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. Australia Antigen and Malignant Hepatoma IN 1970 SHERLOCK AND CO-WORKERS (1) were the first to

describe five cases of malignant hepatoma associated with a positive A u ( l ) serologic test. Some months later, there was a report of a high prevalence of A u ( l ) in the serum of Ugandan patients with hepatocellular carcinoma. These findings "provided suggestive evidence that virus hepatitis B at least is a precancerous condition" ( 2 ) . However, the results of other investigations carried out in different areas of the world to establish this association are controversial. A high prevalence of A u ( l ) has been observed in patients suffering from hepatoma in Senegal, Uganda, India, Spain, Chile, Greece, Kenya, Formosa, and Italy, although in Singapore, the United States, Hong Kong, East Africa, the United Kingdom, South Vietnam, and France the prevalence has not been higher than that found in the general population. In order to reevaluate these contradictory results, we decided to undertake a study concerning the prevalence of A u ( l ) in the serum of Greek patients suffering from hepatocellular cancer by using double immunodiffusion, electroimmunodifTusion, and radioimmunoassay methods. 189 Greek patients, all 50 years of age or older, suffered from either hepatoma with hepatic cirrhosis (Group A, 77 patients) or cirrhosis without evidence of hepatoma (Group B, 112 patients). Their serums were studied for the presence of Au(l) (Table 1). The diagnosis of hepatoma was confirmed histologically in 46 patients, while the clinical diagnosis was supported by biological and scintigraphic data, as well as by a positive alpha 1-fetoprotein test, in the remaining 31 patients. The coincidental cirrhosis was confirmed histologically in 47 patients, while in the remaining 30 patients clinical, biological, and scintigraphic data provided evidence of cirrhosis, inasmuch as clotting abnormalities or great ascites did not permit a liver biopsy. In Group B, the diagnosis of cirrhosis was supported by clinical, biological, scintigraphic, and histologic criteria. Serums from 106 apparently healthy Greek persons, all more than 50 years old as well, have been studied as a control population (Table 1). Serums were tested for the presence of A u ( l ) by these methods: [1] Ouchterlony double immunodiffusion in agarose, 1.5% (buffer:barbital 0.009 M, barbital sodium 0.05 M, calcium lactate 0.005 M, pH 8.5); [2] electroimmunodifTusion, with specific human and rabbit antiserums used in both instances; and [3] radioimmunoassay, with Ausria-125®, done according to the manufacturer's instructions (Abbott Labora-

Table 1 . Prevalence of A u ( l ) in Malignant Hepatoma and Cirrhosis

Groups

Cases no.

Group A: malignant hepatoma with cirrhosis Group B: cirrhosis without hepatoma Normal population

Au(l) Positive by Radioimmunoassay no. (%)

77

44(57.1)*

112 106

60 (53.6) * 5 (4.7)

* Chi-square = 0.113; 0.8 > P > 0.7.

tories, North Chicago, Illinois). When the presence of A u ( l ) was discovered only by the radioimmunoassay test, the possibility of false-positive reaction (3) was excluded by repetition of the radioimmunoassay test after neutralization of the serum with an equal amount of specific anti-Au(l) antiserum, as well as after dilution of the serum 1:1 with NaCl, 0.9% solution. Alpha 1 fetoprotein was detected by the Ouchterlony double immunodiffusion or the electroimmunodiffusion methods (4) using specific rabbit antiserum. Statistical analysis was done by using fourfold tables with Yates' correction. Results are shown in Table 1. The A u ( l ) was found by radioimmunoassay in the serum of 44 of 77 patients in Group A suffering from hepatoma and cirrhosis ( 5 7 . 1 % ) , while A u ( l ) was found in 60 out of 112 patients (53.6%) in Group B. These prevalences are not significantly different. These findings do not support the hypothesis that hepatitis B antigenemia is a precancerous condition. If this hypothesis were correct, one would expect a significantly higher prevalence of A u ( l ) in Group A patients than that found in Group B patients. However, Sutnick (5) has postulated that individuals who are susceptible to persistence of hepatitis B antigenemia with some subsequent liver damage may also be susceptible to some other agents that have the potential of causing malignant hepatoma. This hypothesis is compatible with our results. Indeed, we are not excluding the possibility that cirrhotic patients with persistent A u ( l ) antigenemia will develop a malignant hepatoma when the hepatoma-producing agent(s) is (are) plentiful in their environment. G. THEODOROPOULOS, M.D. A. ARCHIMANDRITES, M.D. B. ANGELOPOULOS, M.D.

