Copyright N° COPYRIGHT DEPOSIT. EPIDEMIC CEREBROSPINAL MENINGITIS EPIDEMIC CEREBROSPINAL MENINGITIS BY ABRAHAM SOPHIAN, M. D. II FORMERLY WITH NEW YORK RESEARCH LABORATORY TWENTY-THREE ILLUSTRATIONS ST. LOUIS C. Y. MOSBY COMPANY 1913 <1 Copyright, 1913, by C. V. Mosby Company Press of C. V. Mosby Company St. Louis •*Jp- ©CI.A346G04 THIS VOLUME IS DEDICATED TO DR. WM. H. PARK AND DR. SIMON FLEXNER WHOSE RESEARCHES HAVE HELPED TO MAKE THE FIELD OP IMMUNE SERUM THERAPY POSSIBLE PREFACE. My studies in the Research Laboratory of New York and during the Epidemic of Texas in 1912, afforded me a rare opportunity to apply the Laboratory studies of meningitis at the bedside of the patient and to demonstrate the importance of utilizing both labo- ratory and clinical observations for systematic control of an epi- demic and for properly treating the disease. The studies in Dallas in the municipal control of the epidemic and the coincident studies in the Dallas Meningitis Hospital, enabled me to apply in connected, systematic order many of the excellent observations which had been recorded by different workers. Many of the experiences in the Laboratory and at the bedside so obtained are recorded in these pages. Particular attention has been given to a description of methods employed in scientific municipal con- trol of epidemics, especially with regard to careful, scientific quar- antine and the application of specific preventive measures. Many observations on the blood-pressure in meningitis are noted and the method of controlling the administration of the antimeningitis serum by changes in blood-pressure is carefully described. Toward the end of the Texas epidemic, experimental studies on prophylactic vaccination against meningitis were carried out. I hope that this study will stimulate further research which will help to establish this measure as a dependable preventive against the disease. The purpose of the work throughout is to convey a thorough yet simple description of the clinical and laboratory findings in the disease and to so interpret the laboratory descriptions as to fa- miliarize the reader with their application in treatment and in clinical analysis of the disease. I take pleasure in expressing my thanks to Dr. William H. Park for his encouragement and assistance to me in my work in the Research Laboratory and to Dr. Simon Flexner for his interest and valuable suggestions during the Texas meningitis epidemic. ABRAHAM SOPHIAN, M. D. Kansas City, Mo. XI CONTENTS. CHAPTER I. PAGE Etiology . . . 1-52 Historical — Predisposing Causes — Bacteriology of the Meningococcus and its Allied Organisms — Portal of Entry of the Meningococcus into the Human Body — Dissemination Disease — Resume of Etiology of Meningitis as to Epidemiology, Bacteriology, Portal of Entry of the Organism, and Mode of Transmission. CHAPTER II. Symptomatology 53-103 Infections Produced by the Meningococcus Preceding Meningitis — Acute General Diseases not due to the Meningococcus, Accompanying an Attack of Epidemic Meningitis — Symptoms in the Acute Form of Meningitis — Chronic Meningitis — Posterior Basic Meningitis — Clin- ical Differential Diagnosis between Epidemic and other Forms of Meningitis Relapses. CHAPTER III. Laboratory Diagnosis of Meningitis 104-133 Cerebrospinal Fluid — Other Laboratory Aids in Diagnosis of Epi- demic Meningitis — Blood Examination — Presence of Meningococci in Other Secretions. CHAPTER IV. Complications 134-147 General Meningococcus Sepsis — Pressure Complications — Complica- tions of Local Involvement of Central Nervous System — Resume of Symptoms Occurring During Convalescence Course of Epidemic Meningitis. CHAPTER V. Studies on Blood-Pressure in Meningitis 148-160 Blood-Pressure in Epidemic Meningitis — Effect on Blood-Pressure of Withdrawal of Fluid by Lumbar Puncture — Effect of Injecting Serum on the Blood-Pressure — Interpretation of Observation on Blood-Pressure in Meningitis — Observations on Pulse Rate During Lumbar Puncture. XIII xiv CONTENTS. CHAPTER VI. PAGE Treatment 161-258 The Anatomy of the Cerebrospinal Meninges, and of Lumbar Punc- ture — Lumbar Puncture — History of the Introduction of Specific Antimeningitis Serum — Preparation of the Antimeningitis Serum — Standardization of the Antimeningitis Serum — Prophylactic Meas- ures Against Epidemic Meningitis — General Remarks on Curative Treatment — Serum Treatment of First or Premeningitic Stage (ac- cumulative stage) (General Bacteremia) — Classification of Active Treatment — Serum Treatment of Meningitis — Cases with very Thick Plastic Exudate — Serum Treatment of Cases with Dry Canal — When to Discontinue the Further Injection of Serum — Relief of Hydro- cephalus in Acute Stage — Acute Meningitis — Treatment of Subacute and Chronic Forms of Meningitis— Treatment of Complications and Sequelae — Analytical Study of the Effect of Serum Treatment of Epidemic Meningitis — Prognosis. ILLUSTRATIONS. FIGURE I. II. III. IV. V. VI. VII. VIII. IX. X. XI. XII. XIII. XIV. XV. XVI. XVII. XVIII. XIX. XX. XXI. XXII. XXIII. PAGE Pure culture of meningococcus 21 Patient actively ill six days with epidemic meningitis .... 72 Boy of eleven, ill forty-eight hours with epidemic meningitis . . 73 Alcoholic patient, ill thirty-six hours with epidemic meningitis . 74 Patient violently ill with acute epidemic meningitis .... 