Cornelio Papp

THE SYNDROME OF SHORT P–R INTERVAL, APPARENT BUNDLE BRANCH BLOCK, AND ASSOCIATED PAROXYSMAL TACHYCARDIA

In 1930, Wolff, Parkinson, and White published the first collected series of eleven patients, who were apparently healthy but had electrocardiograms suggesting bundle branch block combined with a shortened P-R interval. Most of them were subject to attacks of paroxysmal tachycardia and a few to paroxysms of auricular fibrillation. Isolated cases of this nature had been reported by Wilson (1915), Wedd (1921), and Hamburger (1929). Numerous authors since 1930 have added to the published cases and considered the mechanism of the syndrome. Our purpose is to review present opinion, to report further cases, and to examine the various hypotheses advanced in explanation. The electrocardiographic features are as follows. With a rate that is normal, P is upright, and the iso-electric segment from the end of P to R is abolished, so that the ventricular complex starts immediately after P or even overlaps the end of it, reducing the distance from the onset of P to the onset of R (the P-R interval) to less than 012 sec. The ventricular complex resembles that of bundle branch block; it is widened beyond 010 sec., often slurred in its ascent, and notched near its summit. The R-T period may be depressed or elevated, seldom assuming the full diphasic character of ordinary branch block. A surprising fact is that these patients may at other times show a normal electrocardiogram (Fig. 1), or even alternating normal and abnormal complexes without any change in rate (Fig. 2). The records during the paroxysms of tachycardia are generally of supraventricular type. Of these three important features-a short P-R interval, ventricular complexes of bundle branch block type, and paroxysmal tachycardia-the first is a constant finding, the second may be absent in certain cases that are included on other grounds, and the third occurs in the great majority. The lability of the Sh.P-R: B.B.B.* rhythm should not lead to confusion with paroxysmal bundle branch block (Comeau, Hamilton, and White, 1935; Bishop, 1935) in which there is a normal P-R interval, an abnormal QRS only

Toxic Effects of Iproniazid in a Patient with Angina

tory investigations showed an increase in gamma-globulin, a decreased pseudo-cholinesterase, and increased bromsulphthalein retention in the absence of a rise in serum bilirubin. These findings were suggestive of hepatic dysfunction. Pare (personal communication) has studied the effect of iproniazid on the serum transaminase level and found this to be increased in some patients, although other liverfunction tests remained normal. This again might suggest some liver dysfunction. Further evidence of liver involvement is supplied by Fouts and Brodie (1956). These authors discovered that iproniazid inhibited the enzymes in the liver, whose function is to detoxify such drugs as barbiturates, amphetamine, aminopyrine, and acetanilid. Toxic cerebral reactions following injections of pethidine have been reported by Mitchell (1955) and by Papp and Benaim (1958), and can be similarly explained on the basis of potentiation of the drug by iproniazid. Randall (1958) reports slight parenchymatous degeneration in the liver and kidney, engorgement of the spleen, and bone-marrow hyperplasia in animals receiving large doses of iproniazid. Such changes were dependent on the dosage administered, and all were reversible. Our two cases of jaundice occurred during a clinical trial of iproniazid on 60 depressed patients. Case 1 had received the drug for 72 days to a total of 8.6 g. when jaundice developed. The course of the disease was unlike that of infective hepatitis. Prodromal symptoms were minimal, asthenia and anorexia becoming marked only when clinical signs of necrosis supervened. Liver enlargement and tenderness were slight. There was no fever, and the E.S.R. remained normal throughout her illness. The initial liverfunction tests were in favour of intrahepatic cholestasis. In common with other investigators, we found disturbance of protein metabolism with an increase in globulin. Unfortunately, electrophoretic studies were not carried out. The marked change in condition on the twelfth day of jaundice, with the development of clinical signs of liver failure. pointed to the onset of necrosis. This diagnosis was supported by a high serum transaminase level and by the biopsy findings, which showed evidence of focal necrosis in spite of the administration of corticotrophin for three days beforehand. Moreover, the presence of eosinophilia in the sections is strong evidence of drug-induced jaundice (Hollister, 1957). Case 2 had received iproniazid for 75 days to a total of 11.25 g. It is unfortunate that the case was not seen until 22 days after the onset of jaundice, by which time she was recovering. No definite conclusions can be reached on the information available. The hypothesis was originally put forward that jaundice occurring in iproniazid therapy was due to a coincidental occurrence of viral hepatitis and an inhibition of the amine oxidase system by the drug, causing failure of the detoxicating mechanisms of the liver. From the evidence available, however, it is difficult to escape the conclusion that iproniazid may have a direct toxic effect on the liver. The fact that jaundice has occurred in patients receiving as little as 25 mg. daily and that it appears unrelated to the duration of administration (Marks, personal communication) suggests that an element of idiosyncrasy may be present. While it is difficult to decide at this stage whether iproniazid jaundice is of obstructive or hepatocellular type, the severity of some of the cases reported, including our first case, supports the latter possibility. Moreover, our liver biopsy provided definite evidence of hepatocellular damage. The picture was very different from that encountered in chlorpromazine jaundice, obstructive in type and benign in course, in which one invariably finds bile plugs in biliary canaliculi and minimal inflammatory changes (Movitt et al., 1955). It is clear that further research is needed to establish beyond doubt the mechanisms whereby iproniazid produces liver damage and jaundice. It is hoped that such risks can be eliminated and that this very helpful drug can continue to be used by psychiatrists and physicians with a greater degree of safety. Summary Two cases of jaundice occurring during a clinical trial of iproniazid in 60 depressed patients are reported. Both patients recovered. Details of biochemical investigations and of a liver biopsy are given. These, together with the course of the disease, suggest that iproniazid is a hepatotoxic drug. Possible mechanisms of action are discussed and the need for further research is emphasized.