Department of Pathologic Physiology Medical School University of Athens Athens 609, Greece Received 23 December 1974. REFERENCES

1. SHERLOCK S, Fox RA, NIAZI SP, et al: Chronic liver disease and primary liver-cell cancer with hepatitis-associated (Australia) antigen in serum. Lancet 1:1243-1247, 1970 2. SHERLOCK S: Diseases of the liver and biliary system, 4th ed. Oxford and Edinburgh, Blackwell Scientific Publications, 1971, p. 338 3. PRINCE AM, BROTMAN B, JASS D, et al: Specificity of the direct

809

Downloaded from https://annals.org by Tulane University user on 01/22/2019

solid-phase radioimmunoassay for detection of hepatitis B antigen. Lancet 1:1346-1350, 1973 4. ALPERT E, HERSHBERG R, SCHUR PH, et al: a-Fetoprotein

in hu-

man hepatoma: improved detection in serum and quantitative studies using a new sensitive technique. Gastroenterology 61:137143, 1971 5. SUTNICK AI: Australia antigen: progress report. Med Clin North Am 57:1029-1043, 1973

Ascorbic Acid-Induced Hemolysis in G-6-PD Deficiency T H O U G H T H E ORIGINS of e r y t h r o c y t e

glucose-6-phosphate

d e h y d r o g e n a s e ( G - 6 - P D ) deficiency a r e rooted in h u m a n antiquity, t h e presence of drug-induced hemolysis in individuals subsequently felt to have G - 6 - P D deficiency w a s first reported in 1926 a n d t h e biochemical lesion responsible for this p h e n o m e n o n elucidated in 1 9 5 6 ( 1 ) . I n t h e U n i t e d States, hemolysis induced by infection o r drugs is t h e most c o m m o n clinical manifestation of G - 6 - P D d e ficiency ( 2 ) . Ascorbic acid (vitamin C ) , a n essential vitamin, is c o m monly used in p h a r m a c o l o g i c doses for the prevention of the c o m m o n cold a n d to p r o m o t e t h e healing of w o u n d s . W e report here a n individual with G - 6 - P D deficiency w h o developed intravascular hemolysis a n d acute renal failure after being treated with large a m o u n t s of ascorbic acid. T h e G - 6 - P D isoenzyme present in t h e vast majority of people of African descent with G - 6 - P D deficiency, GdA~, is characterized by rapid electrophoretic mobility, m o d e r a t e deficiency in activity, a n d increased in-vivo lability ( 2 ) . T h e details of t h e p r o c e d u r e s used for t h e detection of G - 6 - P D deficiency have been previously described ( 3 ) . A 68-year-old black man was admitted to the University of Mississippi Medical Center for treatment of acute renal failure. Six days before admission he suffered second-degree burns of the hand. He was hospitalized for treatment and received 80 g of ascorbic acid intravenously on each of 2 consecutive days. Before treatment the urinalysis and hemoglobin concentration were normal. On the third hospital day he became oliguric; the urine was noted to be dark in color and the serum red. The creatinine concentration was 3.9 mg/100 ml and the hemoglobin concentration 5.8 g/100 ml. He was transferred to a regional hospital, given 2 units of blood and corticosteroids, and transferred to the University Medical Center. Upon admission the patient was comatose and in respiratory distress. Physical examination showed a right-sided hemiparesis. The liver and spleen were not enlarged and there was no purpura. The last three digits of his left hand were involved with a seconddegree burn. Laboratory data showed a hemoglobin concentration of 11.8 g/100 ml, leukocyte count of 26 000/mm 3 , and platelet count of 45 000/mm 3 . The reticulocyte count was 5.9%. The peripheral blood film showed schistocytes, poikilocytic cells, nucleated erythrocytes, and diminished numbers of platelets. The serum creatinine was 13.8 mg/100 ml. The patient was anuric. The erythrocyte G-6-PD level was 1.76 I U / g hemoglobin (normal, 8.4 ± 1 . 3 I U ) . Electrophoresis of G-6-PD showed a rapidly moving component ( G d A ) as well as a band of normal mobility ( G d B ) . Cytochemical tests of the patient's erythrocytes showed about 5 0 % of cells lacking G-6-PD activity (normal, < 5 % ) . The patient was begun on hemodialysis with little change in his status. The platelet count rapidly returned to normal. The fibrinogen level, prothrombin time, and partial thromboplastin time were normal suggesting that a possible episode of disseminated intravascular coagulation, likely precipitated by intravascular hemolysis, had abated. His neurologic status deteriorated requiring tracheostomy. An electroencephalogram showed no activity, hemodialysis was discontinued, and he died on the 22nd hospital day. G l u c o s e - 6 - p h o s p h a t e d e h y d r o g e n a s e is a k e y link in t h e 310

