LETTERS AND CORRECTIONS

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

We continue to assess and modify the program, but the basic concepts remain and have been well received. We believe the program makes a significant contribution to the Washington University Medical Center and to primary care training in general as a specific functional model. LAWRENCE K A H N , M.D. G E R A L D T. P E R K O F F , M . D .

Division of Health Care Research Washington University School of Medicine St. Louis, MO 63110

Training for Primary Care REFERENCES

TO THE EDITOR: The paper "Primary Care Residency Training: The First Five Years" (1) by J. I. Boufford is an excellent description of a pioneer program for training residents in social medicine. Our experiences at Washington University School of Medicine confirm those of the group at Montefiore Hospital in many but not in all respects. The primary care teaching program here is a residency option in pediatrics or internal medicine at the Medical Care Group of Washington University (MCG), a campus-based teaching and research prepaid group practice. Unlike the Residency Program in Social Medicine (RPSM) at Montefiore Hospital, a pair-system for junior medical residents was unsuccessful, perhaps because we lacked the critical mass identified as important in the RPSM. Currently all six residents in our program, three in each specialty, are in their third year of training. The MCG program is not identified as one in "social medicine" and does not include specific teaching in epidemiology or health services research. Rather it concentrates on the ambulatory care aspects of general internal medicine and pediatrics, including social and economic factors involved in health care, but the latter are not major thrusts. Internal medicine residents spend 8 months of the year at MCG with the remainder in in-patient settings. Of MCG time, half is devoted to patient care responsibilities, and half in the ambulatory care aspects of subspecialty activities. The pediatric program is coordinated with the ambulatory care fellowship at St. Louis Children's Hospital where the resident works in the general and subspecialty out-patient clinics with one fourth to one half his time in MCG. Faculty physicians, residents, nonphysician practitioners, social workers, and registered nurses work together closely to deliver health services in MCG. Residents' instruction is provided by full-time faculty members who serve as role models as practicing physicians as well as preceptors and attending physicians responsible for the teaching. This has worked well. Further, daily "report" conferences are major learning sessions. Reports are interdisciplinary in character, including all members of the team, and focus attention on patient care problems. Primary care rounds alternate with audit sessions on a weekly basis. Staff meetings involving policy and management decisions are attended by residents. Time and motion studies of program costs showed that advanced residents provide services that compensate MCG for the residents' stipends and for faculty physicians' teaching time. These results differ from those presented by the Harvard Community Health Plan (3). Of 17 residents who completed the program, 10 have entered general internal medicine or pediatrics and three are still in training in general internal medicine. One spent a second year in MCG before entering a subspecialty fellowship, and one each entered subspecialty training, public health training, and the National Health Service Corps.

1. BOUFFORD JI: Primary care residency training: the first five years. Ann Intern Med 87:359-368, 1977 2. K A H N L, W I R T H P, P E R K O F F GT: The cost of a primary care teaching

program in a prepaid group practice. Med Care, in press 3. STERN R, J E N N I N G S M, D E L B A N C O TL, D O R S E Y JL, STOECKLE JD,

L A W R E N C E RS: Graduate education in primary care: an economic analysis. N Engl J Med 297:638-643, 1977

TO THE EDITOR: In a recent issue (Ann Intern Med 87:359-368, 1977) Boufford describes the primary care program at Montefiore Hospital. In the past 5 years, health planners have encouraged the training of more primary care physicians. Centers of high quality have established pilot programs to facilitate this training (1, 2). The objection I have to these programs is that we may be training primary care internists who will be deficient in tertiary care. I firmly believe that the existing structured residency programs are able to train competent primary care physicians. The Council on General Internal Medicine of the American Board of Internal Medicine has made its recommendations for this training (3). I add a few to its list. 1. The chairman of the department of internal medicine must be sincerely committed to primary care training and not consider it to be thrust upon him by the federal government. 2. The subspecialty faculty must make the effort to teach primary care within their field. 3. The ambulatory care experience must be meaningful and supervised. The time should end when a clinic functions solely as a service to the community; it should be an organized, long-term, supervised, follow-up facility. In the long run this setting will provide more quality care to the community. When only 53% of Montefiore's primary care housestaff pass the internal medicine boards, are we robbing Peter to pay Paul? Primary care internists need a strong basic knowledge of factual internal medicine. Without this foundation, they function as triage docs. With limited tertiary training this foundation may not be solid. PHILIP ALTUS, M.D. Department of Internal Medicine University of South Florida Tampa, FL 33612 REFERENCES 1. G O R O L L AH, STOECKLE J D , G O L D F I N G E R SE, O ' M A L L E Y T, M A Y L,

W O O B, FOLLAYTTAR S, S W E E T R: Residency training in primary care internal medicine. Report of an operational program. Ann Intern Med 83:872-877, 1975 2. P E R L M A N L, G R A H A M T, CHRISTY W: Primary care internal medicine

residencies. Arch Intern Med 136:111-113, 1976

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3. C O U N C I L ON G E N E R A L I N T E R N A L M E D I C I N E , A M E R I C A N B O A R D OF

INTERNAL MEDICINE: Attributes of the general internist and recommendations for training. Ann Intern Med 86:472-473, 1977

Postpartum Thyroid Disease TO THE E D I T O R : W e read with interest in your journal (Ann Intern Med 87:155-159, 1977) the most recent report, by Amino and associates (1), describing a postpartum syndrome with transient hypothyroidism compatible with autoimmune thyroiditis as its cause. Mentioned in their discussion are two cases with increased circulating levels of thyroid hormone and one unpublished case with a low 24-h l31I thyroid uptake in the early postpartum period. Such cases have been attributed to "silent thyroiditis" (2), "painless thyroiditis" (3), or "chronic lymphocytic thyroiditis" (4). We also have observed transient postpartum hypothyroidism similar to that described by Amino and coworkers (1) b u t have documented and reported five such patients who also had a preceding transient thyrotoxic phase in the early postpartum period associated with clinical and laboratory features of painless thyroiditis (5). Symptoms of thyrotoxicosis developed within 1 to 6 months after delivery. Initially, all patients had elevated levels of thyroid hormones accompanied by a suppressed 24h 131I thyroid uptake. In all patients, thyrotoxicosis resolved within 4 months followed by a subsequent transient hypothyroid phase occurring in four subjects; and one of these patients developed permanent hypothyroidism (5). Two of these patients had persistent elevation of antimicrosomal antibodies and needle-biopsy findings consistent with chronic thyroiditis, including the one patient who became permanently hypothyroid. We wish to emphasize that only the presence of a suppressed radioactive iodine uptake can differentiate painless thyroiditis from Graves' disease. Conceivably some of the patients described by Amino and associates (1) conform to this syndrome of painless thyroiditis, which can be diagnosed only by the demonstration of a preceding thyrotoxic phase in the early postpartum period accompanied by elevated thyroid function indices and a suppressed 24-h m I thyroid uptake. It is, therefore, unfortunate that none of the cases reported by Amino and coworkers (1) had thyroid functional data and 131I thyroid uptake studies earlier in the postpartum period. Furthermore, the association of high thyroid-antibody titers does not rule out a painless thyroiditislike syndrome as a possibility, in that autoimmune thyroiditis has been reported with transient thyrotoxicosis and low radioactive-iodine thyroid uptakes (4). We concur with the views of Amino and associates (1) and encourage the concept that there are likely a spectrum of thyroid disorders that can occur in the postpartum period associated with either hyperthyroidism due to Graves' disease or a spontaneously resolving thyrotoxicosis of painless thyroiditis as well as either transient, relapsing, or persistent hypothyroid syndromes secondary to subacute or chronic thyroiditis. P A U L G. W A L F I S H , M . D . , F . R . C . P . ( C ) , F.A.C.P. JODY GINSBERG, M.D.

