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What the Rockefeller InstituteHasFound Out About Inf antile Paralysis Dr. Simon Flexner, Director of the Laboratory, Announces That the Baffling Disease Travels Up Into the Brain Through the Nerves of Smell in the Nose, and That the it- ■ ■ , Germ Is too Minute for the Most Powerful Microscope to Find, and Can Make Its Way Through the Walls of the Finest Filter. 1 Hy Prof. SIMON FLEXNER, M. 1),, After Effects of the Disease. I ||l Director of the Laboratories of the Rockefeller Institute for Medical Research, N.Y re ' - 11! ilt« following tx taken from Profrnsor ’7< ’nrr'v rer.n/ address before the Charing <'rnsx Hospital. London.) EPIDEMIC poliomyelitis (Infantile pal i ,ysi. i is, pre-eminently a disease of • i\ <-!n)dh>. I and finds the highest ei.eii age of its victims In the first five years of 'll'.- nut does not wholly spare eider ' Iren or eVen adults. It is admit le i , h/o . non-, and while it is true that many ic..ie instances of single than of ~u ijple < iims oeeur, .vet multiple ones, are ' 'i;> rir means rare. The period of great in e is during the months of Au gi. Sep;, ii.aer ami October in the northern urn ,1' and the corresponding months In in hemisphere, but. the epi '. 'iii i■ ; iii> in the early Spring and Sum . u. sit - and the disease does not . . ppi ar during the Winter It does md, therefore, necessarily ;• .d any period of tile year. It" i.i'. n -.w been able to arrive at sev . i i: ; riant n on*-luslons. The monkey u.ido r< iii.iriy to develop an ex agreeing in all essen wit poliomyelitis in man. iii' . ithm is necessary, since keeping ind paralyzed monkeys together J"i 'i to infection. The parasitic "I the disease can traverse the blood, it) 1 nioni ey, to reach the central ner vous organs but will, difficulty, while it •-I 1 \ ; m iso- lhe peripheral (superficial) nerve.> I hat the natural spontaneous dis- so .-ailed In man am' the induced di- in monkeys are very alike is fur how |,y microscopic study of the spinal ord and brain, which exhibit changes ihal are identical. The pathological effects are of two kinds: ’ 11 •" nerve cells, not in the anterior gray matter alone, but in the posterior matter ot the spinal cord ami in the intervertebral ganglia (nerve centres in the spinal eord), medulla (top of the spinal cortb and brain: and cellular invasion of the pia arm huoldnl membrane (the wob llke envelope that covers tile brain and spinal cord) of the spinal cord and medulla that follow the blood vessels into these parts „m| puss into the adjacent gray and whiti matter. I hr- altered vessels permit an escape of albuminous fluid and blood cells into the meshes of the membrane, where they mingle with the cerebrospinal liquid .(fluid sur rounding the brain and spiral cord) and into the spaces in the tissue comimsing the solid white and gray nutter. Sometimes the nerve cells, sometimes the meninges (the different coverings of the brain and spinal cord) vessels and supporting tissues suffe most When the nerve cells arc 1 ex tensive]?- injured the paralysis is marked wi en (he meninges are much affected the svmplonis are like those of meningitis I ; ■ virus of poliomyelitis displays a high Hftmity f.„- nervous tissues, but’it Is the wile involvement of (he nutritive vascular • ii .th* pathologlenl process that sub- Jit* sensitive nerve ceHs to ho high 1 ute <<i injury and < lest ruction. The Infectious Agent of Poliomyelitis The microscopical conditions we ob served tn the course of our were suggestive of two things: first, the Vulture f the parasite itself; and secondly, he process of generation of the effects or •-mils t icinselves. Ip t o this time no defi nite ir isiie could be detected in the ner vous tissues either in human beings or monkeys, u»r was anything of the kind found m the blood of other organs. The s> unity oi polynuclear leucocytes (white blood corpuscles with many centres) in th. 1 <ord its. ■ - pok. against a simple bacterial altered cerebrospinal liquid and spinal parasite lhe 'urge number of mononuclear <■ Is spoke either for a protozoal (animal) 1 'o'.isii. Nerdier could be found, although I " mo-- ailed methods of staining and cultiv.it ion were employed. There remained the possibility ~f tin p irasite heir.; invisible or ultra-micro s 'p: ' and Ii terabl. This it proved to be f.e- when a portion of the spinal eord of a i -ciitiy paralyzed monkey was made into an emulsion with sterile distilled water or simp:, saline solution and then ceqtrifuged to remove the coarse suspended matter mid afterwards pressed through a Berke fe earthenware filter —which excludes or binary cells, bacteria and protozoa -the ...a. i'tuid resulting was still capable of : i .insm:tting the disease. Tile i ivity of the filtrate is very great, sc. i fraetio'n of a thimbleful still suf ues . cause paralysis and death. The . distinction to be noted between the . : i c corresponding amounts of the ei.iui'ioii and tillered lluid is that the form al . .