June 1975 • Annals of Internal Medicine • Volume 82 • Number 6

Downloaded from https://annals.org by Tulane University user on 01/22/2019

hexose m o n o p h o s p h a t e shunt-glutathione system whose p r i m e function in t h e erythrocyte a p p e a r s t o be t h e p r o tection of this metabolically deprived cell from oxidative d a m a g e ( 2 ) . T h e cell deficient in G - 6 - P D c a n n o t respond appropriately to oxidative stress a n d u n d e r such conditions is susceptible to hemolysis. Infection a n d a diverse g r o u p of drugs h a s been associated with hemolysis in p a tients with G - 6 - P D deficiency ( 2 ) . Ascorbic acid is a n essential vitamin for m a n , which h a s recently been used in t h e t r e a t m e n t of w o u n d s a n d p r o p h y laxis of colds. Large doses a r e employed; however, u n equivocal evidence supporting its value in these disorders is lacking ( 4 ) . A l t h o u g h generally considered to be h a r m less, ascorbic acid is a potent reducing agent a n d h a s been associated with mild degrees of hemolysis w h e n individuals with G - 6 - P D deficiency w e r e given doses of 1 5 0 0 m g 5 , and with oxidative d e n a t u r a t i o n of hemoglobin, a n d a fall in erythrocyte glutathione level when incubated with enzyme-deficient cells in vitro ( 1 ) . I n o u r patient, it a p p e a r s as if unusually large intravenous doses of ascorbic acid led to intravascular hemolysis that precipitated disseminated intravascular coagulation a n d acute renal failure. A l t h o u g h blood transfusions were given before testing for G - 6 - P D deficiency, the large n u m b e r of circulating enzyme-deficient cells a n d low level of e n z y m e activity suggest that G - 6 - P D deficiency existed in this patient before transfusion. T h e p h a r m a c o l o g i c use of ascorbic acid h a s received m u c h publicity in both t h e lay a n d medical press. T h o u g h o u r patient w a s given this d r u g intravenously, a n d in a m o u n t s greater than those usually employed, o u r experience suggests that caution a n d a p p r o p r i a t e testing be used before t h e administration of large doses of ascorbic acid to individuals w h o might b e susceptible t o G - 6 - P D deficiency. G. D O U G L A S C A M P B E L L , J R . , B.A. MARTIN H. STEINBERG, M.D., F.A.C.P. JOHN D. BOWER, M.D., F.A.C.P.

Mr. Campbell and Drs. Steinberg and Bower: Divisions of Hematology and Nephrology Department of Medicine University of Mississippi School of Medicine Jackson, Mississippi 39216 Dr. Steinberg: Special Hematology Laboratory Veterans Administration Hospital Jackson, Mississippi 39216 Received 9 December

1974.

REFERENCES

1. BEUTLER E: The hemolytic effect of primaquine and related compounds: a review. Blood 14:103-138, 1959 2. BEUTLER E: Ahnormalities of the hexose monophosphate shunt. Semin Hematol 8:311-347, 1971 3. STEINBERG MH, DREILING BJ: Glucose-6-phosp^ate dehydrogenase

deficiency in sickle-cell anemia: a study in adults. Ann Intern Med 80:217-220. 1974 4. SCHWARTZ AR, TOGO Y, HORNICK RB, et al: Evaluation of the

efficacy of ascorbic acid in prophylaxis of induced rhinovirus 44 infection in man. J Infect Dis 128:500-505, 1973 5. BREWER GJ, TARLOV AR, ALVING AS: Standardization of pro-

cedures for the study of glucose-6-phosphate dehydrogenase. WHO Tech Rep Ser No. 366, 1967, p. 27

Hypercalcaemia and Multiple Pheochrcmocytomas C A T E C H O L A M I N E S have a n i m p o r t a n t function in a wide r a n g e of b o d y processes, b u t their effects on calcium

Table 1 . Catecholamine and Metabolite Excretion*

Date

Preoperative 8 February 15 February Postoperative 1 March 6 March 8 March 27 March 23 May 24 July 14 October

Free Catecholamines

HMMA

ng/24 h

mg/24 h

1800 2820

9.5 15.3

179 282 222 332 268 281 223

5.2 8.4 7.5 7.2 3.3 13.0 10.9

* Normal values: free catecholamines, < 100 /xg/24 h; 4-hydroxy-3methoxymandelic acid ( H M M A ) , < 5 mg/24 h.

