LETTERS

Letters that report new clinical or laboratory observations, cases of unusual importance, and new developments in medical care will be considered for publication in this section. Manuscripts must be typed double-spaced. Text length must not exceed 750 words; no more than five references and one figure or table can be used. See "Information for Authors" on page 1-6 for form of references. Manuscripts should include an abstract of length not exceeding 100 words. Letters will be reviewed by consultants when, in the opinion of the editors, such review is needed. The Editor reserves the right to shorten letters and to make changes that accord with our style. Acute Arthritis Induced by Isoniazid THE ARTHRITIC COMPLICATIONS secondary

to

isoniazid

(INH) usually occur after 4 weeks and within the first 5 months of therapy ( 1 ) . In a single reported case, joint symptoms developed acutely; challenge with INH caused recurrence of the arthralgias ( 2 ) . We report here a patient with tuberculosis who developed acute arthritis, periorbital edema, and fever 9 days after initial treatment. All manifestations disappeared when all drugs were withdrawn. Subsequently, arthritis and joint effusion recurred 6 hours after administration of only 100 mg of INH. In-vitro INH inhibited migration of the patient's leukocytes. A 28-year-old woman enjoyed excellent health until January 1972 when she developed fatigue, diaphoresis, chills, and a fever. She sought medical aid after the rather sudden onset of sharp, pleuritic left anterior chest pain. She had noted cervical lymphadenopathy, a slight decrease in weight, and a dry nonproductive cough. There was no history of hemoptysis, sputum production, or dyspnea. There was no history of arthritis or allergy. Chest film showed a l-X-2-cm cavitary lesion in the superior segment of the left lower lobe; acid-fast bacilli were found in the sputum and gastric specimens. Treatment was initiated with INH, 100 mg three times a day; streptomycin, 1 g once a day; and ethambutol, 400 mg three times a day. Nine days later, the patient developed pain in her left knee, right little finger, and right eye. Results of physical examination were unchanged except that the patient was afebrile. However, 5 hours after the onset of pain, effusions of both knees were demonstrable. The ankles and small joints of both hands were swollen and tender. Her temperature had increased to 40.2 °C. Marked periorbital edema of the right eye was noted. The leukocyte count was 17 400/mm3 with a slight left shift. Sixty ml of cloudy yellow fluid was aspirated from one knee joint; it contained 30 000 leukocytes/mm8 (94% polymorphonuclear leukocytes, 21% lymphocytes, and 4% monocytes), 62 g/dl glucose, and 4.7 g/dl protein. Cultures for acid-fast and pyogenic organisms were negative. Serum glutamic oxalacetic transaminase was 95; serum glutamic pyruvic transaminase was 27. Bilirubin, uric acid, and complement were within normal limits. Rheumatoid factor and lupus erythematosus preparations were negative. Clinical manifestations disappeared in 5 days with analgesics and antihistamine therapy. On the sixth day the patient received 100 mg of INH orally; 6 hours later she developed abrupt painful swelling of the knees and small hand joints. Her temperature increased to 39° C. The diameter of the left knee increased 2.5 cm. After

Table 1 . Leukocyte Migration Study*

Migration Index Dose of Isoniazid Initial study Six months later Nine controls

0.1 ng/ml

Patient 0.47 Patient 1.17 Controls 0.96 ± 0.11

0.01 ng/ml 0.90 1.29 0.96 ± 0.07

* The migration index is the ratio of the area of migration in the presence of antigen (isoniazid) to the area of migration without antigen. One control inhibited; migration index = 0.78 (0.1 /xg/ml) and 1.07 (0.01 fig/ml). All studies were done in duplicate. The control indices are given as arithmetic mean ± standard deviation.

this episode abated, the patient was treated with streptomycin, rifampin, and ethambutol with no adverse reactions. In the leukocyte migration assay 0.1 /Ag/ml of INH causes significant inhibition; eight of nine controls had no inhibition (Table 1). Exposure to greater amounts, (1.0 fig/m\ or more) inhibited some control patients. The one control patient with inhibition had received 1 year of prophylactic INH treatment and may have some immunity. Six months later, exposure to INH caused significant stimulation of migration of the patient's leukocytes. Farrtype assay for antibodies to INH was done at the National Institute of Health in the laboratory of Dr. J. Mitchell; no antibodies were detected. The appearance of symptoms on the ninth day of the INH therapy and their reappearance 6 hours after challenge with INH strongly suggests an allergic reaction. However, the immune mechanism responsible can not be clearly delineated. No antibodies to INH were detected. Although leukocyte migration index studies have correlated with skin results with other antigens, skin testing with INH was clinically inappropriate in this patient. Migration stimulation with INH was seen in this patient 6 months after her initial study; in one animal experiment, immunization resulted in stimulation of migration ( 3 ) . Although several investigations have explored the detection of drug allergy by inhibition of macrophage migration, few studies have used direct leukocyte migration inhibition to detect drug allergy ( 4 ) . The leukocyte migration inhibition assay may allow definition of hypersensitivity within 24 hours and may become clinically useful if supported by further positive studies. This study was supported in part by National Cancer Institute contract no. NOl CP 23251 and National Cancer Institute grant no. CA13851-03. PHILLIP PERIMAN, M.D. T. K. VENKATARAMANI, M.D.

Department of Medicine The George Washington University Medical Center Washington, DC 20037 Received 1 April 1975. REFERENCES