•» aior. quickly. as would be expected ii.'ii'. the fa.-t that it contains a greater i .; ■ the invisible organisms. Thi' o . : .- i- -on comp-nsated by the mul ti; i .-'a o: d.ose iii t!m tiltrate, so thiv the ci. i r.-suit is the same. in i-i.deavo|-jug to trace the channel of i .; the virus inn. the body certain t ; : 1.-.’ "dll its distribution in the body >.n- . ■ r.s , pit u... ..-a ami considered. I .- iutectious agent ..f poliomyelitis nt a- .. . uiedy the central nervous system Hi i. d. it hi. - i.evn detected regularly in ■■ oil . rd and brain, and In the me s.n;. I- ymph nodes (coagulated particles el 'tn;, i in tin- alslomimil walls) among a. . in'crnii) organs. It Ims also been i in the mucous membrane of the and throat, and in the mucus ns of this membrane, and in the ■etioiis of the stomach, and the large intestine. The virus Ims .'.'ted in sui-ii important organs . . ii. kidneys, liver, or bone mar I i ,s gnifi .-.nt, but in at " an- should be ■:- ii si ..> .<• that at presen -m.- n ■ 111, only of detecting th ■ - i. it. its to mon keys, in which it produces characteristic paralysis and anatomical changes. On this account small quantities of the virus may conceivably escape discovery. However, the conclusion is none the less inevitable that detectable amounts of the poliomyelitic virus exist, only in the few situations ami organs mentioned. The dis tribution of the virus is identical in human beings, tile subjects of the so-called spon taneous poliomyelitis, and in monkeys, in which the experimental affection is pro duced. Nor does it. matter how the experi mental inoculation is accomplished, and whether the virus is Introduced by injection into the brain or large nerves or subcu taneous tissue or peritoneum, or whether it is merely applied to the nasal mucous mem brane which it should be emphasized, next to direct intracerebral injection, affords the surest means of causing the experimen tal disease. In whatever way tile infection is produced purposely, the distribution of the virus in infected monkeys is the same as in infected human beings. Ihe virus is one that is not known to increase aside from the infected body, and hence in order that it shall be cap able of |ir<>|>agating poliomyelitis it must B, >. JgWvC X ' '■ X .WW v\ a' \ f i , ..../. \ < JMF M> /• —/ ■ ' '' v f X n n <WIF 'R i f 3v If »m» ul-*’' u h 11 ihSF ti\l - . ; fcx. ;.. /-U —nr w*K i\ 1 * I ..4%;xxx '>■*•* -xw Fl''So- ’’ x I—*® —*■ ♦ 4 I I -31 vw I -<fi : '* v* \ jfeawK^lk^/-. y ■ ■ * via WfIMF•-rWar ?Ay wm ' •>■ X/ ' fXnr" ' *“ff < 1 Wvlx... ’ w -"i Wal j i ■ * W A Spinal Nerve Certtre, Showing a Diff use Inflammatory Process and Beginning Death ok Nerve Cells. : W ’■ i -' 1 ' ere the I.®.- virus distrlb- / i ■ uted by the -"" ■■ blood the me- Diagram Showing Channel by Which the Infantile fV."” « h n 1n n 1 Paralysis Germ Reaches the Spine. A. Nerves of ( . nr d) spin Smell in the Nose, Along Which the Germ Travels. al cord would B. Olfactory Lobe or Centre of Smell in Brain. C. have become Head of Spinal Column, Which the Germ Reaches infective rather by Way of the Olfactory Lobe. t cTr y Vo b eT. secure a means of escape from the infected animal. The escape is now known to occur i alon» with the secretions of the nose and throat ami the discharges from the intes tine. x It Is known that in monkeys the virus is incapable of passing the barrier of the unbroken or slightly abraded skin, of be ing taken up from the stomach or intes tine unless the functions of these organs are previously disturbed ami arrested by opium. and it Is further known that it traverses with difficulty, or even not at all, the substance of the lungs. On the other hand, it is established that the virus passes with readiness and constancy from the in tact, or practically intact, mucous mem brane of the nose to the central nervous system. To illustrate this point I wish to de scribe briefly an experiment. The spinal cord of a paralyzed monkey always con tains the virus we are considering. If a camel's hair (lendl or pledget of cotton *■» covered with some of the broken up tissue of such a cord and painted upon the mucous membrane or rhesus monkeys these ani lmils will develop in due time the paralysis ami other symptoms of poliomyelitis. Hence