metabolism a r e n o t often recognised. This case r e p o r t concerns t h e association of multiple p h e o c h r o m o c y t o m a s with hypercalcaemia, a n d t h e correction of t h e hypercalcaemia by r e m o v a l of t h e p h e o c h r o m o c y t o m a s . A 20-year-old white man presented with blurred vision, retroorbital headaches, and drenching sweats. On examination the blood pressure was found to be consistently raised with a mean of 230/130 m m Hg. Bilateral p a p i l l e d e m a , retinal haemorrhages, and soft exudates were seen on fundoscopic examination. The serum calcium levels were 11.6, 10.9, and 10.6 mg/100 ml on three successive occasions (normal range, 9.1 to 10.3 mg/100 ml) with the heat-labile serum alkaline phosphatase 164, 169, and 176 /miol/min per litre (normal upper limit, 82 /zmol/min per litre). The catecholamine excretion was grossly abnormal (Table 1 ) . The serum electrolytes and the postprandial plasma glucose levels were within the normal range. Creatinine clearance was 87 ml/min. At operation an encapsulated multilobulated tumour, 8 cm X 6 cm X 6 cm, in the right adrenal gland, and an ovoid tumour, 4 cm X 2.5 cm, in the left sympathetic chain below the left renal pelvis were removed. Histologically these tumours showed the characteristic features of a pheochromocytoma. Postoperatively, there was a highly significant reduction in catecholamine excretion (Table 1) although levels have remained elevated presumably due to another undetected tumour of chromaffin tissue. The patient, however, became normotensive, the papill e d e m a subsided, and the visual acuity improved. Postoperative assays of serum calcium during the ensuing 12 months proved to be normal, varying between 9.5 and 10.2 mg/100 ml. Parathyroid hormone levels were not detectable by radioimmunoassay before or after the operation ( 1 ) . T h e involvement of catecholamines with calcium m e tabolism in clinical situations h a s b e e n cited in t h e literature o n several occasions. T h e s e include single case r e p o r t s of h y p e r c a l c a e m i a ( 2 , 3 ) a n d of hypercalcinuria ( 4 ) corrected b y r e m o v a l of p h e o c h r o m o c y t o m a s a n d frequent reports of p a r a t h y r o i d hyperplasia o r t u m o u r s occurring in association with p h e o c h r o m o c y t o m a s . K u k r e j a a n d colleagues ( 3 ) d e m o n s t r a t e d elevated levels of i m m u n o r e a c t i v e p a r a t h y r o i d h o r m o n e that r e t u r n e d to n o r m a l after t h e r e m o v a l of a p h e o c h r o m o c y t o m a . I n o u r case t h e p a r a t h y r o i d h o r m o n e levels w e r e never elevated, and w e believe this fact deserves emphasis. W e postulate that, in this case, t h e a b n o r m a l i t y of calcium metabolism w a s d u e to a direct action o n skeletal tissue of catecholamines secreted by t h e p h e o c h r o m o cytoma. Experimentally, catecholamines have a n effect o n calcium metabolism in p a r a t h y r o i d e c t o m i s e d animals ( 4 ) . W e suggest that t h e m e d i a t o r of this effect is cyclic A M P

as it h a s been d e m o n s t r a t e d that t h e physiologic actions of p a r a t h y r o i d h o r m o n e o n b o n e a n d renal tubules a r e m e d i a t e d b y cyclic A M P a n d epinephrine is p o t e n t in increasing skeletal content of cyclic A M P ( 5 ) . Similarly, p r o s t a g l a n d i n s — w h i c h have a p a r a t h y r o i d h o r m o n e l i k e effect in raising t h e levels of skeletal cyclic A M P — h a v e been shown t o cause h y p e r c a l c a e m i a in mice that d e velop a fibrosarcoma associated with high p l a s m a levels of prostaglandin E 2 . T h e undetectable levels of p a r a thyroid h o r m o n e in o u r patient indicate that, in contrast to a previous r e p o r t ( 3 ) , catecholamines h a d n o direct t r o p h i c effect o n p a r a t h y r o i d gland secretion. JOHN F. FINLAYSON, F.R.C.P.A.

Department of Pathology Lewisham Hospital Petersham, N.S.W. 2049 Australia J O H N H. CASEY, PH.D., F.R.A.C.P.