Department of Medicine, University of Toronto, and Thyroid Research Laboratory, Mount Sinai Hospital Toronto, Ontario REFERENCES 1. A M I N O N, M I Y A I K, K U R O R, T A N I Z A W A O, A Z U K I Z O W A M, T A K A I S, T A N A K A F, N I S H I M, K A W A S H I M A M, K U M O H A R A Y: Transient post-

2. 3. 4.

5.

partum hypothyroidism: fourteen cases with autoimmune thyroiditis. Ann Intern Med 87:155-159, 1977 PAPAPETROU P D , JACKSON I M D : Thyrotoxicosis due to "silent" thyroiditis. Lancet 1:361-363, 1975 W O O L F P D , DALY R: Thyrotoxicosis with painless thyroiditis. Am J Med 60:73-79, 1976 G L U C K FB, N U S Y N O W I T Z ML, PLYMATE S: Chronic lymphocytic thyroiditis, thyrotoxicosis, and low radioactive iodine uptake: report of four cases. N Engl J Med 293:624-628, 1975 GINSBERG J, WALFISH PG: Postpartum transient thyrotoxicosis with painless thyroiditis. Lancet 1:1125-1128, 1977

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Pheniformin and Pancreatitis T O T H E E D I T O R : W e have read "Pheniformin-Associated Pancreatitis" b y D r s . C h a s e a n d M o g a n in t h e S e p t e m b e r issue (Ann Intern Med 8 7 : 3 1 4 - 3 1 5 , 1977). W e w i s h t o a d d a c a s e t o t h e five c a s e s r e p o r t e d p r e v i o u s l y . A 75-year-old black man was first admitted to the hospital by another physician because of acute myocardial infarction. He was found to have elevated blood sugar levels and was initially treated on a "sliding scale" with regular insulin. Later he was treated with DBITD®, 50 mg three times daily. His diabetes became well controlled. His blood urea nitrogen (BUN) level was 53 mg/dl. His 3-week course was uncomplicated. Two days after being released from the hospital he was readmitted in comatose state due to lactic acidosis, with several hours of abdominal pain. It was at this time that he first came under our care. His blood pressure was 80/60 mm Hg. He was in coma with kussmaul respirations. His abdomen was flat. There was hepatosplenomegaly. His heart rate was 100 per minute; his lungs were clear. There was no definite neurologic deficit. Laboratory findings showed a lactic acid level of more than 10 meq/litre (normal, 0.1 to 1.8 meq/litre); blood sugar, 352 mg/dl; BUN, 74 mg/dl; sodium, 138 meq/litre; potassium, 7.4 meq/litre; chloride, 94 meq/litre; and C 0 2 , 4.0 meq/litre. He was treated with intravenous fluid, "sliding-scale" regular insulin, and sodium bicarbonate. On the second day after admission, his mentation gradually improved, but he was found to have abdominal distention with tenderness and decreasing bowel sounds. His serum amylase concentration was 2000 units; calcium, 8.3%; and phosphorus, 2.2%. He was then treated with gastric decompressions and continued fluid therapy. His condition improved. Gastrointestinal studies showed normal gallbladder. Upper gastrointestinal series was normal. Three years later, the patient was being treated with N P H insulin with good control, and he had had no recurrent gastrointestinal symptoms. SHUH-MIN W U , M.D. JACK W. W O L F , M.D., F.A.C.P.

Research Medical Center Kansas City, M O 64131

Cystic Fibrosis in Adults TO T H E E D I T O R : Stern and co-workers (1) have reviewed the adolescent and adult presentation of cystic fibrosis in the August issue (Ann Intern Med 87:188-191, 1977). An adult male was recently discovered to have cystic fibrosis after a unique clinical presentation not mentioned in the review article. A 42-year-old white man came to the emergency room complaining of several days of profuse sweating, muscle cramps, extreme thirst, and abdominal pain. These symptoms occurred during a period of sustained high ambient temperatures. He was consuming from three to five litres of water, beer, and fruit juices daily. He denied vomiting, diarrhea, or other illness. He gave a history of two similar episodes that also occurred during unusually warm weather. Both episodes had resolved promptly with the intravenous administration of saline. Salt tablets had been prescribed but were not taken. Past medical history was positive for recurrent pneumonias at ages 8, 9, 10, 11, and 20. He smoked three to four packs of cigarettes per day and had a chronic cough that produced "one pint" of greenish sputum daily. He and his wife had unsuccessfully tried to conceive a child for 20 years. The patient, however, had refused evaluation for sterility. Pertinent physical findings included marked diaphoresis, a blood pressure of 100/80 mm Hg without orthostasis, a pulse of 100, and a temperature of 38.6 °C. Laboratory findings showed Na" level of 127 meq/litre; K , 3.8 meq/litre; CI , 7 4 meq/litre; C0 2 , 33 meq/litre; blood urea nitrogen, 21 m g / dl; UNa + , O; U K ' , 100; and hematocrit, 5 3 % . Chest roentgenograms findings were normal. His admitting diagnosis was heat exhaustion with metabolic alkalosis and hyponatremia. Records from his most recent previous admission revealed similar initial laboratory findings. Therapy was instituted with normal saline and resulted in symptomatic improvement. With the finding of no source of Na" or fluid loss other than profuse diaphoresis, sweat electrolytes were measured. Pilocarpine iontophoresis at Buffalo Children's Hospital revealed sweat Na + of 128 meq/litre (normal, 50 to 60 meq/litre).