1. GOOD AE: Rheumatism and chemotherapy of tuberculosis. Ann 667

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Patient 3 was a 42-year-old male heroin addict who entered the hospital with a 2-week history of increasing neck and shoulder pain and a 1-week history of mild urinary frequency 3. GORSKI AJ, ORLOWSKI T, POMORSKI Z, et al: The modification of and urgency. Flexion of the neck was severely restricted, and peripheral leukocyte-migration test using preincubation with muscle strength and deep tendon reflexes were slightly diminspecific antigen. Cell Immunol 8:162-164, 1973 ished in both upper extremities. He was afebrile. Cervical spine 4. ROCKLIN RE: Clinical applications of in-vitro lymphocyte tests, in Progress in Clinical Immunology, vol. 2, edited by SCHWARTZ roentgenograms showed a destructive process involving the bodies of C4 and C5 with loss of the disc space. Cultures of RS. New York, Grune & Stratton, 1974, p. 21 urine and of tissue obtained during surgical exploration of the spine grew S. marcescens. Serratia Vertebral Osteomyelitis in Narcotic Addicts Pertinent clinical data on these patients are summarized in Table 1. HEMATOGENOUS VERTEBRAL OSTEOMYELITIS is a wellSerratia osteomyelitis is an infrequently encountered documented complication of parenteral heroin use (1-3). infection that, in virtually every case, occurs in patients In this setting, Gram-negative bacilli such as Pseudomonas, predisposed to its acquisition by host factors, such as Klebsiella, and Enterobacter have replaced Staphylococcus chronic debilitating illnesses, or by such nosocomial factors aureus as the prevailing etiologic organisms. In a recent as prior surgery, urinary or respiratory tract instrumenta12-month period, three long-term heroin addicts with tion, corticosteroid therapy, or prior treatment with broadvertebral osteomyelitis due to Serratia marcescens were spectrum antibiotics ( 4 ) . Although S. marcescens was reseen and treated at Mount Zion Hospital and Medical covered from the urine in two of the three cases presented Center and at the San Francisco General Hospital, and here, neither had had prior urinary tract instrumentation, we report their cases here. Serratia marcescens is a rare and in Patient 3 the symptoms of urinary tract involvecause of orthopedic infections in general and, to our ment clearly postdated the onset of symptoms of osteoknowledge, has been reported only once previously as the myelitis. It would seem that their urinary tract involvecause of osteomyelitis in a narcotic addict ( 3 ) . ment represented secondary infection from an antecedent serratia bacteremia. Patient 1 had received a brief course Patient 1 was a 5 3-year-old male heroin addict who entered of narrow-spectrum antibiotics 3 months before his adthe hospital with severe neck pain of 1 day's duration, with mission for osteomyelitis, but only after his serratia skin tenderness over the cervical spinous processes, and with limiinfection had already been determined. tation of neck motion. Three months earlier, culture of an injection-site abscess on the right shoulder yielded StreptococThe microorganisms that infect parenteral drug users cus viridans and S. marcescens. The abscess healed promptly have reasonably been assumed to originate in contaminated after drainage and after a 7-day course of oral penicillin and drugs or injection paraphernalia. A recent cultural survey dicloxacillin. At admission the patient was afebrile. X rays of these materials has documented microbial contaminaof the spine showed destructive lesions in the bodies of the tion of 6 8 % of the former and 89% of the latter ( 5 ) , 3rd and 4th cervical vertebrae with narrowing of the intervenbut S. marcescens was not among the organisms recovered. ing disc space. Cultures of urine and of material obtained Indeed, most of the organisms cultured from these two during surgical decompression of the spine yielded S. marcescens in pure growth. sources are rarely encountered in infections among narcotic addicts. This finding may be explained by postulating Patient 2 was a 57-year-old male heroin addict admitted to the hospital with a 1-day history of severe low back pain, the presence of Serratia organisms and other pathogens tenderness over the lumbosacral region, and limitation of primarily in the diluent used to dissolve the drugs before straight leg raising to 30° bilaterally. His oral temperature injection, or on the skin of the addicts themselves. was 38.3 °C. Initial lumbosacral spine X rays showed no acute The present cases suggest that S. marcescens be added pathology. Three blood cultures grew S. marcescens, and apto the growing number of organisms known to produce propriate " antibiotic treatment was begun. Repeat roentgenoosteomyelitis in narcotic addicts. Conversely, parenteral grams of the spine on the 25th hospital day showed destructive drug abuse should be included in the list of predisposing lesions in the bodies of the 4th and 5th lumbar vertebrae with narrowing of the disc space, a picture consistent with acute factors to the acquisition of serratia bone infection. osteomyelitis. Finally, it is of some interest that the three cases presented Intern Med 72:752-753, 1970 2. SASLAW S, KLAINER AS: Rheumatoid syndrome during isoniazid therapy. Am Rev Resp Dis 100:221-223, 1969

Table 1 . Summary of Pertinent Clinical and Laboratory Data

Patient

Site of Lesion

Source (and Number) of Serratia Cultures

Admission Laboratory Data Leukocyte Count

Erythrocyte Sedimentation Rate

no./mmz 7500

mm/h 78

1

C3-C4f Bone lesion (1), Urine (1)

2

L4-L5f

Blood (3)

13 300

75

3

C4-C5

Bone lesion (1), Urine (1)

11 300

Not done

Serratia Antibiotic Sensitivities*

Antibiotic Treatment and Dosage

g/day Gentamicin, 0.21 G, K, Ch, Car, S, NA + Carbenicillin, 24.0 Gentamicin, G, K, Ch, 0.21 to 0.32 S, NA, Nf Gentamicin, 0.24 G, K, Ch, Kanamycin, 1.0 S, NA

Duration of Antibiotic Therapy

days 35

46 14 28

Additional Therapy

Surgical decompression and bone graft; Minerva cast Pelvic traction; lumbosacral corset Surgical decompression; Halo jacket

* G = gentamicin; K = kanamycin; Ch = chloramphenicol; Car = carbenicillin; S = sulfonamide; NA = naladixic acid; Nf = nitrofurantoin. t C = cervical; L = lumbar. 668

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here, as well as the previously documented case of serratia osteomyelitis in a heroin addict ( 3 ) , all occurred in California, a finding that suggests that geographic factors may also play a role in the acquisition of S. marcescens osteomyelitis by narcotic addicts. Further studies are needed to clarify this latter point. LAWRENCE M I N T Z , M.D.

Department of Pathology and Laboratory Medicine Mount Zion Hospital and Medical Center San Francisco, California GEORGE H. M O L L E T T , M.D.

Department of Orthopaedics University of California Medical Center San Francisco, California Received 24 June 1975. REFERENCES

1. HOLZMAN RS, BISHKO F: Osteomyelitis in heroin addicts. Ann Intern Med 75:693-696, 1971 2. LEWIS R, GORBACH S, ALTNER P: Spinal Pseudomonas chondro-

osteomyelitis in heroin users. N Engl J Med 286:1303, 1972 3. FISHBACH RS, ROSENBLATT JE, DAHLGREN JG: Pyogenic vertebral

osteomyelitis in heroin addicts. Calif Med 119:1-4, 1973 4. WILKOWSKE CJ, WASHINGTON J A, MARTIN WJ, et al: Serratia

marcescens. Biochemical characteristics, antibiotic susceptibility patterns, and clinical significance. JAMA 214:2157-2162, 1970 5. TUAZON CU, HILL R, SHEAGREN JN: Microbiologic study of

street heroin and injection paraphernalia. / Infect Dis 129:327329, 1974 Gas Gangrene After Intramuscular Injection of Epinephrine: Report of Fatal Case GAS GANGRENE developing at the site of intramuscular injection is fulminating and associated with high mortality. We report here a patient who died 36 hours after injection of epinephrine in oil in the buttocks. Clostridial myonecrosis has occurred under similar circumstances since administration of drugs intramuscularly became common practice at the beginning of this century. Touraine ( 1 ) , reviewing the subject in 1936, mentioned epinephrine as the most frequently offending drug. After World War II additional patients were described by Marshall and Sims (2) and Koons and Boy den ( 3 ) , who referred to another 30 cases in Brazil. Our patient, a 64-year-old farmer with asthmatic bronchitis, was given an injection of epinephrine in oil in the left buttock with disposable needle and syringe. The skin had been prepared with disposable 70% alcohol swabs. Within 6 hours severe pain had developed at the injection site; at 24 hours it became unbearable, and he returned to his physician. The clinical impression was that an abscess had developed. He was admitted to the community hospital and at 30 hours underwent debridement of the area; liquefied, deep red, necrotic muscle and tiny bubbles were detected. The tissues appeared as under pressure. A smear showed Gram-positive rods; other laboratory tests were not available. The diagnosis was changed to gas gangrene, and a polyvalent antitoxin was given immediately. The patient was transferred to another hospital for further debridement. Several hours later crepitation of the skin was noted from the area of the left knee up to the level of the clavicles; also, a brownish hemorrhagic fluid that oozed from the first debridement site. The patient was taken to the operating room for the second debridement. All muscles seemed severely discolored in the gluteal area extending distally to the greater trochanter of the left femur and proximally to the lumbosacral joint and pelvic attachments. Extensive subcutaneous