Garvan Institute of Medical Research St. Vincent's Hospital Sydney, N.S.W. 2010 Australia Received 10 February 1975. REFERENCES 1. KLEEREKOPER M, INGHAM JP, MCCARTHY SW, et al: Parathyroid

hormone assay in primary hyperparathyroidism: experiences with a radioimmunoassay based on commercially available reagents. Clin Chem 20:369-376, 1974 2. SWINTON NW, CLERKIN EP, FLINT

LD:

Hypercalcemia

3. KUKREJA SC, HARGIS GK, ROSENTHAL IM, et al: Pheochromo-

cytoma causing excessive parathyroid hormone production and hypercalcemia. Ann Intern Med 79:838-840, 1973 4. MOREY ER, KENNY AD: Effects of catecholamines on urinary

calcium and phosphorus in intact and parathyroidectomised rats. Endocrinology 75:78-85, 1964 5. CHASE LR, AURBACK GD: The effects of parathyroid hormone on

the concentration of adenosine 3'5'-monophosphate in skeletal tissue in vitro. J Biol Chem 245:1520-1526, 1970

Inappropriate Secretion of Antidiuretic Hormone from Fluphenazine Therapy T H E S Y N D R O M E of i n a p p r o p r i a t e secretion of antidiuretic h o r m o n e ( A D H ) m a y b e p r o d u c e d by several drugs ( 1 ) . Phenothiazines h a v e n o t been implicated so far in t h e p r o d u c t i o n of this s y n d r o m e , although there is a recent r e p o r t of i n a p p r o p r i a t e secretion of A D H associated with the structurally related tricyclic antidepressant amitriptyline ( 2 ) . I wish n o w t o r e p o r t a case of i n a p p r o p r i a t e secretion of A D H m o s t likely associated with fluphenazine therapy. The patient was admitted to the Montreal General Hospital in coma, following a convulsive episode. This 33-year-old man had been diagnosed as schizophrenic 7 years ago, and prescribed daily doses of chlorpromazine, which he never took in a consistent way. In view of the persistent behavioral manifestations of his psychiatric illness, and despite his complaints of weakness and fatigue when on neuroleptics, he was given 50 mg of fluphenazine enanthate, intramuscularly, 2 days prior to the present admission. During these 2 days, according to the family, the patient drank more fluids than usual. Some hours before admission, his family noticed increasing restlessness and confusion, culminating in a generalized convulsion. Physical examination showed a slightly obese man, responLetters

Downloaded from https://annals.org by Tulane University user on 01/22/2019

and

familial pheochromocytoma. Correction after adrenalectomy. Ann Intern Med 76:455-457, 1972

811

sive only to pain, with symmetrical hyporeflexia. There were no signs of edema or dehydration. Blood pressure was 130/70 mm Hg; pulse rate, 104/min; respiration, 22/min; and temperature, 37 °C. Laboratory examinations: blood count, normal; serum sodium, 115 meq/litre; potassium, 3.3 meq/litre; chloride, 76 meq/litre; calcium, 8.5 mg/100 ml; glucose, 260 mg/100 ml; osmolality of plasma, 247 mOsm/kg H.O; blood urea nitrogen, 6 mg/100 ml; osmolality of urine, 322 mOsm/kg H 2 0 ; electrolyte concentration of urine: sodium, 44 meq/litre, and potassium, 10.2 meq/litre. Chest X-ray, skull X-ray, and brain scan were normal, Spinal fluid examination was normal. Shortly after admission the patient had a second convulsion and was given diazepam, 10 mg, intravenously. In order to correct the hyponatremia, he was given 500 ml of 3 % NaCl intravenously during a period of 6 hours. When he recovered consciousness approximately 24 hours after admission, fluids were restricted, and a steady normalization of the clinical and biochemical state ensued {see Table 1 ) . On the third day of hospitalization his electrolytes had returned to normal. Fluid restrictions were lifted on the fourth day, and his electrolytes remained normal. Other studies done during hospitalization that were normal or negative include creatinine clearance, 121 m l / m i n ; thyroid function tests: serum thyroxin, 8.1 /zg/100 ml, and triiodothyronine uptake, 3 1 . 5 % ; adrenal function tests: plasma Cortisol, 11 /ig/100 ml at 800, and 0.5 /zg/100 ml at 1600; urinary excretion of 17-ketosteroids, 25.7 mg/24h; and urinary excretion of 17-OH corticosteroids, 5.7 mg/24h. Investigation of urine for porphyrins was negative. The electrocardiogram was normal. The electroencephalogram showed bilateral theta activity at the temporal lobes, which was attributed to the psychotropic medication. The extreme uncooperativeness of the patient made further studies impossible, and he was finally discharged with the advice to moderate his fluid intake after receiving his medication. T h e clinical features presented b y this patient meet t h e five criteria of the s y n d r o m e of i n a p p r o p r i a t e secretion of A D H set d o w n b y Bartter ( 1 ) : ( a ) h y p o n a t r e m i a a n d hypoosmolality of extracellular fluids, ( b ) persistence of sodium in u r i n e despite h y p o n a t r e m i a , ( c ) absence of signs of dehydration, ( d ) n o r m a l renal function, a n d ( e ) n o r m a l a d r e n a l function. Simple water intoxication arising from polydipsia m a y indeed occur in psychotics ( 3 ) , b u t if A D H secretion is appropriately suppressed, t h e u r i n a r y osmolality is at t h e m i n i m a l possible value f o r t h e particular patient, which is n o t the case in o u r patient. T h e exclusion of other possible causes of i n a p p r o p r i a t e secretion of A D H ( t u m o r s , endocrine disease, a n d cirrhosis with ascites) a n d t h e t e m p o r a l relation t o t h e a d m i n i s t i a t i o n of fluphenazine, point t o t h e latter as t h e most likely cause. T h e previous complaints of weakness and fatigue when taking phenothiazines m a y reflect transient episodes of h y p o n a t r e m i a , secondary to i n a p p r o p r i a t e secretion of A D H . T h e increased absorption of fluids r e Table 1. Normalization of Electrolyte Concentration*

