531

not lead, in either man or animals, to the developmentof ascites, the source of ascitic fluid must apparently bein the liver itself. It could be argued that the increasedflow of lymph from the liver into the thoracic ductinterferes with the flow of peritoneal fluid along the samechannel ; but quantitative studies of Prentice et al.15

(who used water labelled with tritium) have shown thatin ascites the absorption of fluid from the peritoneum isgreatly increased. We must therefore conclude that theincreased flow of hepatic lymph is not obstructing thenormal flow, but contributing abnormally to it. Moreover,the state of the hepatic hilar lymphatics observed byBaggenstoss and Cain indicates that this contribution isquantitatively significant.

15. Prentice, T. C., Siri, W., Joiner, E. E. Amer. J. Med. 1952,13, 668.

16. Banking, J. E., Pardington, G. L. Lancet, 1890, ii, 607.17. Gunther, H. Dtsch. Arch. klin. Med. 1911, 105, 89.18. Waldenström, J. Acta med. scand. 1937, suppl. 82.19. Hierons, R. Brain, 1957, 80, 176.20. Courcoux, A., Lhermitte, J., Boulauger-Pillet Pr. med. 1929,

37, 1609.21. Denny-Brown, D., Sciarra, D. Brain, 1945, 68, 1.22. Baker, A. B., Watson, C. J. J. Neuropath. 1945, 4, 68.23. Marburg, 0. Arb. neurol. Inst. Univ. Wien, 1902, 8, 103.24. Parsons, L. G., Baar, H. S. Acta pœdiat., Stockh. 1947, 36, 60425. Cole, P. G., Lathe, G. H. J. clin. Path. 1953, 6, 99.

NERVOUS SYSTEM IN PORPHYRIA

NERvous and mental symptoms in acute porphyriawere first described by Ranking and Pardington 16 in1890, and our understanding of them is due mainly tothe work of Gunther 17 and of Waldenström.l8 Next tocolicky abdominal pain, they are the principal manifes-tation of acute relapsing porphyria. They include toxicdelirium, which may simulate delirium tremens, ascend-ing neuritis of the Landry type (which may lead to bulbarpalsy and death), and convulsions.The clinical picture has been thoroughly described, but

few papers deal with the histopathology underlying thenervous manifestations. Hierons 19 now reports necropsyfindings in 5 cases and a sural-nerve biopsy in 1. Thisand previous 20-22 work show that in acute porphyria theperipheral nerves undergo patchy demyelination, leadingto gaps in the areas of Ranvier’s nodes. The patchydistribution explains why some workers failed to findpathological changes despite clinical manifestations. Theaxis cylinders are less often and less severely affected.Demyelination may involve the spinal cord (mainly thelateral and posterior columns) and, in the thecentrum semiovale. The nerve-cells affected are mainlythose of posterior-root ganglia and anterior horns, butchanges have also been described in bulbar motor nucleiand the cerebral cortex. The neuronal changes includechromatolysis, vacuolisation of cytoplasm, deep eosino-philia of nuclei, Marburg’s 23 "homogeneous nuclear

shrinkage," increase in cellular lipids, and disappearanceof nerve-cells. In the cerebral cortex Hierons founddiffuse and focal changes: Lymphocytic infiltration hasbeen described, particularly in the spinal cord, andsevere neuronal changes may be associated with glialreaction in which microglia participates to a lesser degreethan neuroglia. Chromatolysis indicates axonal changes,but the vacuolisation and particularly granular incrusta-tions of nerve-cells observed by Hierons in one case

indicate a toxic agent. Ischaemic changes resulting fromvascular spasm play an important role but cannot explainall the findings.Many of the nerve-cell changes, though different in

distribution, resemble those in kernicterus described byParsons and Baar.24 In kernicterus the toxic agent isbilirubin which has not been detoxicated by conjugationwith glucuronic acid.25 In porphyrias the agent isunknown, but only porphyria hepatica (and not the con-genital porphyria erythropoietica) is associated withdamage to the nervous system. The nature of the toxic

agent is still a mystery. An indication may be found in

the a11init.y of porphyrins with myelin,26 recognition ofwhich was the starting-point for the discovery of anexcellent myelin stain with copper-phthalocyanin. The

tetrapyrrolie ring seems to be essential for the affinityof porphyrins with lipids of the nervous system ; andthe monopyrrolic compound porphobilinogen, which isexcreted in the urine of patients with acute relapsingporphyria, is probably not responsible for the damage tothe nervous system. Large amounts of uroporphyrinsmay appear in the urine when there are no nervoussymptoms. It seems, therefore, that a special porphyrinor porphyrin-like substance is the toxic agent. Possiblythis will be found in the Waldenstrom porphyrin, which isa mixture of uroporphyrins i and ill and may, in somepatients, contain an unusual heptacarboxylic por-phyrin.2 7

26. Klüver, H., Barrera, E. J. Psychol. 1954, 37, 199.27. Chu, T. C., Ju-Hwa Chu, E. J. biol. Chem. 1957, 227, 505.28. James, E. F. G. Brit. med. J. Aug. 17, 1957, p. 410.29. Medlar, E. M. Amer. Rev. Tuberc. 1955, 71, suppl., p. 220.30. Aronson, J. D. Ibid, 1951, 63, 121.31. Thompson, B. C. Tubercle, Lond. 1949, 30, 155.32. Dahlstrom. G., Difs, II. Acta tuberc. scand. 1951, suppl. 27.33. Thompson, B. C. Amer. Rev. Tuberc. 1957, 75, 885.