This patient with recurrent episodes of heat exhaustion and hyponatremia had no extraordinary source of Na 4 loss other than his sweat. Normal sweat is hypotonic, and excessive sweat loss with heat exhaustion may result in hypernatremia. It was this inconsistency in laboratory findings, coupled with the history of recurrent pneumonias and probable sterility, that prompted the investigation of the sweat electrolytes and eventually lead

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to the diagnosis. His excessive sweating with high Na + content and replacement with hypotonic fluids most likely explain his unusual presentation. This case represents an important new presentation of cystic fibrosis. Most internists view this disease as one seen only in chronically ill children. Recent reviews call to our attention that with improved therapy many patients now survive past puberty, and asymptomatic young adults have been diagnosed only after detecting the disease in siblings (1-3). Heat exhaustion with unexplained hyponatremia may be a presenting manifestation of adult cystic fibrosis; although both are well described in conjunction with cystic fibrosis (2), these features in the current literature have not been reported as the presenting complaints. CHARLES ANDREWS, M.D.

MARTIN MANGO, M.D. M.D., F.A.C.P.

Rocco C. VENUTO, Buffalo General Hospital Buffalo, N Y 14203 REFERENCES

Meglumine Hepatotoxicity TO THE EDITOR: I have read with interest the article by Sutherland and associates, "Meglumine lodipamide (Cholografin®) Hepatotoxicity" (Ann Intern Med 86:437-439, 1977). I have observed the following case, which was somewhat different from the authors. A 52-year-old Japanese woman underwent a cholecystectomy to remove stones in mid-December 1969. Before and after operation, intravenous cholangiography using meglumine iodipamide (Biligrafin®) was done on three occasions, and no side effects occurred. She was discharged on 19 February 1970 and had apparently recovered. In mid-August 1973, she again visited our clinic for re-examination. All physical and laboratory findings were within normal limits. On 30 August 1973 a fourth intravenous cholangiography was done using 60 ml (18 g) of meglumine iodipamide in 300 ml of 5 % fructose given over 30 minutes. The cholangiogram showed a normal biliary tree. After this cholangiography, fever, rash, and nausea gradually appeared but no hypotension. Two days later serum glutamic oxalacetic transaminase and lactic dehydrogenase levels were elevated at 269 Karmen units per litre and 2054 Wroblewski units per litre, respectively. A liver biopsy done 6 days after the procedure showed slight hepatocyte pleomorphism and fatty infiltration. Two weeks later all liver function test values had returned to normal.

1. STERN RC, B O A T T F , D O E R S H U K CF, T U C K E R AS, M I L L E R RB, M A T -

T H E W S LW: Cystic fibrosis diagnosed after age 13. Twenty-five teenage and adult patients including three asymptomatic men. Ann Intern Med 87:188-191, 1977 2. S H W A C H M A N H, K O W A L S K I M, K H A W K-T: Cystic fibrosis: a new out-

look. 70 patients above 25 years of age. Medicine (Baltimore) 1977

56:129-149,

3. W O O D RE, B O A T T F , D O E R S H U K CF: Cystic fibrosis. Am Rev

Respir

Dis 113:833-878, 1976

Acetaminophen and Liver Disease TO THE EDITOR: The recent reports in your journal (1, 2) that modest dosages of acetaminophen can cause liver damage in individuals are interesting. Both Barker, de Carle, and Anuras (1) and Johnson and Tolman (2) speculate that patients with underlying liver disease may be unusually susceptible to the toxic manifestations of acetaminophen. We recently observed (3) severe liver dysfunction in two family members who took acetaminophen (3.6 g/day) for symptoms of infectious mononucleosis. Both of our patients had severe disturbance of hepatic function (husband: bilirubin 14.0 mg/dl (76% direct), serum glutamic oxalacetic transaminase (SGOT) 188 IU, lactic dehydrogenase (LDH) 552 IU, alkalaline phosphatase, 560 IU; wife: bilirubin 9.5 mg/dl (72% direct), SGOT 410 IU, L D H 880 IU, alkaline phosphatase 940 IU), disproportionate to what is customarily seen in infectious mononucleosis (4). All laboratory variables returned to normal after acetaminophen was withdrawn, and the infectious process resolved. Our observations support the hypothesis of Barker, de Carle, and Anuras (1) and Johnson and Tolman (2) that acetaminophen metabolism may indeed be altered by underlying liver disease and lead to exacerbated hepatic compromise. Physicians should be cautious about recommending acetaminophen to patients with liver disease. D A V I D M. R O S E N B E R G , M . D .

National Heart, Lung, and Blood Institute Bethesda, M D 20014 F R A N C I S A. N E E L O N , M . D .

Duke University Medical Center Durham, N C 27710 REFERENCES 1. B A R K E R J D J R , D E C A R L E DJ, A N U R A S S: Chronic excessive acetamino-

phen use and liver damage. Ann Intern Med 87:299-301, 1977 2. JOHNSON G K , TOLMAN K G : Chronic liver disease and acetaminophen. Ann Intern Med 87:302-304, 1977 3. ROSENBERG DM, M E Y E R AA, M A N N I N G IH, N E E L O N FA: Acetamino-

phen and hepatic dysfunction in infectious mononucleosis. South Med J 70:660-661, 1977 4. G E L B D, W E S T M, Z I M M E R M A N HJ: Serum enzymes in disease. Am J

Med 33:249-261, 1962

The mechanism by which meglumine iodipamide injection produces hepatotoxic reaction has not been elucidated. Sutherland classified this drug as a predictable rather than an unpredictable hepatotoxin because liver biopsy specimens showed the classic appearance of centrilobular necrosis and the usual clinical markers of hypersensitivity were absent. However, in our patient the liver biopsy showed no such change, and allergic manifestations such as fever and rash appeared. Further, at previously repeated intravenous cholangiographies, there were no side effects, unlike the findings reported by Sutherland. From my observations, I presume that our patient was sensitized by meglumine iodipamide at previous cholangiography and responded rapidly to "challenge" with meglumine iodipamide infusion. Thus, at least in this case, meglumine iodipamide acted chiefly as an unpredictable hepatotoxin. SUSUMU IMOTO, M.D. Shinko Hospital Wakinohama, Fukiaiku, Kobe 651, Japan

Abdominal Pain and Slipping-Rib Syndrome TO THE EDITOR: The article "Abdominal Pain Caused by Diabetic Radiculopathy" (Ann Intern Med 86:166-168, 1977) brings to light another seemingly uncommon disorder, which should be added to the list of differential diagnoses of abdominal pain. It is often the obscure causes of pain in the abdominal region that tax physicians' diagnostic acumen, and certainly many discomforts go undiagnosed for a long time. I wish to call attention to a disorder that also causes anterior abdominal discomfort, one not widely recognized as a clinical entity. This is the so-called rib-tip, or slipping-rib, syndrome (1, 2). The following case report illustrates this disorder and the difficulty in making the correct clinical diagnosis. A 39-year-old woman presented to the neurology service with a 2-year history of lancinating right upper quadrant abdominal pain, which would radiate to the back in a band pattern. The pain was at first intermittent, but it soon became continuous, aggravated by movement. A number of examiners believed the pain was of gastrointestinal origin, so numerous studies were done, with normal findings, including: intravenous pyelogram, abdominal echo, retrograde cannulation of the pancreas, upper gastrointestinal studies, barium enema, liver-spleen scan, and myelography. Right paravertebral block with xylocaine greatly diminished the discomfort, but within 2 weeks the pain had recurred. On examination there was pain to palpation along the rib margins in the right T7-T9 areas. An area of hypoesthesia extended from the anterior axillary line to the paravertebral area, and an area of hyperesthesia from the midaxillary line to the anterior rib margins. Her pain increased with the hooking maneuver (1) (the examiner hooks his or her curled fingers under the patient's anterior rib margins, and pulls them anteriorly), and a click was felt. Resection of the patient's right tenth rib margin resulted in her being totally free of the pain, which had made her miserable for 2 years. Letters and Corrections