p o r t e d after receiving t h e fluphenazine p r o b a b l y a g gravated t h e tendency t o w a r d water intoxication, leading to t h e severe clinical picture observed. T h e r e is of course t h e possibility that t h e s y n d r o m e of i n a p p r o p r i a t e secretion of A D H observed in this patient is related to t h e schizophrenia itself o r to s o m e other u n k n o w n factor, b u t t h e evidence presented seems suggestive e n o u g h to justify research o n t h e effects of phenothiazines on A D H secretion, a n d to b e alert to t h e presentation of m i n o r s y m p t o m s of i n a p p r o p r i a t e secretion of A D H in patients taking phenothiazines a n d related c o m p o u n d s . J. L. G . D E R I V E R A , M . D .

Psychiatric Consultation Service Montreal General Hospital Montreal, Quebec H3A 1A1 Canada Received 6 December 1974. REFERENCES

1. BARTTER FC: The Syndrome of Inappropriate Secretion of Antidiuretic Hormone. Chicago, Year Book Medical Publishers, Inc., 1973 2. LUZECKY MH: The syndrome of inappropriate secretion of antidiuretic hormone associated with amitriptyline administration. South Med J 67:495-497, 1974 3. RASKIND M: Psychosis, polydipsia and water intoxication. Arch Gen Psychiatry 30:112-114, 1974

Trimethoprim-Sulfamethoxazole and Brain Abscess WE

Day

Serum sodium, meq/litre Serum osmolality, mOsm/kgHiO Urine sodium, meq/litre Urine osmolality, mOsm/kg HiO

1

2

3

4

10

115

128

141

140

142

247 44

80

284 60

288 18

322

426

442

148

* 500 ml of 3 % N a C l were infused o n day 1. 312

June 1975 • Annals of Internal Medicine • Volume 82 • Number 6

Downloaded from https://annals.org by Tulane University user on 01/22/2019

RECENTLY TREATED A PATIENT with

a brain

abscess

with t r i m e t h o p r i m - s u l f a m e t h o x a z o l e ( T M - S M X ) , a n antimicrobial c o m b i n a t i o n that is relatively n e w in this country. W e were able to d o c u m e n t p e n e t r a t i o n of t h e d r u g into t h e abscess b y m e a s u r i n g levels in p u s obtained at craniotomy. This 35-year-old man was found to have bilateral mastoiditis in July 1973 with an air-fluid level in the mastoid bone on the right. He refused surgical intervention until October 1973, when he underwent a right tympanoplasty and mastoidectomy. Postoperatively, drainage from the right ear resumed, which grew Proteus mirabilis. Gentamicin and cephalothin therapy was begun in another hospital. A lumbar puncture there showed a leukocyte count of 4100/mm 3 with 8 6 % polymorphonuclear leukocytes, glucose 44 mg/100 ml, with blood glucose 202 mg/100 ml, and protein 275 mg/100 ml. Cerebrospinal fluid cultures were sterile. The patient subsequently referred himself to the Nashville Veterans Administration Hospital where skull films showed a large cavity with an air-fluid level in the right hemisphere and a brain scan was compatible with a deep right temporal abscess. Purulent drainage from the right ear grew P. mirabilis and group D streptococci. Chloramphenicol, carbenicillin, and methicillin therapy was begun. The patient gradually defervesced on this regimen, which was continued for 3 weeks, at which time he became febrile and developed a pruritic maculopapular erythematous and urticarial rash. Peripheral blood leukocyte count was 3600/mm 3 with 22% eosinophils. Because of continued high fever and a worsening rash, methicillin and carbenicillin were discontinued and the rash improved. Chloramphenicol was continued at a dosage of 750 mg orally every 8 hours. A repeat culture from the right ear grew Pseudomonas. Two days after methicillin and carbenicillin were discontinued, the patient became more obtunded and febrile to 40 °C [104 °F]. Because of concern over the possibility of inadequate antimicrobial therapy for his abscess in the face of penicillin allergy, treatment was begun with 160 mg trimethoprim and 800 mg sulfamethoxazole in combination twice a day by mouth. Steroids were begun concomitantly. His sensorium cleared somewhat and the fever de-

