FURTHER CONSIDERATIONS IN THE PATHOLOGY OF MALARIAL METHEMOGLOBINURIA* BY WM. KRAUSS, M.D. MEMPHIS. THIS short sketch is intended merely to cover such points as have appeared from time to time as discussions, editorials and informal addresses since the last complete paper written jointly by Dr. Goltman and myself. Although this paper was written in the summer of '97 and comprised labors in part two years old, it was not published until then because it was wanted as the special article for the meeting of the Tri-State Association that year. Like all joint papers, it had the demerit of being the compromise of the opinions of two men, and later investigation, as well as the classic publications of Bastianelli, the Plehn brothers and many other writers, has necessitated a revision of the opinions then held. 1. The tertian parasite was said to be the etiologic factor in most cases. In a report made by the writer, comprising the collected cases of seventeen observers in the vicinity of Memphis, and including reports of 208 cases, the answers for 188 cases were, "intermittent, becoming remittent just before the attack." At the time we did not know of an intermittent estivo-autumnal fever, and as none of the observers had made blood examinations, we took it for granted that they were dealing with the tertian parasite, and it was so incorporated in the report. Half of the cases observed personally since then were consequent upon the estivo-autumnal parasite; most of them were precipitated upon the sporulation of a group of plasmodia, which afterward rapidly disappeared. The last series of 16 cases seen by the author have as blood history, 5, none; 7, intermittent fever, terminating in remittent; 3, examined before attack and estivos found; 1, hematuric chill was first sign of illness. After they were seen by me, 4 were too far along for blood examination; 8, blood examination on first day; 3 had first blood examination Read by title before Tri-State Medical Association (Miss. Ark. & Tenn.), Memphis, November 20, 1901. after third day of hematuria and no plasmodia were found, and of 1 there is no record. Of the 8 seen by me on first day, 7 had sporulating parasites, the other had pigmented leukocytes and inclusions in these which might have been plasmodia. In my earlier work I believed the hematokonia to be embryones and described them as such. Since employing the polychrome methods I have found that these bodies are generally neutrophile, whilst the plasmodia are slightly basophile. The estivo-autumnal parasite is therefore not a "plus infection." In all but 2 the parasites disappeared during attack. 2. The index to the administration or non-administration of quinin, instead of being as stated, is simply this: so long as sporulating parasites are in the peripheral blood and there is no hematuria, push it to the limit. If oral administration is not practicable, give the neutral chlorid in very dilute solution with an antitoxin syringe; no slough follows this mode of administration. Some fear to provoke an attack, but if the quinin provokes it, it is more certain to supervene without it. 3. I wish to reiterate and emphasize the following: "We are therefore forced to the conclusion that, hematuria once begun, quinin has no place in its therapy. This, however, has no reference to its exhibition in tonic doses in the posthematuric period." In this connection it is proper to mention the treatment of 2 of the last 16 cases, in which the plasmodia persisted throughout the attack and fever continued in an increasingly remittent manner. In the first one I feared to give quinin in the exhausted state of the patient, but finally gave, with the consent of the consultant, half-grain doses of quinin every two hours without provoking a chill, then increased to 5-grain doses and had the satisfaction of seeing the fever leave definitely. The other patient would react to every form of the drug, even the elixir of cinchona made from the bark, always with a slight rigor and a tinge in the urine. Even methylene blue jaundiced her. I therefore decided that any anti-malarial treatment would injure such a patient, disregarded the plasmodia and fed her on bone marrow and pepto-mangan (Gude). She was an inmate of St. Joseph's Hospital; there were no other malarial patients in the ward at the time, and as it was in December, I decided to let her immunize herself, and this she did. 4. Quinin hemoglobinuria. This was described as a separate condition from the "malarial", and is still so considered by many writers. At present I do not think so. In a discussion before the medical section of the A. M. A. at the Atlantic City meeting3 I stated that I believed that there was a symbiosis between the plasmodia and the patient, which, if disturbed, either by an unusual invasion or voluminous sporulation on the one hand, or anti-malarial treatment on the other, precipitated a hemolysis. The conditions provoking a paroxysm are divisible into two opposing groups-those favoring the patient and those favoring the plasmodia; and since diametrically opposed conditions appear to produce the same result, we have only two logical conclusions: 1, a reversible enzyme action; 2, a symbiosis, the disturbance of which produces a hemolysis. Marchiafava and Bignami1 call attention to the original work of Bordet on hemolysis which has since been completely exploited, and is now considered to be due to the formation of an anti-alexin which has the property of always dissolving the blood of a species for which the