Royal College of Physicians, Edinburgh-Laboratory Reports, Vol. V. 8vo. 1892. Royal Irish Academy-Proceedings, Third Series, Vol. III. No. 3. 8vo. 1894. Royal Society of Edinburgh-Transactions, Vol. XXXVII. Parts 1-3, 1893-4. 4to. 1894. Proceedings, Vol. XX. Parts 1-4. 8vo. 1892-4. Royal Society of London-Proceedings, No. 339, 340. 8vo. 1894. Philosophical Transactions, Vol. CLXXXV. Part 1 A and B. 4to. 1895. Salford County Borough-Forty-sixth Annual Report. 8vo. 1893–4. Sanitary Institute-Journal, Vol. XV. Part 4. 8vo. 1894. Saxon Society of Sciences, Royal-Mathematisch-Physische Classe, 1894, No. 2. 8vo. Scottish Microscopical Society-Proceedings, 1893-4. 8vo. Scottish Society of Arts, Royal-Transactions, Vol. XIII. Part 4. 8vo. 1894. Selborne Society-Nature Notes for Dec. 1894 and Jan. 1895. 8vo. Sidgreaves, The Rev. W. F.R.A.S. (the Author)-Notes on Solar Observations at Stoneyhurst College Observatory. 8vo. 1895. Silhol, M. 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Upsal International Meteorological Congress-Réunion en août 1894. 8vo. Vereins zur Beförderung des Gewerbfleises in Preussen-Verhandlungen, 1894: Heft 9, 10. 4to. 1894. Yorkshire Archæological Society-Journal, Part 51. 8vo. 1894. Zurich Naturforschenden Gesellschaft-Vierteljahrsschrift, Jahrgang XXXIX. Heft 3, 4. 8vo. 1894. Neujahrsblatt, XCVII. WEEKLY EVENING MEETING, Friday, February 8, 1895. BASIL WOODD SMITH, Esq. F.R.A.S. F.S.A. Vice-President, GERMAN SIMS WOODHEAD, M.D. The Antitoxic Serum Treatment of Diphtheria. THE subject with which we shall deal to-night, though at first sight of interest to the physician only, has been so fully discussed and so bitterly and irrationally opposed, perhaps also unreasonably belauded, that those who take even a general interest in the public health, or who are wishful to obtain some insight into the practical and scientific aspects of a new system of treatment, may well be interested to know something of what is being so freely written up in the columns of our daily newspapers. Beyond this, however, many take a more personal interest in a method of treatment which holds out promise of help in the cure or amelioration of the symptoms and conditions met with in diphtheria, a disease which, very justly, is looked upon as one of the most treacherous with which the physician has to deal. To begin with, I should like to make a frank confession. With that conservatism which is met with even in the most radical of natures, many, of whom I was one, felt disposed to treat antitoxic serum as belonging to the same group of substances as tuberculin, around which was constructed a theory of which the laboratory experimental basis, though apparently fair and firm, was as yet insufficient for the support of the structure of therapeutic treatment that was afterwards raised upon it. I followed the earlier experiments on this new method with great attention; I carefully analysed the principles on which the method was founded, and then with some misgivings watched the gradual development of the treatment as applied to actual cases of diphtheria. I was inclined to receive the statistics with great reserve, as I felt that this new method, like all new methods of treatment, might be making cures in the minds of the observer, and not on the bodies of the patients. Now, however, I am convinced that whatever justification my incredulity may have had from the consideration of previous experiments, none could be claimed in connection with the experiments that were carried out in the investigation of this special subject, and I am thoroughly satisfied that, although the antitoxic serum treatment may not come up to the expectations of all the rash writers on the subject-for many people seem to think that it should be a specific against diphtheria in all its stages-it promises, and this promise has in part been redeemed, to diminish the diphtheria case mortality in a very remarkable manner. Diphtheria is primarily an inflammation of the mucous membrane (the moist skin) of the tonsils, of the soft palate, of the upper part of the gullet, and of the upper part of the windpipe. [Illustration shown.] During the course of this inflammation, which appears to be set up by the action of a special bacillus, there are usually thrown out some of the fluid elements of the blood and some of the white cells that float in the blood; these form a soft toughish layer or film which offers an excellent food and resting place for this bacillus of diphtheria, which under such favourable conditions secretes or manufactures a most virulent poison. This poison is rapidly absorbed into the blood and is carried to various parts of the body; its effects are evident at first only on the nervous system, but afterwards on the muscles. First as to the bacillus. In 1875 Klebs described a short bacillus which he found on the surface of the greyish leather-like diphtheritic false membrane or film. [Illustration shown.] Following up these observations, Loeffler traced a definite etiological relationship between this bacillus and diphtheria. First he obtained pure cultures of the bacillus by growing it on solidified blood serum, or on a mixture of three parts of blood serum and one part of neutralised beef bouillon containing extract of beef, 1 per cent. of peptone, 0.5 per cent. of common salt, and 1 per cent. of grape sugar. This organism may be readily detached from the surface of the false membrane by pressing firmly but gently with a little bit of cotton wadding twisted round the end of an iron wire or an ordinary penholder. [Illustration shown.] When stained and examined under the microscope, the diphtheria bacilli are found to be small rods from 3 to 6 μ (1 μ : = 23000 of an inch) in length, fairly plump, straight, or slightly curved, sometimes wedge-shaped or pointed [Illustration shown], but usually somewhat enlarged and rounded at the ends, where also in stained specimens, the protoplasm is more deeply tinted than in the centre. This organism grows singly or in groups, or felted together to form a net-work; it may occur in irregular masses of considerable size. When these bacilli have been growing for some time on an artificial nutrient medium, they appear to be segmented, the stained material accumulating in small round nodules placed at intervals within a kind of membrane which is only very delicately tinted. During the past five weeks I have examined about 500 specimens taken from the throats of diphtheria patients, and I may say that in nearly every case where the disease has been diagnosed by the physician in charge, as being one of diphtheria, these typical bacilli have been found, whilst