the virus enters the body from this surface, even though no gross Injury has been Inflicted upon the membrane How the Virus Goes to the Brain. We should now ask ourselves if the virus actually ascends to the brain by the direct path of the olfacte-y nerves (nerves of smell) or indirectly after first entering the blood. This Is the same question that has been buffeted about in regard to epidemic meningitis. The meningococcus i germ of meningitis) Is found in the nasal mucus of persons in contact with eases of men membrane of rhesus monkeys these ani ingitis and in the sick themselves. Opin is divided as to whether they go at once to the membranes of the brain or tirsi penetrate into the blood. To produce meningitis in monkeys it does not suffice to inoculate the nasal mem brane; the meningococci must be injected into the meninges themselves. But so in oculated they escai>e in part along the nerves of smell into the nose The virus of poliomyelitis Is so active that implanta tion in the nose does not suiffee to cause infection. If a monkey is sacrificed about forty-eight hours after an intranasal inoeii lation and the brain and spina! cord are removed and then the olfactory lobes, (cen tre of smell in the brain) portions of the medulla and spinal cord are separately in ocnlated into other monkeys, infection Is produced by the olfactory lobes alone, si o in this brief period the virus b.is not ye' reached oilier and more list.in parts at <Uu ueiwus organs. ■ w-yn, Is; “• B-v O fe- WiA # \ i I & i F- < ■'> *, • i . J J I ' ■-/ . f a J . ' ' 'of ' y • Y Simon Flexner, Director „f „ Laboratories of the Rockefeller ! n . r ;s , , stitute for Medical Research, N Y 1 " * •■— ■ ■ r>" ~ ~~ y since they exhibit a greater selective affin ity for the parasite. The conclusion is un avoidable that the virus ascends by the nerves of smell to the brain, multiplies first in and about the olfactory lobes, and in time passes, as I believe into the cerebro-spinal liquid, (fluid between the coverings of the brain and spinal cord I which carries It to all parts of the nerv ous organs. . . Wo have already learned that the virus can pas*-* along a large nerve, such as the sciatic, which carries it first to the lumbar cord, (lower part of spinal cord) whence it ascends to higher levels; we need not. therefore, be astonished to find that it can wander along the olfactory nerves and then descend to lower levels. The large peri pheral nerves are prevented anatomically from becoming infected in nature, while the small olfactory (filaments are advan tageously placed to act as the means of transportation. Hence the view I desire to place before you: that the nasal mucous membrane is the site bqth of ingress and egress of the virus of |H>liomyelitis in man. Support for this view is found also in the study of the microscopic changes in the meninges ami tin* central nervous tissues. Since the virus survives in the dried state It may be car ried in dust; and In one instance it has been detected in sweepings from the room occupied by a j>erson ill with poliomyelitis. Its distribution ns spray in coughing ami spe iking is readily accomplished, and by this means both active cases and passive < arriers may conceivably be produced. Still one link in the chain of causation of poliomyelitis as here outlined remained to be forged. The clinical evidence is strong in the suggestion that human car riers of the poliomyelitic virus exists. The virus has now b<*en detectisi In the secre tions of the nose, throat and intestines of la-rsons suffering from abortive or ambu lant attacks of poliomyelitis. The unrec ognized examples of the abortive disease play a highly important part in the dissem ination of the virus, through which the area of infection is extended, and the num ber of the attacked increased. A similar part has been accorded by clinical observation to the healthy virus carrier, and the healthy carrier is the last to be detected, and Ids existence con firmed experimentally. The obstacles in the way of this confirmation are consid erable, but not insuperable. It is to be remembered that we jtossess no means of ch, .v. ring the virus except that of animal inoculation. Should the experimental re sults arising ft*, nt the inoculation of tne secretions of the nose and throat of such healthy carriers Ih> confirmed the evidence for the mod* • infection as hero out im-d w*'>ild lie complete. The membrat' of the m*se and throat is far more vulner able m young individuals, wheucv arise.; the greater prevalence during childhood of those diseases the causes of which seek this avenue of entrance into the