gas was present over the left abdomen. During the procedure cardiac arrest occurred, and resuscitation efforts failed. This was 36 hours after injection of the epinephrine in oil. The pathologist's report showed necrosis of the tissue, edema, congestion in the muscles, and overlying fat with minimal inflammation. A culture of wound drainage specimens proved positive for Clostridium perfringens; this was later confirmed by the Florida Division of Health laboratory. The disposable needle and syringe used for the injection were not available. The lot number of the multidose vials of epinephrine in oil was known. The manufacturer's investigation showed that the preparation was free of clostridial spores. In some early cases the source of clostridial bacilli may have been contaminated medications or injection paraphernalia, or both. Contamination of needle and syringe could not be excluded in our patient. We believe, however, that the organisms were deposited into the muscle during penetration of skin soiled with clostridial spores. To elucidate the source of the etiologic agent we obtained culture specimens from the skin of the gluteal region of 50 patients. Three specimens were obtained from each one at 10 cm, 15 cm, and 20 cm from the anus, the last from the upper outer quadrant of the gluteal region. In 25 patients there was no skin preparation. The other 25 had the site moistened and rubbed for 1 minute with 70% isopropyl alcohol, in a manner similar to the "usual" preparation of the skin before an injection. Culturing was done for isolation of Clostridium organisms only, without species identification. We processed the specimens using the Gaspak® method (BBL, Cockeysville, Maryland) for anaerobic incubation. Table 1 shows the number of cultures positive for Clostridium organisms obtained at different distances from the anus with and without alcohol swabbing. Sixty-four of 150 (43%) were positive. Distance from the anus, up to 20 cm, made little difference in isolation of Clostridium species (P > 0.05), but there was a higher frequency of culture positivity after alcohol preparation of the skin ( P < 0.005). The study clearly shows that Clostridium organisms frequently are present on the buttocks, and that preparation of the skin with alcohol not only fails to eliminate the bacterial spores but even increases dispersal, causing an apparent increase in their number. A second requisite seems to be vasoconstriction by epinephrine and creation within the muscle of a locus minoris resistentiae for Clostridium organisms. Nevertheless, the development of clostridial myositis after intramuscular injections is rare. Epinephrine injected intramuscularly is commonly used Table 1. Isolation of Clostridium Organisms from Skin Cultures of Gluteal Region With and Without Alcohol Preparation at Different Distances from the Anus Distance From Anus

With Alcohol Preparation

Without Alcohol Preparation

Total

cm 10 15 20 Total

17/25(68%)* 14/25 (56%) 11/25(44%) 42/75 (56%)

6/25 (24%) 8/25 (32%) 8/25 (32%) 22/75 (29%)

23/50 (46%) 22/50 (44%) 19/50 (38%) 64/150(43%)

* Numerators indicate the number of cultures positive for Clostridium organisms, denominators give the total number of cultures obtained, and the numbers between parentheses indicate the percentage of culture positivity. Lett ere

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to treat acute attacks of asthma; however, there are hazards. Severe pain developing shortly after intramuscular injection of vasoconstricting and necrotizing drugs demands prompt consideration of the possibility of clostridial myonecrosis. This should be treated immediately with wide surgical debridement and adequate amounts of parenteral penicillin. If epinephrine has to be given intramuscularly and there is sufficient time, the skin should be cleaned for at least 15 minutes with an iodine preparation in the form of wet compresses ( 5 ) . The newer, more specific beta-2-bronchodilators can be administered subcutaneously, thereby greatly diminishing the danger of severe clostridial infections.

mononucleosis has been well documented ( 1 ) . In congenital and pediatric populations, thrombocytopenia ( 2 ) , as well as hemolytic anemia ( 3 ) , have occurred with cytomegalovirus infection. Recently, two reports have appeared that suggest a link between this virus and adult thrombocytopenic purpura (1, 4 ) . We have recently encountered a case of thrombocytopenic purpura and hemolysis due to cytomegalovirus in an adult. To our knowledge, this entity has not heretofore been described in the adult.

A 27-year-old white man presented at the Mt. Sinai Hospital with thrombocytopenia and purpura. He had been healthy until 20 days before admission, when general malaise, ROBERT VAN HOOK, M.D. pharyngitis, coryza, and cervical lymphadenopathy occurred. Six days later he noted the onset of ecchymoses over areas of 555 Jasin Drive minor trauma, which progressed during the next few days to Gastonia, North Carolina 28052 diffuse ecchymotic and petechial lesions. At examination the ALEXANDER G. VANDEVELDE, M.D. patient was well developed and well nourished, with obvious Department of Medicine ecchymoses covering legs, arms, and trunk. He was afebrile. University of Florida College of Medicine There was no lymphadenopathy. The spleen was palpated 2 cm University Hospital below the left costal margin. The physical examination showed Jacksonville, Florida 32209 otherwise normal results. His hemoglobin level was 14.7 g/dl; leukocyte count, 66007mm3, with 63% neutrophils, 2% bands, Received 12 May 1975. 25% lymphocytes, and 10% monocytes; reticulocyte count, 1.3%; platelets, 18 000/mm3. Erythrocytes on smear were REFERENCES normochromic and normocytic without schistocytes or abnor1. TOURAINE A: La gangrene gazeuse apres injections medicmal forms. Prothrombin time, activated partial thromboplastin amenteuses. Presse Med 44:674-677, 1936 time, and fibrinogen were normal. Fibrin split products were 2. MARSHALL V, SIMS P: Gas gangrene after injection of adrenalinenot present. Antinuclear antibody, lupus erythematosus cell, in-oil with report of three cases. Med J Aust 2:653-656, 1960 3. KOONS TA, BOYDEN GM: Gas gangrene from parenteral inand heterophil tests were negative. Serum haptoglobin was jection. JAMA 175:46-47, 1961 84 mg/dl. Direct antiglobulin (Coombs') tests (IgG, IgA, 4. BISHOP RF, MARSHALL V: Enhancement of Clostridium welchii IgM, C*3, C'4) were negative. Serum immunoelectrophoresis infection by adrenaline-in-oil. Med J Aust 2:656-657, 1960 showed a diffuse increase in IgM of 340 mg/dl. Acute titers 5. DREWETT SE, PAYNEfDJH, TUKE W, et al: Skin distribution of for Coxsackie virus, adenovirus, echovirus, mycoplasma Clostridium welchii: use of iodophor as sporicidal agent. Lancet pneumoniae, measles, rubella, toxoplasma, and cytomegalo1:1172-1173,1972 virus were not elevated. Bone marrow was normally cellular with increased numbers of megakaryocytes and normal maturation of all elements. Antiplatelet antibody was not detectable. Cytomegalovirus-lnduced Thrombocytopenia and A technetium-99m liver-spleen scan showed borderline hepatoHemolysis in an Adult splenomegaly. A presumptive diagnosis of idiopathic thrombocytopenic purpura was made, and prednisone therapy, 60 mg daily, was begun. On Day 2, a reticulocytosis of 3.2% was THE ASSOCIATION of thrombocytopenia with viral infections noted, which rose to 6.4% by Day 6, and remained elevated such as rubeola, rubella, varicella, mumps, and infectious