creased. He was begun on polymixin B because of recurrence of fever 3 days later. At surgery, 5 days after beginning TM-SMX and 15 to 18 hours after the last dose, a poorly encapsulated abscess containing 20 ml of pus was aspirated from the right temporal region. Numerous polymorphonuclear leukocytes, but no organisms were seen on Gram stain. Aerobic and anerobic cultures of the pus were sterile. Trimethoprim and sulfamethoxazole levels (done by Drs. S. R. M. Bushby and C. W. Sigel, Burroughs-Wellcome Laboratories, Research Triangle Park, North Carolina) in the aspirated pus were 1.16 /xg/ml and 15.47 /xg/ml by a quenching fluorimetric technique ( 1 ) ; chloramphenicol and polymyxin B do not interfere with the measurement. The fluid was cidal at 1:32 dilutions when tested against the P. mirabilis from the ear drainage. The minimum inhibitory concentration (MIC) for TMSMX against this organism was 0.02 /xg/ml T M combined with 0.32 /xg/ml SMX; minimum bacterial concentration (MBC) was 0.04 /xg/ml TM combined with 0.63 /xg/ml SMX; for chloramphenicol the MIC and MBC were 25 and 50 /xg/ml. In-vitro resistance to polymyxin B was shown both by Kirby-Bauer disc sensitivity assay, and lack of synergism between TM-SMX and polymyxin B as indicated by a "killing curve" technique ( 2 ) . Therefore, most if not all the cidal activity would appear to have resulted from the TM-SMX in the fluid. A major problem in treatment of brain abscess is poor penetration of antimicrobials into brain tissue ( 3 ) . The experience with this case supports a recent report of good penetration of trimethoprim-sulfa into a nocardia brain abscess ( 4 ) . This combination, with its broad spectrum of antimicrobial activity, might offer considerable promise in the therapy of bacterial brain abscess in the future. BRUCE M. G R E E N E , M.D. FRANK E. THOMAS, JR., M.D. ROBERT H. ALFORD, M.D., F.A.C.P.

Infectious Disease Section Medical Service Veterans Administration Hospital and Vanderbilt University School of Medicine Nashville, Tennessee 37203 Received 20 November 1974. REFERENCES 1. SIGEL CW, GRACE ME: A new fluorescence assay of trimethoprim

and metabolites using quantitative thin-layer chromatography. / Chromatogr 80:111-116, 1973 2. ROSENBLATT JE, STEWART PR: Combined activity of sulfameth-

oxazole, trimethoprim, and polymixin B against gram-negative bacilli. Antimicrob Agents Chemother 6:84-92, 1974 3. BLACK P, GRAYBILL JR, CHARACHE P: Penetration of brain abscess

by systemically administered antibiotics. J Neurosurg 38:705-709, 1973 4. MADERAZO EG, QUINTILIANI R: Treatment of nocardial infection

with trimethoprim and sulfamethoxazole. Am J Med 57:671-675, 1974

Acute Myocardial Infarction in 'Miliary Tuberculosis' ACUTE MYOCARDIAL INFARCTION due to caseous thrombo-

embolism in disseminated hematogenous tuberculosis has not heretofore been cited. It is the purpose of this report to describe a patient with this unique complication of tuberculosis. A 30-year-old social worker, a two-pack per day cigarette smoker, was admitted to The Brookdale Hospital Medical

Figure l f Top. Coronary vessel and medial infiltrate and intact toxylin and eosin; magnification, ure 1 Top under oil immersion (Ziel-Neelsen stain.)

with mild-to-moderate adventitial intima filled by embolus. (Hemax 100.) Bottom. Embolus in Figshowing typical tubercule bacilli.