experiment animal has been treated. They conclude as follows: "This hypothesis would explain the fact that attacks of hemoglobinuria occur only after the malarial infection has lasted a long time; since the assumed alteration in the plasma would require a long time for its production. It would also explain the apparent irregularities and accidental character of the phenomenon, which depends upon the complexity of conditions which are necessary for its production. It further explains the irregularity in the action of quinin and of the existing parasitic invasion; indeed, in the same individual we may have hemoglobinuria with parasites in the blood without the intervention of quinin, hemoglobinuria after the action of quinin, and finally spontaneous hemoglobinuria without the presence of parasites in the blood and without the previous administration of quinin. All this inclines us to assume, as affirmed in the hypothesis, that the action of the parasites or of the quinin possesses a secondary importance in compar ison with some other unknown factor which, according to the theory, is represented by a newly developed property of the plasma. The malarial parasites and the quinin represent only the agent which liberates the hemolytic substance, like the addiment in the experiments of Pfeiffer and Ehrlich; they represent therefore only the occasion of the attack." Bastianelli's group of conditions necessary to produce an attack are: 1. Pre-existing alteration in the hemopoietic organs. 3. Precedence of one or more attacks of malaria. 5. A provocative agent. There is nothing in this which contradicts the hemolysin, anti-alexin or reversed enzyme action theory. He mentions three classes of hemoglobinuria: 1. The attack comes on with the sporulation of a group of parasites which continue throughout the attack. 2. Same as the preceding, the plasmodia disappearing during the progress of the disease. 3. Post-mala rial. Some writers contend that all cases are post-malarial in effect, i. e., the existing parasites are no factor in the attack. The first cases I have had the opportunity to study were truly post-malarial. I reported such a case before the Tennessee State Medical Society, and in a personal letter from Dr. Osler he congratulated me "on the interesting case of non-malarial hemoglobinuria." The reversible enzyme idea would presuppose the existence-very probably in the spleen-of a substance either as a normal enzyme or a "side chain," whose function it is to maintain the corpuscular balance, which when disturbed would precipitate a hemolysis Its effect would necessarily be indirect because the generation of erythrocytes is the result of cellular activity of the erythroblasts. The effect of quinin on susceptible individuals seems to me to be due entirely to the amount of the hemolytic body stored up. This certainly varies with different individuals. Some set free their storage after a single dose of quinin; subsequent doses can obviously do no further harm. Others eliminate their storage after a few days' duration of the syndrome, and finally, some seem never to lose it, as the one mentioned above, in which all treatment had to be suspended. In my experience, the storage seems in most cases to be in direct relation to the disappearance of the parasites; the patients whose urine clears up promptly are not as certainly freed from the infection as those in which there is an excess of this storage, the same case mentioned above being again an exception, but in this case it is likely that the immunizing effect is impaired and they are said to have "chronic" hemoglobinuria. Dr. Brister reported such a case to me.6 5. Just how much the liver has to do with this perverted metabolism is not clear, but the previously announced pathology, as far as it has reference to the liver, is clearly erroneous. It is true that the liver makes an incomplete bile, and that there must be resorption into the lymph paths as a result of the increased pressure within the bile channels, but this, if continuous, will simply cause a pressure-injection of the bile canaliculi and focal necroses in the liver. Sections of such livers have been exhibited on this floor. The hemoglobinemia cannot result from this bile resorption, as such is not proved to take place in other obstructive jaundices, and because it clearly antedates this hepatic obstruction. Nor is the hemoglobinemia in the peripheral circulation in some cases very marked. The blood destruction appears to take place in the splanchnic area, certainly in the kidneys, as can be seen from the sections, and very probably also in the spleen. The spleen is disintegrated; no definite picture can be made out; in some it might be called hemorrhagic degeneration; in others there is great round cell infiltration; in all we find very great pigmentation. Of course, some allowance is due to such changes as resulted from the preceding chronic malaria. In the kidneys I have found fine pigment in the glomeruli, in the convoluted tubules, scattered in very fine particles,but in the Bellini tubules it is found in great rodshaped blocks imbedded in the epithelia; as this is not secreting epithelium, the pigment must have been picked up from the lumen of the tubule, which is difficult to understand; degeneration of the convoluted tubules is always the most marked; the limbs of Henle's tubes are in all my cases blocked up with débris having a siderin color, thus showing a mechanical obstruction. Some writers deny this, claiming that suppression is due to |