Figure 1 . Temporal relation between cytomegalovirus (CMV) antibody titer and platelet count. CF = complement fixing. 570

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for 3 weeks. There was no evidence of blood loss, nor any fall in the hemoglobin or hematocrit level. The erythrocyte survival (Cr61) was determined at the end of the 3-week period when the reticulocytes had fallen to 2.4%, showing a moderately decreased half-life of 23 days. Thrombocytopenia (platelets were 20 000/mm3) persisted despite 2 weeks of prednisone, up to 100 mg daily, and splenectomy was contemplated. However, convalescent titers for cytomegalovirus showed a significant rise (1:16 to 1:1024) (Figure 1). Because it seemed that the cytomegalovirus was etiologically related to the thrombocytopenia and hemolysis, consideration of splenectomy was deferred, and the course of the illness was followed. As noted in Figure 1, concomitant with falling titers of cytomegalovirus antibody, a rise in platelet count occurred. Steroids were then progressively tapered and the platelet count returned to normal, reticulocytosis disappeared, and the serum haptoglobin rose to 200 mg/dl. A fourfold rise in titer of cytomegalovirus antibody is considered diagnostic of acute infection ( 5 ) . The sixfold increase in complement fixing antibodies in this patient confirmed the diagnosis of cytomegalovirus infection. The temporal relation of a viral syndrome, thrombocytopenia, hemolysis, and rising cytomegalovirus antibody titers, followed by a normalization of the platelet count that paralleled a fall in antibody titers, suggests a causal relation. Splenectomy remains the treatment of choice for idiopathic thrombocytopenic purpura unresponsive to medical therapy, that is, steroids. In viral-induced thrombocytopenia, therapy seems less clear. Chanarin and Walford (1) treated their case of cytomegalovirus thrombocytopenia with prednisone, 60 mg daily, and got a response. Fiala and Kattlove (4) treated their case for 16 days with prednisone, 120 mg daily, and then proceeded to splenectomy, without improvement. Prednisone therapy was then reinstituted with the platelet count reaching normal values on the 46th day. In the case presented here, platelet counts rose as the viral titer fell. It is suggested that in documented cases of viral associated thrombocytopenia, splenectomy be withheld as long as possible, with careful monitoring of serial viral antibody titers. Cytomegalovirus must now be considered as one of the etiologic agents in adult-onset thrombocytopenia, occurring either alone or in combination with hemolysis. Before the diagnosis of idiopathic thrombocytopenic purpura is made, a careful search for a viral cause should be undertaken. ALLAN I. HARRIS, M.D. RICHARD J. MEYER, M.D. EUGENE A. BRODY, M.D., F.A.C.P.

Department of Medicine Mt. Sinai School of Medicine City University of New York New York, New York 10029

Received 16 June 1975. REFERENCES

1. CHANARIN I, WALFORD D: Thrombocytopenic purpura in cytomegalovirus mononucleosis. Lancet 2:238-239, 1973 2. OSKI A, NAIMAN JL: Hematologic Problems in the Newborn. Philadelphia, W. B. Saunders Co., 1967, p. 37 3. COOMBS J: Cytomegalic inclusion disease associated with autoimmune haemolytic anemia. Br Med J 2:743-744, 1968 4. FIALA M, KATTLOVE H: Cytomegalovirus mononucleosis with severe thrombocytopenia. Ann Intern Med 79:450-451, 1973 5. DEIBEL R, SMITH R, CLARK L, et al: Cytomegalic virus in-

fection in New York State. NY State J Med 74:785-791, 1974

Cephalothin-lnduced Granulocytopenia SINCE its introduction in 1962, cephalothin (Keflin®) has assumed a major role in the therapy of bacterial infection. There have been only sporadic reports of granulocytopenia caused by cephalothin therapy (1-3). The appearance of four such cases in a 1-year period has prompted us to report the experience at our institution. A computer survey of hospital discharge summaries for 1974 was done, and all cases reported as neutropenia or granulocytopenia secondary to medication were reviewed. Criteria for study included a granulocyte count of less than 1000/mm 3 and absence of any other cause of neutropenia such as malignancy, collagen disease, hypersplenism, or treatment with radiotherapy or chemotherapeutic agents. Table 1 summarizes the four cases of cephalothin-induced granulocytopenia. The patients received the medication intravenously in doses of 4 to 12 g/day. None of the patients developed ulcerative pharyngitis or a fulminant illness as a result of the granulocytopenia. N o depression of the erythrocyte or platelet count was evident. Bone marrow examination was done in two patients and showed the feature of "maturation arrest" at the myelocyte or metamyelocyte stage. In each case, omission of cephalothin was followed by a rapid rise in granulocytes in the peripheral blood and complete hematologic recovery within 5 days. Other medications being administered included procainamide, aspirin, acetaminophen, diazepam (Valium®), flurazepam hydrochloride (Dalmane®), Seconal, and morphine sulfate. These medications were excluded as offending agents, since they were either continued during the episode of granulocytopenia, or were resumed after hematologic recovery without a recurrence of the granulocytopenia. Although severe sepsis is recognized as a cause of granulocytopenia, none of the patients seemed to have sufficient infection present to act as a causal agent for granulocytopenia. N o patient had a history of penicillin allergy, and no other manifestation of penicillin sensitivity

Table 1. Cephalothin-lnduced Granulocytopenia Patient

1 2 3 4

Condition

Staphylococcal pyarthrosis Unexplained fever after coronary artery bypass surgery Unexplained fever after total hip replacement Pneumococcal pneumonia

Count (Granulocytes) Immediately Before Cephalothin Therapy

Nadir of Leukocyte Count (Granulocytes)

Onset from Time of Cephalothin Therapy

Duration of Granulocytopenia

no./mm3 11000(8140) 7500 (3770)

no. /mm3 1725 (275) 1200 (290)

22 days 3 days

2 days 5 days

7100 (5000)

3700 (330)

20 days

5 days

6200 (4100)

1625 (750)

2 days

2 days Letters

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was noted. The mechanism of cephalothin-induced granulocytopenia is unknown and may involve either inhibition of bone marrow myeloid production or the development of anticephalothin antibodies that lead to peripheral granulocyte destruction ( 2 ) . The wide disparity in the onset of granulocytopenia from the initiation of cephalothin therapy may possibly reflect these two different mechanisms. Unfortunately, we were unable to test for anticephalothin antibodies. Granulocytopenia secondary to semisynthetic penicillins also seems to be associated with both early and delayed development of granulocytopenia (4,5). We uncovered only 14 additional cases of idiosyncratic, drug-induced granulocytopenia during 1974, including one case due to nafcillin and one case due to ampicillin. Only one agent was responsible for more than a single case of granulocytopenia (propylthiouracil, two cases). Cephalothin has emerged as a major cause of druginduced granulocytopenia at our institution. Two additional cases have been detected during the first 5 months of 1975. On the basis of information provided by the hospital pharmacy, it is estimated that 3800 patients received courses of cephalothin in 1974. The incidence of cephalothin-induced granulocytopenia seems to be about 0.1%. N o case of granulocytopenia due to other cephalosporin antibiotics was detected, possibly because these agents are not extensively used at our institution. Our experience indicates that the leukocyte count should be monitored during therapy with cephalothin. MARIO-ANTOINE DICATO, M.D.