hotly Among them are included diphtheria, measles, scarlet fever and meningitis. Would the establishment of the respira tory avenue of entrance of the virus ex clude all other modes of possible infection? By no means. Plague bacilli are known to be Inoculated Into man by rat fleas; bitt, the pneumonic form of the plague is ad mittedly caused by respiratory inoculation Diphtheria arises upon the mucous mem brane of the throat, but can develop in a wound of the skin; the virus of smallpox enters byway of the throat and nose, but can enter by a skin abrasion; the virus of foot and mouth disease. Is taken in with food, hut produces infection when injected into the skin. Hence at the moment, while knowledge is still recent and not yet per fect. lite too absolute adherence to one point of view is to be avoided. 1 Indeed, the propondetance of cases in the late Sumi»’r and Autumn months early suggested an insect carrier of the infec tion. House flies can act as passive con taminators, since the virus survives upon the body and within the gullet of these in sects. Hens May Be Disease Carriers. The frequent prevalence of epidemics in sparsely populated country districts has led, moreover, to consideration of domestic , animals as sources of the infection. Paralysis of dogs, horses, pigs and fowl has been observed not uncommonly, but ' thus far without clear correlation with paralysis in man. Perhaps the most fre quently observed coincidental paralytic.dis i eases have been between hens and human beings. . We have, happily, made some progress I in a method of direct, local treatment by Injections that have given excellent re sults in meningitis. Remote as some of them may <eem, the i considerations to which I have called your I attention have a bearing more or less vital upon the problem of a specific and effective treatment of poliomyelitis. Poliomyelitis is not a disease with a very high mortality; its chief terror lies ’ in its appalling power to produce deformi ties. When death does occur it is not the result, as in many infections, of a process * of poisoning that robs the patient of strength and consciousness before its im- ' minenee. but is caused solely by paralysis of the respiratory function, sometimes witli merciful suddenness, but often with pain till slowness, without in any degree ob scuring the consciousness of the suffocating victim until just before the end is reached. No more terrible tragedy can l>c witnessed The employment for treatment of the immune serum, taken from monkeys or * from human beings, exercises a definite if not very strong protective action gpon in oculated monkeys. Either the disease is prevented altogether or’ its evolution is 1 modified in such a manner as to diminish its severity. When the virus used for ii * octtlation is highly adapted to the monkey, and thus very virulent, it is more difficult to control the result than when ii departs less from th*: ?rigiual human typo and t less active The immune serum has thus far acted best when it’was in jected into the subdural space on several successive days. 4<-, <•» nAnfiimnlt v ti-it It F 11. . This Is in conformity with th z fact that, however introduced into the body, the virus establishes itself in communication with the cerebro-spinal liquid, where it propagates for a time. After a time the virus localizes in the nervous tissue itself, and becomes accessible not only from this liquid, but probably from the general blood ; also. The serum introduced into the subdural (under the outermost covering of ; the brain) space soon escapes into the f blood; and thus a double action is secured, i On the one hand it reaches the nervous [ tissue directly from the cerebro-spinal , liquid, and on the other with the blood An immune horse serum at first gave dis . appointing results, but latterly its employ meat by intramuscular injection has given more promise. But none of the sera men , Honed*can be regarded as having more than touched the fringe of the problem of a cure for the disease. Such brilliant success has been rei.ntly recorded in respect to the specific chemical therapeutics of infection that an effort has been, and still is being, made to attack the problem from tais quarter. Here, also, , only a starting point has been secured and the subject merely opened to'further ex ' perimentation. The point of departure t which we have adopted is the drug hex amethylenamine (urotropine), which pos ! sesses a degree of antiseptic, action in flic body and is known to be secreted in the cerebro-spinal liquid. When the drug is 1 administered by’ mouth it can be detected by chemical tests in the