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The rib-tip syndrome frequently is not diagnosed, most likely because of unfamiliarity with the disorder. Often the pain produced is sharp and stabbing, and localized in the epigastric or upper abdominal areas, although sometimes the pain radiates posteriorly in a radicular fashion. It is frequently aggravated by movement. Hyperesthesia can often be found along the course of the intercostal nerve, and patients may relate previous trauma to that area. The hooking maneuver is always positive, and because this condition is often unilateral, performing this maneuver on the asymptomatic side will produce no discomfort. This procedure should reproduce the patient's symptoms, and often a clicking noise is heard or felt. This condition is associated with hypermobility of the anterior end of the intercostal cartilages, most often the 7th to tenth rib areas. Because the 8th to tenth ribs are not attached to the sternum but only to each other by a fibrous band, they have increased mobility and a greater likelihood to be damaged by trauma. Pathologically there is a curling upward of the cartilage end so that it rises to the inside of the rib above and comes into close contact with the intercostal nerve (2). Excision of the appropriate rib margin affords a total relief from the discomfort; local nerve blocks may produce temporary relief, but the " c u r e " lies with the surgeon. The rib-tip syndrome should be considered when patients with abdominal pain are being examined. A positive hooking maneuver clinches the diagnosis and should prevent potentially dangerous and needless tests from being done.

their use should thus be avoided in this particular group of patients. WILLIAM G. HOCKING, M.D. Division of Hematology-Oncology Department of Medicine U C L A School of Medicine Los Angeles, C A 90024 REFERENCES 1. EYSTER M, B O W M A N HS, H A V E R S T I C K JN: Adverse reactions to factor

VIII infusions. Ann Intern Med 87:248, 1977 2. M I L L S DCB, ROBERTS GCK: Membrane active drugs and the aggregation of human blood platelets. Nature 213:35-38, 1967 3. K A N E S H I R O MM, M I E L K E CH, K A S P E R CK: Bleeding time after aspirin

in disorders of intrinsic clotting. N Engl J Med 281:1039-1042, 1969

In

comment:

In reply to Dr. Hocking's letter, we disagree that "antihistamines are ancillary drugs in the treatment of life-threatening allergic reactions." Because these reactions may be histaminemediated, we believe that the potential benefit of diphenhydramine (Benadryl®) outweighs the possible risk that the drug may enhance bleeding in hemophiliacs who experience severe reactions after factor VIII infusions. We do not, however, advocate the routine "prophylactic" use of antihistamines in hemophiliacs for the reasons stated by Dr. Hocking. M. E L A I N E EYSTER, M.D., F.A.C.P.

F R E D E R I C K M. V I N C E N T , M . D .

Division of Hematology Department of Medicine The Milton S. Hershey Medical Center The Pennsylvania State University Hershey, P A 17033

Division of Neurology Department of Medicine Dartmouth Medical School Hanover, N H 03755 REFERENCES

1. H E I N Z GJ, ZAVALA DC: Slipping rib syndrome: diagnosis using the "hooking maneuver." JAMA 237:794-795, 1977 2. M C B E A T H AA, K E E N E JS: The rib-tip syndrome. / Bone Joint Surg 57A:795-797, 1975

Adverse Reactions with Factor VIM TO T H E EDITOR: Eyster and associates (1) have recently described their experience with adverse reactions to factor VIII infusions. They report a 1 9 % incidence of adverse reactions after the infusion of factor VIII concentrates, with reactions ranging from fever and urticarial eruptions to anaphylactoid reactions. The authors state that "we now routinely issue antihistamines and prednisone as well as sublingual isoproterenal glossets to all hemophiliacs on home therapy." Although the authors do not advocate the prescribing of antihistamines for all hemophiliacs on home therapy, their letter implies that routine use of an antihistamine is indicated in these patients. I suggest caution in administering antihistamines to patients with hemophilia or other disorders of coagulation. Antihistamines interfere with platelet function, probably by stabilizing platelet membranes and impairing platelet aggregation in response to physiologic stimuli (2). In patients without pre-existing disorders of coagulation, this effect on platelet function is generally of no clinical importance. However, in patients with underlying coagulopathies interference with platelet function may bypass the principal remaining hemostatic mechanism and lead to a more severe bleeding diathesis (3), at a time when the factor VIII concentrate is presumably being administered to treat an early hemorrhage. Patients in home-treatment programs with factor VIII concentrates and their families should recognize the potential danger of these allergic reactions and be instructed in their initial management. I suggest that this consist of the administration of sublingual/isoproterenal or subcutaneous epinephrine as well as oral prednisone while arrangements are made to provide for immediate medical attention. Antihistamines are ancillary drugs in the treatment of life-threatening allergic reactions, and 130

Intravascular Coagulation and Hepatic Injury T O T H E EDITOR: The role of disseminated intravascular coagulation in hepatic injury is controversial (1). In the case of Sbarbaro and Bennett (Ann Intern Med 86:183-185, 1977) we miss further coagulation studies, especially factor VIII, which is normal or elevated in liver disease and decreased in disseminated intravascular coagulation. This is in contrast to factor VII, which is normal in disseminated intravascular coagulation and decreased in liver disease (2). DAVID KOHN, M.D. ZEV ESTROV, M.D. Department of Internal Medicine ' B ' Kaplan Hospital Rehovot, Israel REFERENCES 1. H I L L E N B R A N D P, P A R B H O O SP, J E D R I C H O W S K I A, SHERLOCK S: Signifi-

cance of intravascular coagulation and fibrinolysis in acute hepatic failure. Gut 15:83-88, 1974 2. SHERLOCK S: Disease of the Liver and Biliary System, 5th ed. London, Blackwell Scientific Publications, Inc. 1975, p. 58

In

We appreciate the point made by Drs. Kohn and Estrov regarding the association of disseminated intravascular coagulation and hepatic injury. The striking temporal relation of the microangiopathic blood picture to the transaminases and abnormal liver histologic features in our patient certainly suggests a relation of a compensated disseminated intravascular coagulation to hepatic injury. We concur that this relation does not necessarily incriminate hepatic injury as the cause of the intravascular coagulation, a fact borne out by the absence of previous reports linking salicylate hepatotoxicity to disseminated intravascular coagulation. We can only surmise that the observed intravascular coagulation was primarily an effect of aspirin on the coagulation system and was probably potentiated by the concomitant hepatocellular injury (1).