67, Avenue de la Liberte Differdange, Luxembourg LEONARD ELLMAN, M.D.

Hematology Unit Massachusetts General Hospital Boston, Massachusetts 02114

The patient, a 67-year-old woman, was found to be polycythemic in January 1970. At that time, her hemoglobin level was 18.5 g/dl; hematocrit, 58%; leukocyte count, 14 800/mm"; and platelet count, 1 056 000/mm3. The erythrocyte mass was 49 ml/kg, and the leukocyte alkaline phosphatase score was 139 (normal, 30 to 70). She was treated by phlebotomy and thrombocytophoresis, with improvement in her blood counts. At no time during the course of her disease was she treated with 32P. She was hospitalized in October 1971 with thrombophlebitis of the lower extremities and again in December 1971 for a suspected pulmonary embolus. At that time her platelet count was 672 000/mm3. She was treated with chlorambucil, 6 mg daily, which was tapered and stopped after her platelet count had returned to normal. In October 1972 monoblasts were seen on her peripheral blood smear for the first time. In February 1973 her hemoglobin level was 12.2 g/dl; hematocrit, 34%; and leukocyte count, 69 000/mm3 (28% segmented neutrophils, 4% bands, 3% metamyelocytes, 1% myelocytes, 2% promyelocytes, 9% lymphocytes, 14% monocytes, and 49% monoblasts). Her platelet count was 175 000/mm3. The bone marrow aspirate showed 43% monoblasts and 10% myeloblasts. The myeloid:erythroid ratio was 6.4:1. Megakaryocytes were present but small in number. Sections of the marrow clot were "100%" cellular. Leukocyte alkaline phosphatase score was 60 (normal, 30 to 130). She received no chemotherapy at that time. By March 1973 she became pancytopenia with a hemoglobin level of 8.4 g/dl; platelet count, 37 500/mm3; and leukocyte count, 3200/mm3. She was treated with two 5-day courses of cytosine arabinoside and 6-thioguanine. By April 1973 she was in remission. During the next 3 months her blood counts continued to rise, and by June 1973 her hemoglobin level was 18.4 g/dl; hematocrit, 58%; platelet count, 530 000/mm3; and leukocyte count, 24 000/mm" (69% segmented neutrophils, 28% lymphocytes, and 3% monocytes). The erythrocyte volume was 2400 ml, with a calculated normal volume of 1300 ml. She received another course of cytosine arabinoside and 6-thioguanine, and her blood counts returned to normal. In September and November 1973 she again became polycythemic, and each time after chemotherapy her blood counts returned to normal.

In January 1974 she developed increasing numbers of monoblasts in her peripheral blood. Her hemoglobin level was 13.1 g/dl; platelet count, 154 000/mm3; and leukocyte count, 23 300 (35% monoblasts). She received another course of cytosine REFERENCES arabinoside and 6-thioguanine but failed to respond. She be1. DAVIS A, SIEGLMAN SJ, HEWITT WH, et al: Neutropenic reaction to cephalothin therapy. Antimicrob Agents Chemother 1963, pp. came anemic and thrombocytopenic, and her leukocyte count continued to rise. At the time of her death in March 1974, 272-277 her hemoglobin level was 8.5 g/dl; platelet count, 71 000/mm"; 2. LEVIN AS, WEINER RS, FUDENBERG HH, et al: Granulocytopenia caused by anti-cephalothin antibodies (abstract). Clin Res 19:424, and leukocyte count, 104 800 (76% monoblasts). 1971 3. SILBER SJ, DIOKNO A: Agranulocytosis from cephalosporins Neither polycythemia vera after acute leukemia nor the (letter). JAMA 224:1427, 1973 sequence of polycythemia vera —> acute leukemia —> poly4. GRAF M, TARLOV A: Agranulocytosis with monohistiocytosis cythemia vera —> acute leukemia has been reported preassociated with ampicillin therapy. Ann Intern Med 69:91-95, 1968 viously. A partial explanation for the absence of such 5. MARKOWITZ SM, ROTHKOPF M, HOLDEN FD, et al: Nafcillinreports may be the apparent rarity of obtaining a complete induced agranulocytosis. JAMA 232:1150-1152, 1975 remission in acute leukemia after polycythemia vera. Only two such cases are reported in the literature, and neither Polycythemia Vera and Acute Leukemia mentions the return of a polycythemic state after remission of acute leukemia (3, 4 ) . Another possible explanation THE TRANSFORMATION of polycythemia vera into acute may be that acute leukemia represents an irreversible leukemia is a well-documented phenomenon and is retransformation in a single, abnormal clone of cells that ported to occur as a terminal complication in approxioriginally manifested the characteristics of polycythemia mately 15% of polycythemia vera patients (1, 2 ) . The vera. Chromosomal studies of bone marrow cells from our role of 32P-therapy in the cause of leukemia in this setting patient were done when she manifested polycythemia vera is controversial. We have recently treated a patient with and again when she had acute leukemia and might have polycythemia vera who developed acute myelomonocytic resolved the question of whether there were one or two leukemia. Subsequent to remission induction with chemoabnormal clones of cells. Unfortunately, these studies were therapy, she developed polycythemia vera once again technically unsatisfactory. before eventually dying of acute leukemia. To our knowlFinally, the question of the relation, if any, between the edge, this is the first recorded instance of this sequence treatment of polycythemia vera with alkylating agents and of events. the development of acute leukemia is raised ( 1 ) . In our Received 14 April 1975.

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patient, there was an interval of less than a year between initiation of treatment with chlorambucil and the development of acute leukemia. The likelihood that the two were related is remote. It seems more likely that our patient had a single underlying hematologic disorder expressing itself alternatively as polycythemia vera and acute leukemia. L E O T. N E U , M.D., F.A.C.P.

Smith-Glynn-Callaway Clinic 1211 South Glenstone Springfield, Missouri 65804 MARC A. SHUMAN, M.D. E L M E R B. BROWN, M.D.

