like the flash of a 1. WALLACH L, NYARAI I, DAWSON KG: Stimulated renin: a screening test for hypertension. Ann Intern Med 82:27-34, 1975 flashbulb. The "highest daily temperatures" shown in the 2. DAVIS JO: The control of renin release. Am J Med 55:333-350, graph obviously do not portray the whole febrile reaction. 1973 If more measurements had been recorded, the fever 3. ASSAYKEEN TA, GANONG WF: The sympathetic neuron system and renin secretion, in Frontiers in Neuro-Endocrinology, edited curve, no doubt, would appear blunted or humped (humpby MARTININ L, GANONG WF. New York, Oxford University fever?). Press, 1971, p. 67 Two items of information are missing: [1] how long did 4. ROSSE P, YOUNG IS, PANKE WF: Techniques, usefulness and the febrile bouts last; [2] did recurrences cease after the hazards of arteriography of pheochromocytoma. Review of 99 cases. JAMA 205:547-553, 1968 drug was permanently withdrawn? If they then resumed at "5 to 7 days" intervals, periodic fever with "unrevealing" laboratory data, excepting occasional.leukopenia, might be considered. In that case, short febrile episodes may have Unabsorbable Carbohydrates and Insulin Need recurred spontaneously regardless of medication (Am J Med Sci 243:729, 1962). TO THE EDITOR: We compliment Dr. Douglass on his reHOBART A. REIMANN, M.D., F.A.C.P. freshing approach to the dietary control of two diabetic patients who wished to reduce their insulin therapy ( 1 ) . Department of Medicine While accepting that the effect of the raw food diet in Hahnemann Medical College and Hospital Philadelphia, Pennsylvania 19102 reducing insulin requirements may be due, at least partly, to trapping of otherwise absorbable carbohydrate within intact cellulose cell walls ( 2 ) , we think that other factors In reply: may be important. For example, we have shown that unabsorbable carbohydrate reduces post prandial rises of blood sugar ( 3 ) . The duration of the two febrile "bouts" shown in our figure illustrating the "goalpost" fever pattern was approximately The addition of Guar gum (a storage polysaccharide 18 to 20 hours. Fever has not recurred since the offending obtained from the cluster bean, Cyamopsis tetragonoloba) drug was withdrawn. to the bread, and pectin (a polymer of galacturonic acid We suspect that Dr. Reimann is not a football fan. The obtained from apples) to the marmalade of a breakfast illustration depicts two fever "spikes" connected by a test meal resulted in significant reductions of the mean horizontal (crossbar) line and, as such, is not unlike the postprandial rise of blood sugar in 7 subjects at 15 minutes top half of a set of football goalposts. (97.1 ± 2.6 mg/dl and 116.9 ± 5.1 mg/dl, P < 0.002) We agree that had the patient's temperatures been and at 30 minutes (108.9 ± 7.8 mg/dl and 138.2 ± 13.8 plotted every 4 hours, the result would have been a mg/dl, P < 0.001). "double humpfever" (? "camel back fever") pattern. But The total quantity of unabsorbable carbohydrates and who would have published a letter entitled "Humpfever"? "dietary fibre" in the raw foods diet prescribed by Dr. Division of Endocrinology Royal Victoria Hospital Montreal, PQ H3A 1A1, Canada


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Johns Hopkins Hospital Baltimore, Maryland 21205

Medical Care for the Elderly TO THE EDITOR: I have followed with interest the paper of Dr. Brickner and colleagues concerning his program for care of the elderly at home (Ann Intern Med 82:1-6, 1975) and the editorials and letters engendered by it. Doctor Mumford and associates' letter of July 1975 (Ann Intern Med 83:125-126, 1975) was most interesting and delineated programs long in existence for the chronically ill elderly patients of New York City through the New York City Health & Hospitals Corporation. Doctor Brickner's reply to this letter was inaccurate in that he apparently is under the impression that services delivered to patients in these programs are limited to those allowed by legislation, and that "there are limiting factors as to the type of patient included. Most of the patients in homecare programs are people previously known to the hospital." Many services that are not covered by payment from fiscal intermediaries are provided to patients on a need, rather than reimbursable, basis. Patient's needs have been, and continue to be, the primary determinants of types of services provided. Twenty percent or more of our patients had not been known to the hospital before acceptance on home care. Case finding in the community is done by community residents and visiting nurses, as well as by local hospital staffs. Referrals come from these and a multiplicity of other sources, and evaluations and care are then provided, as needed and acceptable to each patient. I would refer Dr. Brickner and staff to the Columbia Study on Home Health Agencies done in 1967 for a clear picture of the Corporation programs. JOSEPHINE A. LOCKWOOD, M.D.

Department of Community Medicine New York Medical College New York, New York

TO THE EDITOR: I suspect that your problems in copy editing are not yet solved. Why in the world would hypercalcemia be "indicated as preferred in American usage to" hypercalcinuria? It is one thing to insert an extra "n" in making neologisms. It is quite another thing to convert urine into blood. ALVAN R. FEINSTEIN, M.D.

Department of Internal Medicine School of Medicine Yale University New Haven, Connecticut TO THE EDITOR:

at least dr feest and dr wrong are right when the editors pen inserted an en in front of their uria though the calcium was there it did not disintegrate but did precipitate causing pain to the recipient and an ache to the redactient which all goes to show how much we should know about how many angels with all of their spangels can dance on the head of a pin apologies to edward estlin cummings and see ann int med aug 1975 p 288 K E N N E T H B. OLSON, M.D.

810 Oakview Drive New Smyrna Beach, Florida 32019 And with apologies to the anonymous author of the famous Ginsberg story: Milk or mud, urine or blood, Calcium strikes again. This one we can hang on the printer—small consolation! The Editor Scene in Print: Wife-Beaters?

Correction: Apology for "Hypercalcinuria" In the August 1975 issue, lines 21 and 22 of column 2 on page 288 should have read: ". . . hypercalciuria" is indicated as preferred in American usage to "hypercalcinuria."

Distinguished leaders in the field of policy and decisionmaking have been invited to share opinions, information and action strategies to address the national problem of the increasing population of female substance abusers. [From an announcement of a conference in Miami Beach, issued by the National Institute of Drug Abuse.]

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Letter: Asbestos pleural effusion?

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