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comment:

R O B E R T M. B E N N E T T , M . D . J A M E S A. S B A R B A R O , M . D .

Division of Immunology and Rheumatology University of Oregon Health Sciences Center Portland, O R 97201 REFERENCE

1. C O L E M A N RW, R A B B O Z SJ, M I N N A JD: Disseminated intravascular co-

agulation (DIC): an approach. Am J Med 52:679-789, 1972

Arthralgia and Rubella Immunization TO T H E EDITOR: In a paper on our 1969 clinical trial of H P V 77:DE-5 live attenuated rubella virus vaccine in adolescent girls and young women (1), we described in detail a 17-year-old vaccinee (subject # 2 8 1 ) who developed moderate arthralgia of her knees and hips, moderate-to-severe arthritis of her fingers, and a painful ganglion. We noted that intermittent arthralgia of her knees and hips had persisted for a year after vaccination. W e report here an 8-year follow-up. Subject # 2 8 1 is now a 25-year-old resident in internal medicine. At 2-to3-month intervals and in association with the onset of cool, damp weather, she experiences pain in one of her knees or hips. The pain is dull and aching, increases with weight-bearing, and lasts 2 to 3 days. Although it causes her to limp and occasionally requires aspirin for relief, the pain does not interfere with her work or recreational activities. She has no swelling or redness of her hips or knees, has had no finger discomfort since the immediate postvaccination period, and has not had a recurrence of the ganglion. Tests for antinuclear antibody and rheumatoid factor remain negative. Her rubella hemagglutination inhibition antibody titer, measured in parallel with earlier serum specimens, is 1:32, unchanged from titers at 4 and 8 weeks after vaccination.

Natural rubella arthritis may be followed by intermittent symptoms that involve the initially affected joints and last as long as 4 years (2). T h e same phenomenon has been described after joint reactions caused by live attenuated rubella virus vaccine for as long as 3 years (3, 4). T h e current report extends the possible duration of recurrent symptoms after vaccination to 8 years. This joint involvement, however, does not progress to chronic, disabling rheumatic disease. S T E P H E N J. L E R M A N , M . D . M A R C I A R. S I L V E R , M . D . G E O R G E A. N A N K E R V I S , P H . D . , M . D .

Pediatric Infectious Disease Unit University of Nebraska Medical Center Omaha, N E 68105 REFERENCES 1. L E R M A N SJ, N A N K E R V I S GA, H E G G I E A D , G O L D E: Immunologic re-

sponse, virus excretion, and joint reactions with rubella vaccine. A study of adolescent girls and young women given live attenuated virus vaccine (HPV-77:DE-5). Ann Intern Med 74:67-73, 1971 2. K A N T O R TG, T A N N E R M: Rubella arthritis and rheumatoid arthritis. Arthritis Rheum 5:378-383, 1962 3. SPRUANCE SL, KLOCK LE, BAILEY A: Recurrent joint symptoms in children vaccinated with HPV-77:DK-12 rubella vaccine. / Pediatr 80:413-417, 1972 4. THOMPSON GR, WEISS JJ, ELOISE MI: Intermittent arthritis following rubella vaccination. A three-year follow-up. Am J Dis Child 125:526-530, 1973

Sarcoidosis in the Nervous System T O T H E E D I T O R : T h e comprehensive review of "Neurological Manifestations in Sarcoidosis" by D r . Peyton Delaney in the September issue was an excellent survey of a not well-known association. We have recently also reviewed this subject because of the presentation at our institution of three unusual neurologic deficits in cases of sarcoidosis. Because these patients presented in such a short period (March through July 1975), we believe this association may be relatively common.

Our patients presented with myasthenia gravis, acute polyradiculoneuropathy (Guillain-Barre syndrome), and oculocraniosomatic neuromuscular disease ("ragged-red" fiber disease). The association of these deficits with the sarcoidosis may have been coincidental. However, the former two diseases have long been thought to be immunologic, and we speculate that a common underlying immunologic disturbance may influence the occurrence of sarcoidosis with these syndromes. T h e association of sarcoidosis with the oculocraniosomatic myopathy is obscure at present, particularly because this entity has only recently been described (1). Only three previous cases of sarcoidosis associated with myasthenia gravis have been reported (2-4) and one other case of Guillain-Barre syndrome not mentioned by Dr. Delaney in his review (5). All three of our patients presented with the neurologic deficits and were subsequently found to have sarcoidosis with hilar adenopathy on chest roentgenogram, with the diagnosis proved by scalene node biopsy and other studies. T h e patients with myasthenia gravis and Guillain-Barre syndrome responded very well to systemic steroids with disappearance of their initial symptoms. T h e third patient was not treated with steroids and had spontaneous regression of the hilar adenopathy, without any change in her symptoms of external ophthalmoplegia. A s Dr. Delaney states, the most common neurologic manifestations of sarcoidosis seem to be by direct involvement of the cranial and peripheral nerves and infiltration of the surrounding tissues and blood vessels. However, he also comments that "sarcoidosis may have a remote effect on neural and glial elements." We submit that these three cases may help substantiate the latter mechanism of action. A more comprehensive report of these cases has been accepted for publication. JUSTUS FIECHTNER, M.D. M A R K REINECKE, M.D. PHIROZE HANSOTIA, M.D.

Marshfield Medical Foundation 510 N o r t h St. Joseph Avenue Marshfield, W I 54449 REFERENCES 1. O L S O N W, E N E L WK, W A L S H GO, E I N A N G E E R R: Oculocraniosomatic

neuromuscular disease with "ragged-red" fibers. Arch Neurol 26:193211, 1972 2. JAVITT NB, DANIELS RA: Myasthenia gravis with sarcoidosis. Mt Sinai

JMedNY26M7-\Sl,

1959

3. W O L F SM, R O W L A N D LP, SCHOTLAND DL: Myasthenia as an autoim-

mune disease: clinical aspects. Ann NY Acad Sci 135:517-535, 1966 4. M E N K E S CJ, CHOURAKI L, L E M A I R E V: Sarcoidosis, myasthenia, and

chronic polyarthritis in connection with an observation. Ann Med Interne 122:1015-1022, 1971 5. STRICKLAND GT, MOSER K M : Sarcoidosis with a Landry-Guillain-Barre syndrome and clinical response to corticosteroids. Am J Med 43:131-135, 1967

TO T H E EDITOR: In his excellent and thorough review, "Neurologic Manifestations in Sarcoidosis" {Ann Intern Med 87:336345, 1977), Dr. Delaney states that, "Because of the frequency of anergy, opportunistic infections can occur, often with cerebral involvement and encephalopathy." This opinion contradicts the observations of Mitchell and Scadding (1), that patients with sarcoidosis are not unusually prone to viral or fungal infections. Indeed, skin homografts are rejected normally in anergic patients with sarcoidosis (2), implying normal cell-mediated immunity. Any unusual susceptibility to viral or fungal infections in sarcoid patients is probably secondary to steroid therapy (3). One would not expect to see such infections in patients with sarcoidosis not on steroids. Such infections are probably rare in patients on alternate-day steroid therapy (4), which may be of considerable value in the treatment of sarcoidosis (5). L E O N A R D A. PALLOR, M . D .