Division of Hematology Washington University School of Medicine 660 South Euclid St. Louis, Missouri 63110 Received 28 April 1975. REFERENCES

1. MODAN B, LILLIENFELD AM: Polycythemia vera and leukemia— the role of radiation treatment. A study of 1222 patients. Medicine 44:305-344, 1965 2. LAWRENCE JH, WINCHELL HS, DONALD WG: Leukemia in poly-

cythemia vera. Relationship to splenic myeloid metaplasia and therapeutic radiation dose. Ann Intern Med 70:763-771, 1969 3. PERLIN E, GRANATIR RG, ROCHE J, et al: Remission of leukemia

associated with polycythemia vera (letter). JAMA IIZ-.Y)!, 1973 4. LEE SL, ROSNER F: Treatment of AGL. Arch Intern Med 123: 205-206, 1969

IgA Myeloma Globulin and Bence Jones Proteinuria in Diffuse Plasmacytoma of Small Intestine WHETHER single or multiple, primary plasmacytomas of the small intestine are usually nodular and circumscribed tumors ( 1 , 2 ) , whereas alpha chain disease is usually characterized by a diffuse plasma cell proliferation of the whole length of the small intestine and of mesenteric lymph nodes ( 3 , 4 ) . This disease affects young patients of particular geographic origin and may include most cases of so-called "Mediterranean-type" of abdominal lymphoma with malabsorption ( 5 ) . We have studied a Turkish patient with clinicopathologic features analogous to those of alpha chain disease. We found in him a true IgA myeloma globulin and Bence Jones protein. A 40-year-old man complained of diarrhea and loss of weight during the previous 5 years. No relevant information was found in his past history. Physical examination showed negative results. There was no enlargement of liver, spleen, or peripheral lymph nodes, and no palpable abdominal masses. Examination of the stools showed marked steatorrhea. An oral glucose tolerance test gave a flat curve. Blood electrolyte and calcium levels were normal, as well as renal and hepatic functions. Roentgenologic study of the gastrointestinal tract showed marked irregularity of the jejunal mucosa, with numerous filling defects and dilatation of the ileum. Skeletal X-ray survey disclosed no osteolytic lesions. Blood counts were normal except for anemia (hemoglobin, 8.8 g/dl). Repeated bone marrow examinations gave normal results. The serum protein level was 8.9 g/dl. A narrow band was easily detectable in the j32 region at serum electrophoresis. Immunoelectrophoretic analysis with monospecific antiserums identified this monoclonal component as an IgA myeloma globulin with K light chains and a 1 heavy chains. Kappa Bence Jones protein was found in the serum and urine, the urinary output being 0.8 to 2 g/day.

On laparotomy, the whole length of the jejunum and ileum seemed thickened, and the mesenteric lymph nodes were enlarged. Biopsy specimens (examined by Professor Henry Rappaport) showed a diffuse and massive infiltration of the lamina propria by a purely plasmacytic proliferation without blunting of the villi. The epithelial architecture of the intestine was within normal limits. The mesenteric fat tissue and the lymph nodes showed a massive infiltration with plasma cells, with a complete effacement of the follicular architecture of the nodes. In many areas, true sheets of plasma cells were found. The plasma cells seemed well differentiated, with relatively little variation in size and shape of the nuclei and little mitotic activity. Despite therapy with cyclophosphamide, melphalan, chlorambucil, and prednisolone, the patient did not improve and died a year later. Postmortem study was not done. The clinical features and the geographic origin of this patient simulated alpha chain disease. The pathologic findings were similar to those observed in this condition except for the absence of blunting of villi and of significant separation of the crypts. However, the monoclonal components found in serum and urine were a typical myeloma IgA protein with free light chains. This case represents an exception to the statement that the plasma cell proliferation resulting presumably from the antigenic stimulus by intestinal microorganisms (strongly suggested by the geographic distribution of alpha chain disease) seems to lead always to alpha chain disease and never to IgA plasmacytoma ( 5 ) . Y. TANGUN Z. SARACBASI S. INCEMAN

Department of Hematology Clinic of Internal Medicine Istanbul Medical Faculty Capa Istanbul, Turkey F. DANON M. SELIGMANN

Laboratoire d'Immunochimie Hopital Saint Louis 75475 Paris, Cedex 10, France Received 18 April 1975. REFERENCES

1. GOLDSTEIN WB, POKER N: Multiple myeloma involving the gastrointestinal tract. Gastroenterology 51:87-93, 1966 2. DOUGLASS HO JR, SIKA JV, LEVEEN HH: Plasmacytoma: a not

so rare tumor of the small intestine. Cancer 28:456-460, 1971 3. SELIGMANN M, DANON F, HUREZ D, et al: Alpha chain disease:

a new immunoglobulin abnormality. Science 162:1396-1397, 1968 4. RAMBAUD JC, BOGNEL C, PROST A, et al: Clinico-pathological

study of a patient with "Mediterranean" type of abdominal lymphoma and a new type of IgA abnormality ("alpha chain disease"). Digestion 1:321-336, 1968 5. SELIGMANN M: The main immunochemical, clinical and pathological features of alpha chain disease. Arch Intern Med 135: 78-82, 1975

Disulfiram Hepatotoxicity K E E F F E AND SMITH (1) recently reported a case of hepatotoxicity caused by disulfiram. Despite wide use of disulfiram for the treatment of alcoholism, hepatotoxic reactions had not previously been noted. Hepatotoxic reactions may be extremely rare; alternatively, drug-related hepatic disease may have been overlooked because of the high prevalance of alcoholic liver disease in the population treated with disulfiram. We describe a patient who deLetters

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veloped severe hepatic dysfunction after two separate exposures to disulfiram. The patient is a 49-year-old black man with a history of chronic alcoholism. He has been in good health and had been hospitalized only once for an appendectomy 20 years ago. He took disulfiram (250 mg daily) for 4 months in 1973. In April 1974 while living in a rehabilitation center for alcoholism he again was given disulfiram, 250 mg daily. He took no other medications. Four weeks later, while still on disulfiram, he developed jaundice and mild pruritis. Physical examination on

Figure 1A. Liver biopsy, obtained during the patient's first hospital admission, showing mononuclear cellular infiltrate, hepatocellular necrosis, and Councilman-like bodies. B. Higher magnification of the same biopsy specimen. C. Exposure to disulfiram occurred during the times indicated by horizontal bars. Serum bilirubin ( O - - - O ) and serum glutamic oxalacetic transaminase (SGOT) activity ( # — # ) are depicted. 574