SUPERINFECTION IN TUBERCULOSIS

YOUNG people are suffering less from tuberculosis.Of the notifications of respiratory tuberculosis in theyears 1946-49, 62-4% referred to patients under 35 years,but by 1956 the percentage had fallen to 51-7 ; and itis generally conceded that a growing proportion of thesenotifications refer to patients with minimal disease. Mass

radiography, by detecting such lesions, has helped tomaintain the rate of notifications, thus masking a con-siderable decline-of which clinicians are well aware 28-

in the proportion of young people with severe or extensivedisease.The diminution in total notifications itself suggests a

substantial decrease in the size of the " infector pool,"which is further borne out by the smaller proportion ofchildren reacting positively to tuberculin. Does this also

explain the lessened amount and severity of disease inthe young ’? Certainly the relationship between infectionand disease is usually more direct in adolescents and

young adults than in older patients, in whom breakdowncan more often be attributed to the effect of stress factorson lesions resulting from infection many years previously ;and the decline in notifications of meningeal tuberculosissuggests that those lesions which most quickly followprimary infection are becoming less common. It is alsoreasonable to assume that chemotherapy has reducedthe possibility not only of infection but of repetition ofinfection. Though Medlar 29 and others believe that theresponsibility for producing disease rests wholly uponthe bacilli which produce the primary lesion, or theirdirect descendants, it seems hard to believe that con-tinued exposure, particularly to heavy infection, is of noaccount. The waxing and waning of tuberculin-sensitivitycertainly seems to be related to exposure to furtherinfection,3o 31 and occasionally tuberculosis arises in apatient vaccinated with B.C.G.32 In a follow-up of over1500 children aged 13 or less, Thompson 33 found thatpulmonary tuberculosis developed in 31 during an

observation-period averaging twelve and a half years.Of these, 24 were initially in contact with a patient whowas infectious, and in most cases contact was maintainedmore or less without interruption for several years ; 15were still in contact at the time of, or within two years of,the first detection of their tuberculosis, and earlierdetection might have added 6 more cases. In only 3instances did pulmonary tuberculosis develop more thantwo years after contact was broken. While this evidenceis suggestive rather than conclusive, it would clearly beunwise to dismiss too lightly the possibility of super-infection as a factor in producing disease ; exogenousbacilli may themselves produce a Koch’s phenomenon in

532

the lung or give rise to a focal reaction in dormant lesionsleading to activation. The matter is of more thantheoretical importance, for if the liability to actualdisease is increased by continued exposure to infection,chemotherapy, by establishing control of the sputum-positive patient, has a wider preventive scope than ifliability to disease in his contacts were not so increased.If indeed the development of many lesions depends oncontinued or repeated infection, chemotherapy, byrendering large numbers of infectors sputum-negative,is likely to prove even more effective as a preventivemeasure than was at first thought ; and the existence ofthis possibility renders it even more imperative todiscover and treat unknown infectious patients. It is

perhaps significant that, in Thompson’s series, no newcases have arisen since 1953-by which year chemo-therapy was beginning to exert a noticeable effect.

1. College of General Practitioners. Research Newsletter, no. 14,1957.

2. College of General Practitioners. Ibid, no. 11, 1956.3. Tyler, H. R. Medicine, 1957, 36, 147.4. Allen, J. E. Pediatrics, 1957, 20, 87.

COMPLICATIONS OF MEASLES

"MEASLES," it was once said, "is called a childishillness because it kills so many children." If that is no

longer true, it remains a fact that the complicated diseasecan still kill and maim. Little wonder, then, that thiscondition, recognised since the 9th century, and first

clearly described by Sydenham, should still attract

investigators. The College of General Practitioners madeit the subject of its first major investigation, and part 11of its report 1 amplifies some of the findings publishedin part 1.2 Unfortunately such complications as" catarrh " and " subacute chest " mean little ; but ifone can accept these indefinite terms, then the reportshows that " the severity of the viral infection itself isthe most potent single factor which influenced the

complications rate after measles," and that the severity,in turn, is influenced by feeding, age, and social status.Tyler 3 describes the detailed observation of 85

children with neurological complications of measles ;67 of these had encephalomyelitis. Tyler points out thatthe long-accepted and widely used term " encephalitis "is inaccurate, since, although the pathogenesis isunsettled, the lesion is a demyelinating encephalomyelitisin which spinal changes sometimes predominate. As