E. J. Meyer Memorial Hospital Buffalo, N Y 14215 Letters and Corrections

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REFERENCES 1. M I T C H E L L

Drug Therapy for Asthma DN,

SCADDING

JG:

Sarcoidosis.

Am

Rev

Respir

Dis

110:774-802, 1974. 2. SNYDER GB: The fate of skin homografts in patients with sarcoidosis. Bull Johns Hopkins Hosp 115:81, 1964 3. JOHNS CJ: Sarcoidosis, in Harrison's Principles of Internal Medicine, edited by T H O R N GW, A D A M S RD, B R A U N W A L D E, ISSELBACHER KJ,

PETERSDORF RG. New York, McGraw-Hill, 1977, pp. 1119-1124 4. D A L E DC, F A U C I AS, W O L F F SM: Alternate-day prednisone: leukocyte

kinetics and susceptibility to infection. New Engl J Med 291:1154-1158, 1974 5. BLOCK AJ, LIGHT RW: Alternate-day steroid therapy in diffuse pulmonary sarcoidosis. Chest 63:495-500, 1973

TO T H E EDITOR: In his review, "Neurologic Manifestations of Sarcoidosis" (Ann Intern Med 87:336-345, 1977) Dr. Delaney does not mention the syndrome of pseudotumor cerebri occurring in sarcoidosis. Review of the previous literature (1-4) also fails to show evidence of patients with sarcoidosis presenting with pseudotumor cerebri. I have recently seen a 29-year-old black woman with progressive headaches for 2 months associated with blurring of vision for 1 week. On examination the patient was completely normal in every way except for papilledema and a few small retinal hemorrhages. Neurologic findings were completely normal. Laboratory data were also normal except for a minimal elevation of serum globulins (3.4 g/dl) on one of three occasions; 24h urine calcium was 102 mg; postioanterior and lateral chest showed a somewhat prominent left hilum and on tomography showed bilateral hilar adenopathy. Hand roentgenograms were normal. N o evidence of sarcoid involvement of the eyes was found; P P D and mumps skin test findings were negative. A C A T scan of the brain with contrast medium showed no evidence of masses or ventricular abnormalities. A t mediastinoscopy a lymph node was removed and found to be compatible histologically with sarcoid. Lumbar puncture was done, with an opening pressure of 550, spinal fluid protein of 20 mg/dl, sugar 64 m g / d l , 39 erythrocytes, and 1 leukocyte, thought to be due to traumatic tap. T h e patient was treated with dexamethasone and had two further spinal taps of 330 and 310 pressures with acellular fluid. She was seen for 3 months as an outpatient, with progressive decrease in her papilledema and improvement in her vision. Both sarcoid and pseudotumor cerebri are most common in young women and both respond to steroids. Even in Delaney's series, which is biased toward autopsy cases, only 16 of 23 patients with neurologic sarcoid showed evidence of "stigmata of sarcoidosis, that is, hilar adenopathy, anergy, hypercalcemia, uveitis, and positive Kveim test". Without this patient's hilar adenopathy, the diagnosis of neurologic sarcoid would not have been considered. Delaney mentions that hydrocephalus secondary to central nervous system sarcoid was seen and could be "multifactorial: granulomatous infiltration of the ependyma and choroid plexi altering C S F dynamics, chronic meningitis causing obliteration of the subarachnoid space or aqueductal stenosis or outlet obstruction of the fourth ventricle by interventricular granulomas." Some of these cases could have presented as pseudotumor cerebri but if they did this was not mentioned. I suggest that sarcoidosis be considered an occult cause of pseudotumor cerebri. S H I A H. E L S O N , M . D .

West Paces Ferry Hospital Atlanta, G A 30327

T O T H E EDITOR: The paper " D r u g Therapy in the Management of A s t h m a " by VanArsdel and Paul (Ann Intern Med 87:68-74, 1977) is an interesting review. In the discussion, however, I found two controversial comments that warrant clarification. The authors suggest that Venturi masks may be needed for those patients with asthma who require oxygen and are mouthbreathers. Both theoretically and practically, there are inherent dangers with these masks for patients in respiratory distress who do not require controlled oxygen therapy (1). Although a fixed inspired oxygen concentration may be adequate at one moment under steady-state conditions, it may become seriously inadequate if the patient's condition suddenly deteriorates because of long continued coughing or increased bronchospasm. Inspired alveolar oxygen tension not only is determined directly by the inspired oxygen tension and the alveolar carbon* dioxide tension, but also is an inverse function of the exchange ratio, R. It is unlikely that R would remain constant during a sudden attack of increased bronchospasm, (R falls from 0.8 to 0.3 within 10 seconds after the onset of breath-holding in a normal subject (2). The inverse relation between alveolar oxygen tension and exchange ratio is not taken into account in the calculations forming the basis for the recommendations of ventimask use (3). Attacks of bronchial asthma are characterized by transient periods of unsteady state that must result in fluctuations in the exchange ratio. Accordingly, unless it can be shown in a given patient that ventilation is being depressed by oxygen, one should consider the use of the ventimask contraindicated and the use of high inspired oxygen concentrations delivered by humidified masks or conventional masks encouraged. The second issue was the delivery of aerosolized bronchodilator by oxygen or compressed air. I believe that the use of compressed air can also create a potential hazard in the course of asthmatic therapy. T h e benefits of the administration of bronchodilators by this method on gas exchange as reflected by the arterial oxygen tension and carbon dioxide tension may be more apparent than real, and its continued use without oxygen therapy should be discouraged (4). Accordingly, in a comparison of the immediate effects of six different modes of therapy in acute asthma, the most dramatic and consistent falls in arterial oxygen tension and increments in carbon dioxide tension were seen with intermittent positive pressure breathing. Although our study did not include intermittent positive pressure breathing with oxygen delivery, it seems reasonable to assume that the arterial oxygen tension would increase, as reflected in an initially higher inspired oxygen concentration. The effective treatment of bronchial asthma indeed requires not only knowledge of bronchodilators, steroids, and newer pharmacologic agents, but also the judicious use of oxygen therapy. R O B E R T D. B R A N D S T E T T E R , M . D .