75 Patient ill eight and one-half months with epidemic meningitis . '84 Patient ill six weeks with epidemic meningitis 90 Diagram to show the connection of the subarachnoidal space in the brain and the cord 162 Scheme to show the relations of the Pacchionian bodies to the sinuses 163 Diagram of a cross section through the dorsal spine, showing how the arachnoid membrane may be adherent to the poste- rior surface of the cord 166 Diagram of a cross section through the dorsal spine, showing how the subarachnoid space may completely surround the cord 167 Diagram of cross section of dissection opposite the fourth lum- bar interspace 168 Diagram of cross section of dissection at level of fourth lumbar interspace 169 Illustrating the operation of lumbar puncture and the technique in injecting the antimeningitis serum . . . . '. . . . 171 Apparatus for injecting antimeningitis serum ....*.. 210 Needle and trocar for author's apparatus 210 Serum container for author's apparatus 210 Rubber tube for author's apparatus . . . . . . . . . 210 Rubber bulb for author's apparatus 210 Microphotograph illustrating stained sediment of cerebrospinal fluid removed from a case of epidemic meningitis at the be- ginning of the disease, before serum treatment was instituted 245 Microphotgraph illustrating appearance of sediment 24 hours after 30 c. c. of serum had been injected subdurally . . . 245 Microphotograph illustrating stained sediment of cerebrospinal fluid obtained 24 hours after the second dose of antimenin- gitis serum 245 Microphotograph illustrating sediment of the cerebrospinal fluid 48 hours after the third dose of serum 245 xv CHAPTER I. ETIOLOGY. HISTORICAL. (FROM HIRSCH.) Hirsch divides the history of epidemic meningitis for epidemio- graphical purposes into four periods. The first, from 1805 to 1830, shows us the disease in isolated epidemics at various places in Europe, but more general in the United States. In the second period, from 1837 to 1850, meningitis becomes prevalent in widespread epidemics in France, Italy, Algiers, the United States, and Denmark. During the third period, from 1854 to 1875, the malady reaches its widest diffusion throughout most of Europe, the adjoining countries of Nearer Asia, the United States, and some parts of Africa and South America. The fourth period, from 1876 to the present day, is a return to merely casual epidemic outbreaks, or to more or less considerable groups of cases here and there within its former distribution-area. First Period. — The earliest information on epidemic meningitis dates from 1805, in which year the disease was prevalent in Geneva and the vicinity of the city in the months of February, March, and April, and among all ranks equally. Next came the epidemic outbreak at Grenoble in February, March, and April, 1814, among the soldiers of the garrison, and the concurrent epidemic in the garrison of Paris. In 1815 there was an epidemic at Metz, and one in the spring of the same year at Albenga, Cereale, and two or three more villages in the province of Genoa. In the spring of 1822, many cases of epidemic meningitis occurred at Vesoul, and in the winter of that year the disease was epi- demic at Dors ten' in Westphalia. In the United States, the disease reached a very considerable diffu- sion in the first of our periods, and was spoken of by those who saw it under the names of "sinking typhus" or "spotted fever." It appeared first in New Hampshire and Massachusetts, later in Connecticut, New Jersey, Vermont, and Maine (1814). The epidemic kept up contin- uously at one place or another in New England until 1816. Meanwhile it showed itself in Canada in 1807, in Virginia, Kentucky, and Ohio in 1808, in New York State and Pennsylvania the year after, and, accord- ing to not altogether trustworthy information, it was prevalent at a later date in the Southern and Western states as well. The year 1816 l 2 EPIDEMIC CEREBROSPINAL MENINGITIS. formed the close of that time of sickness. With the exception of two rather localized epidemics, one at Middletown, Conn., in 1823, and the other at Trumbull, Ohio, in 1828, the United States was absolutely free from epidemic meningitis from that date down to the year 1842, so far, at least, as* we may infer from the silence of the epidemiographical authorities. Second Period. — The second period begins with the breaking-out of epidemics of meningitis simultaneously in two localities of the South of France — Bayonne and the department of the Landes on the one hand, and the districts of Foix and Narbonne on the other. From these centers the malady extended over a great part of France within the next ten years. Its first appearance at Bayonne, in 1837, was in epi- demic form, and it was again epidemic there in 1840 ; but between these dates the cases were only occasional, and from first to last it was strictly limited to the garrison. Almost at the same time as at Bayonne, it appeared in the Landes, among a number of villages and small towns along the course of the Adour. In these it affected the ordinary residents ; but it was solely the troops of the garrison whom it attacked at Bordeaux and LaRochelle (where it had been seen already in 1837) ; and it was again confined to the garrison when it reappeared at Bor- deaux in 1839. Early in 1838 it showed