liquid in a short time. When i •illation of virus and ad ministration of the drug are begun to -1 gether and the administration continue*! lor some days afterwards tin* development of the paralysis is sometimes but not al ways averted. Hexamethylenamine lends itself to modi fications by the addition of still other anti septic groups to its molecule. We have tested a large number of such modifica tions and have found certain lines to ex ' ceed the original compound in protective power, and others to promote the onset of paralysis. This is the common story of ’ drugs. None are without wholly some d* gree of injurious action upot the sensitive and vita! organs of the body. But manipu ’ lative skill has already succeeded in elirn- L imiting the objectionable and improving the valuable features of drugs so that they ' exert their action but little upon the organs 1 and severely upon the parasites when they become useful as therapeutic agents The House Fly Conveys Infection. Since Dr. Flexners address further re searches by the Rockefeller Institute ex perts seem to have definitely proved that the common housefly is the main source of infantile paralysis infection. Drs. ('. W. Howard and Paul F. Clark experimented with flies, mosquitoes, lice and bedbugs. Wit it the exception of the 1 mosquitoes, the insects were permitted to teed on a portion of a spinal cord taken from a monkey which died of the disease. Mosquitoes fed upon figs, which had been * injected with a mixture of blood ami in fected spinal matter. All the insects ittr-i t<'..-l > g w*-i- killed Little Convalescent Trying to Walk with Specially Constructed Chair. w ith el her, ground up with sand and sail solution and passed through a Berkefeld filter. The filtrate was infected, in the manner described by Dr. Flexner, into th« brain of the Rhesus monkeys. The flies were the ordinary species ot housefly, bred in the laboratory. Every monkey infected with the filtrate from their bodies died from infantile paralysis. No monkey inoculated with the filtrates from mosquitoes or lice showed a trace of infection. One monkey out of sixteen in oculated with the bedbug filtrate showed the characteristic symptoms of poliomye litis. Tite lieduct ions from these experiineu s says the experts’ report, are clear. The domestic fly may become contaminated with the poliomyelitic virus which it may obtain in nature from infected discharges from the noseband throat or intestine. He cause of the resistance of the virus to ordinary physical changes, especially when combined with mucous secretions, it can be transported in a living state on the sur face of tlwir bodies for two or more days and because of the resistance it display; to digestive secretions, within the eso phagus and stomach for at least several hours. The survival in the gullet permits of the contamination of objects during tiie feeding process through the act of re gurgitation which the fly performs in moistening and dissolving its food. The flight of the house fly is consider able. Copeman, Howlett ami Merriman found marked flies one-half to three-quar ters of a mile from the (dace of their libera lion. On this account these potential pas sive contaminators are theoretically <apa hie of carrying and depositing the virus at a considerable distance from the point at which the original contamination occurred. I hrough the ordinary active habits of the fly the virus may be transferred to persons or to tilings with which persons com* D.o * lose relation, and by the death of the flies they may through disintegration liberate surviving virus: that may possibly be con verted into dust. The finding of the ' hi the sceretions of the nose, throat. ‘ '* gastro-intestinal tract of human beings suggests that through the agency of •■■ ■ a passive eontaminator as the fly, the Dru.- may be taken into tne bodies ot liui '.* b*ings in which, conditions favoring, may develop and cause infection. The conclusions of the experts are: “ Fhe domestic fly (J/usca ilomi'ttii fi) cm < arry the virus of poliomyelitis in an five state for several days upon the sir. . of the body : nd foi several in urs within n east to intestinal tract. '.Mosquitoes tCule.r pipicni Cuhi * 1 I'itmis, and ( tilc.r rnntator) in our experi i.ients, nave not taken up and nmintai 1 in a living state the virus from the spina cord of monkeys “Lice (P< rliculitx capitis and Pcdt i 1 have not taken the vim of the blood of monkeys or maintain in it living slate. ‘■rhe bedbug fCinie® Icctulai ui taken the vires with the blood from ■*■'•*-d monkeys ami urnintaine*! i' ib nig state within the body foi * p’ l seven days/’