The New York Hospital New York, N Y 10021 REFERENCES 1. M I T H O E F E R JC, R U N S E R R H , K A R E T Z K Y MS: Respiratory acidosis in

bronchial asthma. Lancet 1:661-662, 1966 2. MITHOEFER JC: Breath holding, in Handbook

of Physiology,

section 3,

vol. 2, edited by F E N N WO, R A H N H. Washington, D.C., American

Physiological Society, 1965, pp. 1011-1025 3. CAMPBELL EJM: Respiratory failure: The relation between oxygen concentrations of inspired air and arterial blood. Lancet 2:10-11, 1960 4. K A R E T Z K Y MS, BRANDSTETTER RD, M E Y E R RC, T E D A L D I EM: Acute

asthma. I. A comparison of the immediate effects of six different modes of therapy. Am J Med Sci 267:213-224, 1974

REFERENCES

1. JAMES DG, SHARMA O: Neurologic complications of sarcoidosis. Proc R Soc Med 60:1169-1170, 1967 2. JAMES DG, ZATOUROFF MA, TROWELL J: Papilledema in sarcoidosis.

Br J Opthalmol 51:526-529, 1967 3. WIEDERHOLT WC, SIEBERT RG: Neurologic manifestations of sarcoido-

sis. Neurology (Minneap) 15:1147-1154, 1965 4. NORWOOD CW, KELLY DL JR: Intracerebral sarcoidosis acting as a

mass lesion. Surg Neurol 2:367-372, 1974 132

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comment:

The first topic, so carefully discussed by Dr. Brandstetter, was covered in previous correspondence. Although the issue remains controversial, as he points out, it is rarely necessary to

use any type of mask to deliver oxygen to an asthmatic patient. On the second issue, I think we stressed the importance of oxygen therapy quite clearly in a paragraph preceding the statement in question. Obviously when oxygen therapy is needed, it would be inappropriate to use compressed air to deliver the bronchodilator. P A U L P. V A N A R S D E L , J R . , M . D .

c / o Cardiothoracic Institute London SW3 6 H P , England

REFERENCES 1. G A U L T HM, JEFFREY JR, C H I R T O E, W A R D LL: Studies of digoxin

dosage, kinetics and serum concentrations in renal failure and review of the literature. Nephron 17:161-187, 1976 2. J E L L I F F E RW, BROOKER G: A nomogram for digoxin therapy. Am

J

Med 57:63-68, 1974 3. K O U P JR, JUSKO WJ, E L W O O D CM, K O H L I R K : Digoxin pharmacoki-

netics: role of renal failure in dosage regimen design. Clin Pharmacol Ther 18:9-21, 1975 4. F L E C K E N S T E I N L, B E N E T LZ, THOMSON PD: Pharmacokinetic evalua-

Predicting Digoxin Dosage from Creatinine Clearance T O T H E EDITOR: Various published nomograms attempt to use serum creatinine to predict a digoxin dosage that will be in the therapeutic, but less than the toxic, range in patients with decreased renal function ( 1 , 2). W e recently studied a patient whose measured pharmacokinetic parameters of digoxin deviated considerably from those predicted from available nomograms. A 75-year-old euthyroid white man received digoxin for prophylaxis of paroxysmal atrial tachycardia. He was admitted to the hospital with symptoms of digoxin toxicity and with a serum digoxin level of 4.6 ng/ml. Despite a serum creatinine of 1.1 mg/ml, his serum digoxin level fell very slowly over several days. Therefore, after having digoxin therapy discontinued for several weeks, the patient was admitted to a clinical study unit and given an intravenous injection of 0.75 mg of digoxin. Serial plasma samples for digoxin and 24-h urine samples for digoxin and creatinine were collected for 11 days. Digoxin levels were measured in triplicate by radioimmunoassay using tritium-labelled digoxin. The following pharmacokinetic parameters were calculated based on a multicompartment model fit of the data: [a] digoxin body clearance of 60 ml/min • 1.73 m2; [b] digoxin renal clearance of 11 ml/min • 1.73 m2; [c] digoxin nonrenal clearance of 49 ml/min • 1.73 m2; [d] volume of distribution of 640 litres (10.9 litres/kg); and [e] digoxin half-life of 5.4 days. Twenty-four hour creatinine clearances during this study period averaged 41 ml/min • 1.73 m2.

The nonrenal clearance of digoxin was in reasonable agreement with that reported in the literature (3). However, the measured renal clearance was considerably smaller than what would have been predicted based on this patient's creatinine clearance. Based on a rearrangement of the relationship presented by K o u p and colleagues (3), a renal digoxin clearance of 53 m l / m i n • 1.73 m2 would have been predicted, as compared to the observed value of 10 m l / m i n • 1.73 m2. Applying the nomogram of Gault and co-workers (1) to this creatinine clearance yielded a predicted digoxin half-life of 2.7 days, considerably shorter than the measured value of 5.4 days. Fleckenstein, Benet, and Thomson (4) have reported the case of a patient with an unusually high metabolic and renal clearance of digoxin. Based on this case, and ours, it is evident that although the various methods employed in digoxin dosing have been shown to be useful in reducing the incidence of toxicity and inadequate therapy, there will be patients who handle digoxin abnormally. Therefore, measuring of serum digoxin levels is essential after initiation of therapy in patients with decreased renal function. R O B E R T D. O K A D A , M . D . W. D A V I D H A G E R , M . D . F R A N K I. M A R C U S , M . D . DONALD PERRIER, PH.D. PENELOPE GRAVES, PH.D.

University of Arizona Colleges of Medicine and Pharmacy Tucson, A Z 85724

tion of a patient with unusually high digoxin requirements. Clin Pharmacol Ther 21:102, 1977

Conduction Disease with Aortic Stenosis TO T H E EDITOR: T h e recent article by Dhingra and associates (1) postulates that the cause for syncope and sudden death in patients with aortic stenosis could be related to conduction disease. This statement adds confusion to the already difficult subject of managing patients with chronic conduction disease, as the natural history of this disease is just beginning to be known. These authors have documented a high prevalence of latent and manifest conduction-system disease (trifascicular disease) in their series. Besides aortic stenosis, conduction disease is known to occur in pure aortic regurgitation, where one third of the patients are reported to manifest first-degree atrioventricular (AV) block (2). In Table 1 is a 12-lead E C G analysis of 15 patients with pure or predominant aortic regurgitation under current study at our institution. Although the numbers are small, it is apparent that symptomatic patients with aortic stenosis and aortic regurgitation have a similar spectrum of conduction disturbance; however, the prevalence of syncope in aortic regurgitation is seemingly rare, being reported as 8 % as against a prevalence of 5 8 % in aortic stenosis (3). Are we to assume from these data that conduction disease secondary to aortic valve disease behaves differently than primary degenerative disease, and by the same token is the insult of chronic aortic regurgitation more benign than aortic stenosis? Clarification is vital because the authors make a strong case for considering permanent pacemaker insertions in those patients with aortic stenosis and recurrent syncope. Also, if progressive conduction disease is responsible for syncope and sudden death, valve replacement would theoretically not be protective against these occurrences. Perhaps Dhingra's conclusion was colored by the eight patients who presented with advanced A V block. However, an erroneous conclusion could be inferred if the presence of latent disease (electrophysiologic abnormalities) is considered to progress to manifest clinical disease (recurrent syncope and A V block). Only in recent years have excellent prospective studies (4, 5) challenged the old concept that advanced A V block is the natural end-result of chronic bifascicular block. These studies went further to show that even H V prolongation in chronic bifascicular block (trifascicular disease) does not identify a high risk subgroup for syncope or complete A V block. In an analysis of causes of sudden death in chronic bifascicular block patients, ventricular fibrillation, and not advanced AV block, was the postulated mechanism (5). Similarly, marked H V prolongation ( > 80 msec), though associated with more advanced heart disease, only progressed to advanced AV block in one of 20 patients (5). Prospective evaluation is needed of patients with aortic valve