admission to the hospital showed a muscular, well-nourished man who was deeply icteric. Vital signs were normal; there was no lymphadenopathy. Abdominal examination showed an old appendectomy scar. The liver span was 15 cm to percussion. The liver edge was palpable 1 cm below the right costal margin. The edge was firm and slightly tender without nodularity. There was no splenomegaly, ascites, or peripheral edema. The testes were normal. The bilirubin was 43.0 mg/dl; serum glutamic oxalacetic transaminase (SGOT), 1650 nm/ml; alkaline phosphatase, 220 nm/ml; lactic dehydrogenase (LDH), 504 nm/ml; and serum glutamic pyruvic transaminase (SGPT), 801 nm/ml. Disulfiram was stopped. A transcostal liver biopsy was done on the second hospital day (Figure \A and B). The SGOT decreased markedly and on the fourth hospital day was 278 nm/ml. Total bilirubin was 33.9 mg/dl (27.5 mg/dl direct and 6.4 mg/dl indirect reacting); HBS Antigen was negative by radioimmunoassay. The patient was discharged and seen 1 week later. He felt well and liver function tests showed continued improvement. Four weeks after discharge, unknown to us, disulfiram was again started at the rehabilitation center. Within 4 days he noted the onset of jaundice and was again admitted to the hospital. Physical examination was essentially unchanged. Hematocrit was 39.5; leukocyte count was 5600 with 48% neutrophils, 41% lymphocytes, 10% monocytes, and 1% eosinophils. Reticulocyte count was 1.9%. Erythrocyte G6PD activity was within normal limits. Hemoglobin electrophoresis showed hemoglobin A. The bilirubin was 25.0 mg/dl; SGOT, 1245 nm/ ml; LDH, 397 nm/ml; alkaline phosphatase, 211 nm/ml; and SGPT, 407 nm/ml. Prothrombin time was 14.3 seconds with a control of 11.4. Total protein was 7.4 gm/dl and albumin was 3.2 gm/dl. Liver function tests showed gradual improvement. Transcostal liver biopsy on the 20th hospital day again showed hepatocellular necrosis, with bridging and mononuclear cellular infiltrates; HBsAg was negative. Antibodies to the hepatitis A virus as measured by immune electron microscopy (done by Dr. J. Deinstag and Dr. R. Purcell, Bethesda, Maryland), were absent in acute serums and in serum obtained 5 months after discharge. The patient was discharged on the 24th hospital day. Liver function tests slowly returned to normal during the next 3 months. Representative bilirubin concentrations and SGOT activities are shown in Figure 1C. This patient had two episodes of severe hepatic dysfunction, which occurred after two separate exposures to disulfiram. Liver biopies showed evidence of extensive hepatocellular necrosis, but no evidence of active alcoholic liver disease such as steatosis or hyaline degeneration. The patient reported by Keeffe and Smith (1) exhibited similar, but less severe, evidence of hepatocellular necrosis after two separate exposures to disulfiram. Although there is a close temporal relation between the exposure to disulfiram and the development of hepatotoxicity in this patient, conclusive proof of a causal role for the drug would require rechallenge in a hospital setting. However, the extent of hepatic necrosis in this patient and the unpredictable effects of further exposure to the drug precluded rechallenge. Viral causes were considered. Hepatitis B is unlikely because radioimmunoassays for HB 8 Ag were repeatedly negative. Hepatitis A is more difficult to exclude; however, acute and convalescent serums from this patient did not contain antibodies to an antigen associated with Hepatitis A as measured by immunoelectron microscopy (2). HOWARD J. EISEN, M.D. ALLEN L. GINSBERG, M.D.

Division of Gastroenterology Department of Medicine

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George Washington University School of Medicine Washington, DC 20037 Received 30 May 1975. REFERENCES

1. KEEFFE EB, SMITH FW: Disulfiram hypersensitivity hepatitis. JAMA 230:435-436, 1974 2. FEINSTONE SM, KAPIKIAN AZ, PURCELL RH: Hepatitis A: de-

tection by immunoelectron microscopy of a virus-like antigen associated with acute illness. Science 182:1026-1028, 1973

Bleeding Diathesis in Fresh Water Drowning NEAR-DROWNING in humans is a well-recognized clinical entity associated with a wide range of physiological derangements. Among the most frequent findings are acidosis and hypoxemia (1-3). Hemolysis occurs with varying frequency ( 1 , 2 ) , especially in fresh water drowning. The following case illustrates an acquired bleeding disorder associated with the above findings. A 20-year-old man was recovered from a fresh water lake while swimming. He had reportedly been drinking beer earlier that day, though he was not intoxicated. Use of any other drug was strongly denied by companions. Treatment in a local emergency room consisted of intubation with ventilatory assistance, oxygen therapy, parenteral epinephrine, and corticosteroids. Upon arrival at the Riverside General Hospital he had fixed and dilated pupils, mild cyanosis, frequent ectopic beats of multiple origin, and was being maintained on assisted ventilation. He had no history of bleeding tendency. Initial laboratory tests showed hemoglobin, 17.1 g/dl; leukocyte count, 29 000/mm3 with 34% segmented neutrophils, 26% bands, and 40% lymphocytes. Platelet count on admission was 191 000/mm3. The urine was grossly bloody and had detectable free hemoglobin. Arterial blood gases on 100% oxygen showed pH, 6.95; Po2, 45 mm Hg; Pco2, 67 mm Hg. All blood specimens showed evidence of gross hemolysis. During the following 8 hours bloody fluid was suctioned from the endotracheal tube and the patient had onset of bleeding per rectum, bloody return via nasogastric tube, and bleeding around the indwelling urinary catheter. Sites of venous and arterial puncture developed hematomas and required prolonged application of pressure for hemostasis. Clotting studies at that time showed hemoglobin, 15.2 g/dl; partial thromboplastin time greater than 200 sec with control of 36 sec; and prothrombin time greater than 100 sec with control of 10.5 sec. Fibrinogen levels on two occasions were less than 15 mg/dl. Fibrin split products were undetectable. Therapy with fresh frozen plasma, whole blood, 5000 U of intravenous heparin during 6 hours, and vitamin K produced notable abatement of the bleeding. Despite 2 litres of normal saline plus 1 U each of whole blood and fresh frozen plasma, the patient continued to exhibit a state of clinical shock with hypotension, oliguria, and a central venous pressure less than 2 cm water. Assisted ventilation with 100% oxygen and intermittent positive-pressure breathing with ethanol failed to reverse the hypoxemia and the patient expired 14 hours after admission. One review of near-drowning (2) refers to minor bleeding phenomena associated with the submersion syndrome. No information regarding the mechanism of this problem is given. The above case shows an acquired bleeding diathesis that is compatible with the syndrome of disseminated intravascular coagulation ( D I C ) . Data confirming this pathophysiology is, unfortunately, not available but the clinical setting suggests several etiologic factors that may be initiators of intravascular coagulation in drowning victims. Two major derangements cited as provoking intravascu-

lar coagulation are intravascular hemolysis with release of erythrocyte thromboplastin and severe hypoxemia (4, 5). A promoting factor of the coagulation process is acidosis ( 5 ) . As previously noted, severe hypoxemia and acidosis are virtually universal findings in drowning, and hemolysis is a common occurrence in fresh water submersion with its severity related to the quantity of water absorbed and degree of expansion of the blood volume ( 1 ) . A review of 10 cases of fresh water submersion seen in the Loma Linda University Hospital in the past 5 years failed to show any bleeding episode, but in no case was there significant hemolysis, and the acidosis and hypoxemia were mild in each case. The clinical course and laboratory findings of the above case suggest that victims of fresh water submersion should be evaluated for intravascular hemolysis and, should bleeding occur, appropriate studies for DIC be undertaken. ROY M. CULPEPPER, M.D.