Center for cough productive of bright red blood, chest discomfort, and shortness of breath. During the 2 months before admission he experienced night sweats, registered a 9.07 - kg [20 - lb] weight loss, and although unusually fatigued continued to work regularly. One week before admission he began to complain of midsternal chest discomfort on exertion, and on the day of admission he was brought to the emergency room because of cough productive of bright red blood, chest discomfort, and marked shortness of breath. The family history was negative for tuberculosis and coronary artery disease. On admission the blood pressure was unobtainable. The pulse was 144/min and the rhythm regular; the temperature was 39.4 °C, and the respiration was 40/min. The sclerae were icteric, the neck veins were not distended, and the chest was clear. Cardiac examination showed a summation gallop. The liver edge was palpable 7 cm below the right costal margin. There was no peripheral edema. The hemoglobin was 12.2 g/100 ml and the leukocyte count was 3100/mm3. The electrocardiogram showed a right bundlebranch block with marked ST-segment elevation and small Q waves in leads II, III, and AVF, and was consistent with acute inferior-wall myocardial infarction. The creatinine phosphokinase was 640 U/ml and a portable chest X ray showed a diffuse interstitial infiltration involving both lung fields from bases to apices. The pulmonary artery wedge pressure was 10 mm Hg and a blood pressure of 90/60 mm Hg was obtained immediately after the infusion of Vs normal saline. A progressive fall in arterial oxygen tension from 86 mm Hg (with nasal oxygen) to 50 mm Hg required intubation and assisted Letters

Downloaded from https://annals.org by Tulane University user on 01/22/2019

813

ventilation. Antituberculous therapy and intravenous corticosteroids were administered, but 12 hours after admission repeated bouts of ventricular tachycardial and ventricular fibrillation could not be terminated and attempts at resuscitation were unsuccessful. The pertinent gross and histopathologic findings consisted of bronchogenically disseminated fibrocaseous nodules varying from 2 to 5 mm in diameter. There was direct extension of the caseous necrosis (acid-fast positive bacilli) from one of the larger nodules into a pulmonary venule. The myocardium contained multiple caseous granulomata. Within the lumen of several medium-sized coronary arteries there were acid-fast positive caseous necrotic emboli occluding the lumens (Figure 1 top and bottom). In some vessels these lesions extended into the arterial wall. There was no endocardial or pericardial involvement. The hilar lymph nodes contained ancient fibrocalcific evidence of tuberculous disease. The dissemination appeared to be of more recent origin. Caseous granulomas were present in kidneys, liver, spleen, and bone marrow. A tuberculous small-vessel c o r o n a r y arteritis h a s long been recognized as a n occasional autopsy finding in both disseminated h e m a t o g e n o u s tuberculosis a n d tuberculous pericarditis ( 1 ) . Myocardial infarction, o r ventricular aneurysm d u e to such a vasculitis, o r both, however, is a rarity ( 2 - 5 ) . I n t h e present case t h e c o r o n a r y arteries involved were both medium-sized vessels a n d showed t w o types of lesions. I n o n e instance t h e caseous embolus

314

June 1975 • Annals of Internal Medicine • Volume 82 • Number 6

Downloaded from https://annals.org by Tulane University user on 01/22/2019

p r o d u c e d a tuberculous arteritis with thrombosis, a n d in the other t h e caseous e m b o l u s originating from a p u l m o n a r y venule completely occluded a n otherwise n o r m a l medium-sized c o r o n a r y artery. M y o c a r d i a l necrosis consistent with t h e clinical a n d electrocardiographic picture of acute t r a n s m u r a l infarction was evident in t h e corresponding areas of m y o c a r d i u m supplied by these vessels. W A R R E N A. KOSSOWSKY, M.D., F.A.C.P. SHAHROKH RAFII, M . D . GUILLERMO GOMEZ-LEON, M.D.

Sections of Cardiology and Pathology The Brookdale Hospital Medical Center Brooklyn, New York 11212 Received 23 December 1974. REFERENCES 1. GOULEY BA, BELLET S, MCMILLAN TM:

Tuberculosis of

the

myocardium. Arch Intern Med 51:244-263, 1933 2. TSENG HL, ROULET F: Cardiac involvement in miliary tuberculosis. Am Rev Tuberc 68:771-774, 1953 3. NESVADBA P, CHLUMSKY J: Beitrag zur entriindlichen Aitologie

der Koronargefabveranderungen. Cardiologia 30:376-386, 1957 4. JACOBS HD, ELLIOT GA: Cardiac ventricular aneurysm in South Africa. Acta Med Scand [Suppl] 306:84-95, 1955 5. KINARE SG, BHATIA BI: Tuberculous coronary arteritis with aneurysm of the ventricular septum. Chest 60:613-616, 1971