in those cases in which there was any doubt as to the nature of the disease, similar bacilli were found in some, but not in others. This is of importance, because we shall find that this bacillus gives us the substance with which animals are rendered immune to the attacks of the bacillus itself, these immune animals in turn sup plying the antitoxic serum. To prove that this bacillus is really the cause of the disease, Loeffler, in an elaborate series of experiments, inoculated the pure cultures of the bacillus grown on artificially prepared media, into animals; he was thus able to set up characteristic lesions, especially if he took the preliminary precaution to abrade slightly the mucous membrane, thus, as it were, ploughing the ground before scattering the seed. On such abraded surfaces the bacilli grew very luxuriantly, and false membranes were produced; in these lesions the bacilli could afterwards be found and again separated in pure cultures, whilst the characteristic toxic symptoms of diphtheria were, in each case experimented upon, repeated with the utmost fidelity. Loeffler also pointed out a most important fact in connection with the presence of the organism in the body. He found that it was strictly confined to the local wounds or lesions in the throat and posterior part of the nose, and he was also able to prove that in this position these organisms commenced to manufacture most virulent poisons, which, unlike the bacilli, can become diffused throughout the body. Klein and Sydney Martin in this country have both made very valuable contributions to our knowledge, the former concerning the bacteriology of the disease, the latter in regard to the chemical action on the tissues of the toxic or poisonous products of the bacillus. Martin found that after the poison formed in the throat has made its way into the internal organs of the body it undergoes certain changes; it is broken down into somewhat less poisonous compounds, but these, accumulating at certain points, act especially on the nerves and muscles. It appears then that we have to deal with two sets of poisons: a very virulent poison formed by the bacilli directly from the fibrin and albuminoids of the fluids of the blood, exuded on the surface of the mucous membrane; and secondly, a less poisonous series which appear to accumulate especially in the spleen. So long as these poisons remain in the body we have the general fever, rise of temperature, and altered conditions of circulation (as evidenced by the pulse), so characteristic of the disease. At a later stage, sometimes after all the primary symptoms of diphtheria have passed away, there are often met with what are called post-diphtheritic paralyses, which are due apparently to alterations in the nerves going to muscles, especially those going to the delicate muscles of the soft palate and around the opening into the windpipe, though other groups of nerves and muscles may be similarly affected. These post-diphtheritic paralyses may be due then to the action either of the virulent poison (ferment) formed in the membrane, or of the somewhat less poisonous, but more stable toxines that are formed in the later stages of the disease. Through the kindness of Dr. Martin I am enabled to show you figures of nerves and muscles, the degeneration of which is due to the action of these poisonous substances [Illustration shown]. It is here unnecessary to enter into any detail as to the minute changes that take place in the nerve and muscle fibres, but on comparison of the affected nerve fibres with a healthy nerve fibre, it is evident that we have here grave structural alterations which must interfere most materially with the power of the nerve to conduct nerve impressions from the spinal cord to the muscle. The outer part or sheath of the nerve is in some places entirely wanting, whilst in other cases the axis cylinder or core of the nerve is either greatly attenuated or entirely absent. The poison in these cases has set up changes by which the communicating paths between the muscles and the spinal cord and brain have become thoroughly disorganised. The muscles, too, instead of being formed of cleanly striated fibres, have this striation greatly obscured, first by a kind of cloudy or ground-glass look, and later by the appearance of a number of strongly refractile granules. These, when stained with osmic acid, become black, from which we argue that they are composed of fat, and it is said that the muscle has undergone a fatty degeneration, the muscular protoplasm being partially converted into fat; ultimately the striation may be almost lost. In a case of diphtheria, then, the following stages may be traced a sore throat (often simple enough to begin with), by which the mucous membrane is prepared for the reception of the diphtheria bacillus. The diphtheria bacillus becoming implanted on this surface, gives rise to an acute inflammatory condition, and, subsisting on the inflammatory exudate, sets up a local manufactory of a most virulent poison. This poison, absorbed into the circulation, at once acts on the nervous system, although a certain proportion seems to be broken down into a more stable, but less virulent, poison, which remains in the body, and may continue to act for a considerable time on the nerves and muscles. Whilst these poisons are attacking the more highly organised, and therefore less stable tissues, they are stirring up or stimulating the other tissues of the body to resist their invasion and action. If this were not the case, any one attacked by diphtheria must eventually succumb to the disease; but we know that a considerable proportion of the cases of diphtheria recover even when no treatment at all is resorted to. Whatever may be the exact explanation of this recovery, we know that it depends upon the power of certain cells in the body to accommodate themselves to the presence of the toxines, and to go on doing their work of scavenging and of removing foreign substances from the body even under what originally were adverse conditions; during this process the cells become so profoundly and permanently altered that the patient is for some time protected against further attacks of the same disease. It was originally maintained that this alteration was entirely confined to the cells, but it is now generally accepted that these cells form or secrete substances which, thrown into the blood, either act directly upon the toxines so as to interfere with their activity, or so react upon the cells that they are able to continue their work in the presence of the toxine. At all events, a certain immunity against the disease is |