Episodic, Postural, and Linked Angina

7. It is most important to follow plasma calcium and phosphorus levels about twice weekly post-operatively. The calcium gives the best measure of the success of operation and of the subsequent recovery of remaining normal parathyroid tissue. The phosphorus level usually remains low for some time after and does not help much in management. A rise to abnormally high levels suggests temporary hypoparathyroidism (unless it can be adequately explained as due to worse renal function) and means that therapy may be required to correct hypocalcaemia even if there is no bone disease present. 8. Temporary post-operative correction of calcium and phosphorus levels with subsequent return to preoperative levels indicates that another parathyroid tumour has been left behind and is situated near the site of operation. No change in calcium and phosphorus levels means that a tumour remains far from the site of operation, or else that a misdiagnosis has been made. 9. Alkaline phosphatase levels should be followed every one or two weeks when they were raised preoperatively. A fall to normal means that the bone disease is nearly healed and there is no likelihood of a recurrence of tetany. If vitamin D is being given this can usually be stopped. In some cases many months may elapse before this occurs. 10. Rarely, signs resembling tetany persist for a short time post-operatively when plasma calcium levels are nearly normal. This may be due to Mg lack and will then respond to intravenous MgSO4. One should always bear Mg-lack in mind if a patients mental and neuromuscular symptoms do not immnediately respond to treatment of hypocalcaemia.

Urea, the Forgotten Diuretic

disbanded, and all those residents who were not ill were sent home. Close contact was kept with them, and in no case did they or any of their home contacts develop illness. The ward in which Case 8 was working before contracting encephalomyelitis was closed from June 8 to 18 for the admission of all except urgent cases. There was no spread to patients, although the probationers in training were visiting various hospitals in the group. All the patients admitted to the sick bay of the Royal Free Hospital, Grays Inn Road, were transferred to the infectious disease hospital of the group at Lawn Road as soon as the outbreak was diagnosed as acute infective encephalomyelitis, and succeeding cases were admitted directly to Lawn Road. Every attempt was made to correlate this epidemic with the previous outbreaks in the various hospitals of the group, but no success was achieved. Such pathological examinations as were carried out showed the same negative results as in previous epidemics. Some idea of the difficulties which arise during an outbreak of this description are typified by the fact that at the time of this small epidemic eight people working in or associated with the Royal Free Hospital were admitted or transferred to Lawn Road as suspected cases of acute infective encephalomyelitis which were not confirmed as such, the final diagnoses being as shown in the accompanying Table.

The changing electrocardiogram in Wilson block.

The significance of the Wilson variety of right bundle-branch block was investigated on the basis of serial electrocardiographic changes seen in almost half of the series. Wilson block may originate from both anteroseptal and posterior infarction; in the former it may form a solitary relic without prognostic significance; in the latter it denotes extensive septal involvement. It may modify the injury pattern of anterior infarction and may abolish the signs of posterior infarction; cardiac infarction may approximate it to the classic form of right bundle-branch block. Except in two patients, less than 4 per cent of the series, it was related to pathologic causes; it should therefore be regarded as a sign of organic heart disease.

Electrocardiographic assessment of posterior cardiac infarction

Abstract In a consecutive series of one hundred patients with posterior cardiac infarction assessed according to severity of the attack, 22 per cent were slight, 21 per cent moderate, and 57 per cent severe. This was in contrast to anterior cardiac infarction where this incidence was 42.2 per cent, 22.6 per cent, and 35.2 per cent, respectively. Greater gravity in posterior infarction can be explained by the frequency of arrhythmias and by the tendency of some slight posterior infarctions to become severe, a development exceptional in slight anterior infarction. In slight posterior cardiac infarction, the following electrocardiographic patterns were shown: absent pathologic Q waves in more than one-half the cases; R-T and T changes of the subacute type, for example, bowed R-T with isoelectric take-off and deep inversion of T; and electrocardiographic restoration in about one-fourth of the cases. The severe cases, in contrast, exhibited pathologic Q waves in almost every instance; an acute pattern, for example, high R-T take-off and monophasic T wave in the great majority, and arrhthmias were found in more than one-third of the cases. In the moderate group, the incidence of these signs was transitional, except that no arrhythmias were observed. There was no mortality in the slight and moderate group during the first two months. The mortality in the severe group of treated and untreated cases was 33 per cent. The diagnostic difficulties in slight posterior cardiac infarction were solved by effort test, Leads III R and aV FR . Recent bipolar leads advised for posterior infarction proved disappointing. No diagnostic problems have arisen in the moderate and severe cases. The absence of secondary T-wave changes in anterior chest leads proved an important point in the diagnosis of posteroanterior cardiac infarction. In five patients, slight cardiac infarction was followed by increasingly severe angina; two of these developed severe posterior cardiac infarction within a fort-night and one of them died. Early anticoagulant treatment appeared to delay the severe attack by months in one patient, while in the other two it seemed to prevent it. All the five showed electrocardiographic signs suggesting posterior subendocardial infarction, consisting in sagging or flat R-T depression in Leads II, III, and aV F . Effort test caused temporary extension of ischemia and transformed these dubious records into unequivocal ones. This result was considered an important indication for prompt anticoagulant treatment.