might be expected in a neurological disease in which thesites of the lesions are unpredictable, the physical findingsvaried widely from case to case. All the children in thisseries had the more serious type, for, as Tyler points out,those with the commonest variety-with transient head-ache, drowsiness, and irritability-are not generallyadmitted to hospital. The outcome of the disease in thismore serious group is a salutary reminder that even todaymeasles is not to be taken lightly, for only 42 recoveredfully ; 4 died in status epilepticus during the illness and1 eight years later. Tyler believes that most of thedeaths were caused by the fits and not directly by theencephalomyelitis, and that the mortality-rate dependson the efficacy of anti-epileptic treatment. Of the

surviving children, 15 were mentally retarded ; behaviourproblems all cleared completely within three years inthose children whose i.Q.s had not been affected. In 10of the 85 cases permanent hemiplegia developed, which,Tyler deduces, is caused not by encephalomyelitis,but by vascular occlusion. Of the rest, 3 had cerebralcedema (all died), 2 retrobulbar neuritis, 1 retinitis, and2 transient psychoses.The work of Allen 4 illustrates yet further the impor-

tance of clear pathological and clinical definitions.Believing that the so-called measles encephalitis is a

demyelinating encephalomyelitis, he administered largedoses of adrenal steroids, using cortisone, corticotrophin,and (unfortunately from the purely scientific point of

view) antibiotics as well. He compared the results in his10 patients with those in two other groups of comparablesize, one of which was given gamma-globulin and theother "

supportive therapy." These cases are not

controls in the usual sense since they arose in differentoutbreaks at different times. Allen admits that thenumbers are too small for definite conclusions to be drawn,but as all his patients recovered rapidly and fully he feltthat early publication was justified. Since there is noother established method of treatment, this line is wellworth following. It is always exciting to watch thedevelopment of a new therapy which appears to yielddramatic results ; but those who remember the supposedvalue of specific serum in streptococcal infections and ofchloramphenicol in pertussis will retain a modicum ofscepticism.

1. Lancet, July 6, 1957, p. 34.2. Gayliss, H., Laws, J. W. Brit. med. J. 1956, ii, 1141.3. Sutton, D. Ibid, 1957, i, 225.4. Farinas, P. L. Radiology, 1946, 47, 344.5. Seldinger, S. I. Acta radiol., Stockh. 1953, 39, 368.6. Gregg, D. McC., Allcock, J. M., Berridge, F. R. Brit. J. Radiol.

1957, 30, 423.7. Odman, P. Acta radiol., Stockh. 1956, 45, 1.

SELECTIVE RENAL ARTERIOGRAPHY

WE have lately discussed some of the commoiiei

complications of renal arteriography and methods of

avoiding them.1 Among the more important of thesecomplications are extravasation of dye, oliguria or anuria,dissecting aneurysm, and mesenteric thrombosis due tomisdirection of the contrast medium. Extravasation andthe injection of dye into vessels other than the aorta areusually associated with direct trans-lumbar aortography;and Gayliss and Laws 2 have shown that with this proce- I

dure intramural injection of the dye results in dissectinganeurysm. Reports of cases in which anuria developedsuggest that quantities of sodium acetrizoate or diodoneexceeding 35 ml. had been used, and that often this .

volume of dye was directed more to one kidney than tothe other. Sutton 3 has remarked that large volumes ofdye and repeated injections are both dangerous andunnecessary. To control the site of the injection, Farinas Iintroduced the technique of retrograde injection through ,

a catheter introduced into the aorta via the femoral

artery, and Seldinger 5 simplified this technique by intro-ducing his catheter through a needle inserted into thefemoral artery without " cutting down." Gregg et al.,’of Addenbrooke’s Hospital, Cambridge, now describe atechnique of renal angiography, based on Odman’s,;which apparently combines the benefits of low dosageand of controlled injection. They pass the tip of thecatheter, via the femoral artery, into the renal artery onthe side to be examined, and inject only 6-8 ml. of 60%, Urografin.’ This small volume of contrast-medium

displays the renal vessels adequately, and dilution bythe blood reduces the concentration in the kidney toonly 10-15%. Subsequent examination of the urine hasgiven no indication of renal damage. An image-intensifiereases screening control during the insertion of thecatheter, but films obtained by means of the intensifierhave not on the whole been as satisfactory as those madeon the cassette changer. Though the technique is simplein most cases, large lumbar arteries or a hypotrophicrenal artery may give rise to difficulty, and the operatormust be mindful of the possibility that aberrant renalvessels are present.

THE INDEX and title-page to Vol. I, 1957, which wascompleted with THE LANCET of June 29, is publishedwith our present issue. A copy will be sent gratis tosubscribers on receipt of a postcard addressed to theManager of THE LANCET, 7, Adam Street, Adelphi, W.C.2.Subscribers who have not already indicated their desireto receive indexes regularly as published should do so now.