Table 1. Conduction Abnormalities in 15 Patients with Chronic Aortic Insuffic iency Abnormality

Patients

Percentages

First-degree heart block (PR > 0.21) Second-degree AV block (type I) Left anterior hemiblock Bifascicular heart block Left bundle branch block Right bundle and left anterior hemiblock

6 2 2 4 3 1

40 13 13 27

Letters and Corrections

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disease to determine the rate of progressive conduction disease before and even after valve replacement. Only then can we accurately assess the true significance of AV conduction abnormalities in the context of their natural history. R I C H A R D K. M A U T N E R , M . D .

Veterans Administration Hospital New Orleans, LA 70140 M O O I D E E N M E E R A N , M . D . , M.R.C.P., F . C . P . (SA>

Louisiana State University Medical Center New Orleans, LA 70140 REFERENCES 1. D H I N G R A RC, A M A T - Y - L E O N F, PIETRAS RJ, W Y N D H A M C, D E E D W A -

patients with first-degree AV block and two with Wenckebach periodicity (presumably A-V nodal). In our experience, A-V nodal dysfunction is common and His bundle and trifascicular disease uncommon in patients with pure aortic regurgitation. The clinical behavior of conduction disease in these patients with A-V nodal dysfunction is appropriately benign (4). Drs. Mautner and Meeran's final statement on prospective evaluation appears to be in agreement with the concluding sentence of our manuscript, which reads: "Prospective study of patients with aortic stenosis undergoing electrophysiologic tests will be necessary to delineate the importance of these studies in predicting subsequent risk of manifest conduction disease and sudden death." R A M E S H C. D H I N G R A , M . D . K E N N E T H M. ROSEN, M.D.

NIA PC, W u D, D E N E S P, ROSEN KM: Sites of conduction disease in aortic stenosis. Significance of valve gradient and calcification. Ann Intern Med 87:275-280, 1977 2. REICHEK N, SHELBURN JC, PERLOFF JK: Clinical aspects of rheumatic valvular disease. Prog Cardiovasc Pis 15:131 -177, 1973 3. R O T M A N M, M O R R I S JJ, BEHAR VS, P E T E R RH, K O N G Y: Aortic valvu-

lar disease. Comparison of types and their medical and surgical management. Am J Med 51:241-257, 1971 4. D H I N G R A RC, D E N E S P, W U D, W Y N D H A M CR, A M A T - Y - L F O N F,

T O W N E WD, ROSEN KM: Prospective observations in patients with chronic bundle branch block and marked H-V prolongation. Circulation 53:600-604, 1976

Abraham Lincoln School of Medicine Chicago, IL 60680 REFERENCES

1. YATER WM, CORNEEE VH: Heart block due to calcareous lesions of the bundle of His. Review and report of a case with detailed histopathologic study. Ann Intern Med 8:777-789, 1935 2. ROSEN KM, Wu D, K A N A K I S C J R , D E N E S P, BHARATI S, L E V M:

Return of normal conduction after paroxysmal heart block. Report of a case with major discordance of electrophysiological and pathological findings. Circulation 51:197-204, 1975

5. D E N E S P, D H I N G R A RC, Wu D, W Y N D H A M CR, A M A T - Y - L E O N F,

ROSEN KM: Sudden death in patients with chronic bifascicular block. Arch Intern Med 137:1005-1010, 1977

3. F R I E D M A N HS, Z A M A N Q, H A F T JI, M E L E N D E Z S: Assessment of A-V

conduction in aortic valve disease (abstract). Am J Cardiol 39:314, 1977 4. A M A T - Y - L E O N F, D H I N G R A R, D E N E S P, W U D, W Y N D H A M C, R O S E N

In

comment:

We disagree with Drs. Mautner and Meeran that our paper adds confusion to the subject of aortic stenosis, syncope, and conduction disease. We believe that we have clarified one possible mechanism of syncope in patients with calcific aortic stenosis. O u r message is clear: aortic stenosis is associated with a high prevalence of manifest and latent disease involving the His bundle and trifascicular conduction system. The extent of conduction disease correlates with the extent of calcification and the severity of valve obstruction. O u r results are in agreement with previous observations on calcific involvement of the His bundle and trifascicular conduction system in patients dying with calcific aortic stenosis ( 1 , 2). Patients with syncope and calcific aortic stenosis deserve careful scrutiny in regard to both hemodynamics and conduction. Syncope in a patient with calcific aortic stenosis could be an indication for valve replacement, pacemaker implantation, or both, depending on results of diagnostic evaluation. In regard to Drs. Mautner and Meeran's patients with aortic insufficiency, we believe that their sample size is inadequate for deriving firm conclusions on the prevalence of conduction disease in aortic insufficiency. A recent abstract by Friedman and co-workers (3) noted a high incidence of A-V nodal disease in patients with aortic insufficiency. This would seem to be consistent with that of Drs. Mautner and Meeran, who had six

234

K: The natural history of chronic second degree A-V nodal block (abstract). Am J Cardiol 39:324, 1977

Marathon Running and Atherosclerotic Plaques T O T H E EDITOR: Barndt and associates have found angiographic evidence of regression of atherosclerosis in all of the patients who had improvement of lipid levels with drugs and diet {Ann Intern Med 86:139-146, 1977). We have seen plaque removal in marathon runners who take up the sport late in life. A man in his 60s was under medical care for a myeloproliferative syndrome. He took up marathoning and completed several 42-km runs and a 50-km run. He stopped running for a minor surgical procedure and died unexpectedly of a cerebral hemorrhage due to malignant thrombocytosis. Sections from his left main coronary artery showed resorption of a calcified plaque.

We are aware of over 50 cardiac patients who are now running 42-km marathons. They have been trained by cardiologists in formal rehabilitation programs and represent 250 patientyears of experience. Follow-up should be interesting.

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T H O M A S J. B A S S L E R , M . D .

American Medical Joggers Association Centinela Hospital Inglewood, C A 90307