Department of Medicine Loma Linda University Medical Center Loma Linda, California 92354 Received 22 May 1975. REFERENCES

1. MODELL JH: The pathophysiology and treatment of drowning. Acta Anaesth Scand 29 (suppl) :263-271, 1968 2. FULLER RH: The clinical pathology of human near-drowning. Proc Roy Soc Med 56:33-38, 1963 3. HASAN S, AVERY WG, FABIAN C, et al: Near-drowning in hu-

mans. A report of 36 patients. Chest 59:191-197, 1971 4. MCKAY DG: Progress in disseminated intravascular coagulation. Calif Med 111:186-198, 1969 5. HARDAWAY RM: Syndrome of DIC. Springfield, Illinois, Charles C Thomas, 1966

Polydipsia and Inappropriate Secretion of Antidiuretic Hormone Associated with Hydrocephalus HYPONATREMIC SEIZURES and coma associated with acute psychosis were recently reported in the Annals of Internal Medicine (1). The patient is a 26-year-old white woman with undifferentiated schizophrenia and intermittent compulsive water drinking. Since her prior evaluation documenting episodic inappropriate secretion of antidiuretic hormone (ADH) (1), the patient has been treated for hyponatremic seizures in at least four hospitals in the western United States and Canada. The patient was admitted to Stanford University Hospital, unresponsive with generalized seizures after drinking a large quantity of water. Urinary incontinence not associated with coma had been noted. There were no localizing neurological signs. A chest X ray showed pulmonary edema. Serum sodium was 113 meq/litre. Urine osmolality was 207 milliosmols/litre. Twenty-four hours after treatment with hypertonic saline and furosemide the patient was alert and had 3 litres net urinary output. Urinary sodium was 14 meq/litre. Urinary osmolality was 883 milliosmols/litre when serum osmolality was 318 milliosmols/litre. A lumbar puncture and brain scan were normal. After 1 week of stabilization in the hospital, 0800-h serum Cortisol levels were 3.1 and 9.4 mg/dl on two occasions; 2000-h serum Cortisol was 1.6 mg/dl. A cosyntropin test was normal. The result of a serum tetraiodothyronine by the Murphy-Pattee method was 3.3 mg/dl (normal, 3.9 to 7.5 mg/dl), a triiodothyronine resin test was normal, and the thyroid-stimulating hormone level was less than 5 U. Urinary follicle-stimulating hormone and luteinizing hormone were normal. A vaginal Papanicolaou smear showed 4% basal cells, 93% intermediate cells, and 3% superficial cells. The urinary delta-amino levulinic acid level was normal. An electroLetters

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Figure 1 . AP brow-up polytome laminogram. The anterior third ventricle is widened and the upper outer portions of the lateral ventricles are rounded, an early sign of enlargement. The foramina of Munro are patent.

encephalogram showed diffuse slowing of background rhythms and intermittent irregular bifrontal delta and theta activity. A pneumoencephalogram with polytomography of the hypothalamus showed enlargement of the third ventricle without suprasellar tumor (Figure 1). The lateral ventricles showed early signs of enlargement and there was air over the convexity. A three-vessel cerebral arteriogram showed no further abnormalities. An indium111 cisternogram was normal. Since discharge, the patient has been healthy and free of seizures for 12 months while receiving bimonthly intramuscular fluphenazine hydrochloride. Transient inappropriate secretion of ADH has been previously noted in a schizophrenic man who periodically drank water to excess ( 2 ) . "Water intoxication" in patients with psychiatric illness has been reported by several authors. In most cases there is not sufficient information to exclude transient inappropriate secretion of ADH as a contributing factor along with compulsive water drinking in the development of hyponatremia and seizures or coma. It is usually assumed that voluntary ingestion of water in healthy people cannot produce water intoxication unless there are complicating factors such as diuretic therapy. Normal subjects given as much as 8.5 litres of daily fluid during a 4-week period showed no change in serum osmolality and a tendency to reduce urine osmolality ( 3 ) . However, a normal child with severe toothache and polydipsia developed hyponatremic convulsions, presumably with pain-induced ADH release ( 4 ) . Salt depletion, on the other hand, does reduce the capacity to excrete a water load independent of changes in ADH. The inappropriate secretion of ADH syndrome divides into two general groups: patients with ectopic production of ADH activity by neoplasms and patients with abnor-

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malities in control mechanisms for endogenous ADH production and release. Because inappropriate secretion of ADH is usually not diagnosed by direct hormone assay, but rather by a collection of physiologic effects of ADH, cases will likely be found indistinguishable from inappropriate secretion of ADH by classical criteria but with immunologically distinct chemical mediators. A variety of central nervous system pathology has been associated with water intoxication and inappropriate secretion of ADH. Subarachnoid hemorrhage, pituitary neoplasm, neoplasia metastatic to the central nervous system, mamillary body atrophy, ruptured cerebral aneurysm, and basilar skull fracture have all been seen in association with inappropriate secretion of ADH. Obstructive hydrocephalus has been associated with hyperdipsia as an early symptom (5). Stimulation of a hypothalamic thirst center by the enlarging third ventricle was postulated as a mechanism. The current patient is the first reported case of hydrocephalus associated with inappropriate secretion of ADH. The finding of normal isotope cisternography indicated this hydrocephalus was of the nonobstructive communicating type without likelihood of benefit by cisternal shunting procedures. The relation of polydipsia, inappropriate secretion of ADH, and hydrocephalus in this setting cannot be completely defined. Conceivably, cerebral atrophy and hydrocephalus could be the sequels of repeated episodes of cerebral edema from hyponatremia. Alternatively, dilatation of the third ventricle could exert pressure effects on the anatomically adjacent thirst and vasopressin centers resulting in both so-called "psychogenic" polydipsia and inappropriate secretion of ADH. In experimental animals it is possible to elicit thirst, antidiuresis, or both, depending upon which single area of the anterior hypothalamus is stimulated electrically ( 6 ) . Thus organic lesions of the hypothalamus could be expected to commonly result in combined aberrations of thirst and vasopressin control. The authors thank Dr. J. S. Kroger and Dr. Donna Larson of Longmont, Colorado, who have cared for the patient and reported her subsequent course. DANIEL T. PETERSON, M.D. WILLIAM H. MARSHALL, M.D.

Departments of Medicine and Radiology Stanford University Medical Center Stanford, California 94305 Received 18 April 1975. REFERENCES 1. DUBOVSKY SL, GRABON S, BERTL T, et al: Syndrome of inap-

propriate secretion of antidiuretic hormone with exacerbated psychosis. Ann Intern Med 79:551-554, 1973 2. HOBSON J A, ENGLISH JT: Self-induced water intoxication. Case study of a chronically schizophrenic patient with physiological evidence of water retention due to inappropriate release of antidiuretic hormone. Ann Intern Med 58:324-332, 1963 3. HABENER JF, DASHE AM, SOLOMON DH: Response of normal

subjects to prolonged high fluid intake. / Appl Physiol 19:134136, 1964 4. PICKERING L, HOGAN G: Voluntary water intoxication in a normal child. J Pediatr 78:316-318, 1971 5. HOGAN PA, WOOLSEY RM: Polydipsia associated with occult hydrocephalus. N Engl J Med 277:639-640, 1967 6. ANDERSSON B: Polydipsia, antidiuresis and milk ejection caused by hypothalamic stimulation, in The Neurohypophysis, edited by HELLER H. New York, Academic Press, 1957, pp. 131-140

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