itself at Rochefort, at first in isolated cases in a regiment that had arrived from the Landes ; but at the end of that year it broke out in the Bagnio, both among the convicts and among the civil and military staff of the prison, while occasional cases were seen at the same time among the inhabitants of the town. At the beginning of 1839 the epidemic appeared at Ver- sailles, in the first instance among those very soldiers who had come from the Landes to Rochefort and had been transferred thence in 1838 to Versailles. It quickly attained the dimensions of an epidemic, which was strictly within the limits of the garrison, as were also the occasional cases of the following year and the second epidemic in the year 1848. Although the malady disappeared from Versailles in 1841, many cases of it came to notice in Paris in the summer of 1842. In the meantime three new centers of the disease had sprung up in the northwest and northeast of France. One of these was almost en- tirely within the basin of the Loire. The malady occurred first at Laval in the spring of 1840. It continued to be epidemic in the garrison until the end of the following year, but among the townspeople it showed itself only here and there toward the end of its prevalence. After that, in the winter of 1840-41, there were a good many cases at Le Mans and Chateau-Gonthier among soldiers who had been trans- ferred from Laval ; and at the same time the disease became epidemic, ETIOLOGY. 3 or at all events very frequent, at various places in the country around, having occurred among both the soldiers and the townspeople. The second new focus, smaller than that which we have been speaking of, but also in the northwest of France, included the following : the winter epidemics of 1840 and 1841 among the marines in the barracks at Brest, that of the winter of 1840 among the tioops at Caen, and that of the spring of 1841 in the garrison of Cherbourg. The third new center was in the northeast of France. It began with an epidemic of meningitis in the winter of 1839-40 in the garrison of Metz ; in the autumn of 1840 the sickness appeared at Strassburg, where it lasted both among the military and in the town until the summer of the year following, having meanwhile spread, along with detachments of troops, to a number of places near, such as Schlettstadt, Hagenau, Buxweiler, and Wasselonne, at all of which, except Schlettstadt, it was confined to the military. Its next appearance was in 1841 at Nancy, where all the cases but one were among the soldiers; and lastly it showed itself at Colmar, but only in occasional cases in the garrison. With the year 1842 that succession of epidemics comes to an end. In the years immediately following, it would appear that cases of the disease were seen only now and then in various garrison-towns of France. It is not until 1846-50 that we again meet with references to extensive epidemics of meningitis among the military, including the following : in the garrison of Avignon and Lyons from autumn, 1846, to spring, 1847 ; among soldiers at Nimes, Toulouse, St. Etienne, and Metz in the winter of 1847-48 ; during the same season in Paris, where the disease went on until the spring of 1849 ; also in Orleans, where there were some cases among the townspeople toward the end of the epidemic, and in Bourges ; at Lille in the spring of 1848, and at Toulon in 1850. Among the civil population during this period, the malady became epidemic only twice — in the winter of 1848-49 at Corbeil, and the same winter at Petit-Bourg (Bourbon- Vendee), where it was seen among the pupils of the "colony" and in some other young persons. The occurrence of epidemic meningitis in Algiers had probably some connection with its general prevalence in France. It appeared in that colony first at the beginning of 1840 in the villages of Setif and Bathna, situated on the plateau of the province of Constantine ; at the same time it occurred at the military post of Douera, not far from Algiers, being also in an elevated situation, where most of the cases were among the French troops. Early in 1841 the disease appeared in the town of Algiers itself, and in the village of Blidah on the slope of the Lesser Atlas to the southwest of Algiers ; it was general among both the mili- tary and the civil population, and in the winter following (1841-42) it 4 EPIDEMIC CEREBROSPINAL MENINGITIS. attained a very wide diffusion through the central and eastern parts of the country (provinces of Algiers and Constantine). In 1844 menin- gitis was epidemic in the town of Constantine; and in the winter of 1845-46 in Philippeville, Doura, and other towns and villages of each of the above-named provinces, on this occasion principally among the French troops. But the worst epidemic in Algiers was in the winter of 1846-47, when the disease was prevalent not merely in a number of towns of Algiers and Constantine, but also, and for the first time, among the Arab population in remote parts of the country. Next to France, the widest diffusion of epidemic meningitis on Europeon soil during the second period was in Southern Italy. Our earliest information of it there came from the villages of Mignano and Cervaro (Terra di Lavoro) in the winter of 1839-40. This Italian epidemic closes with the outbreak in the spring of 1845 in the Terra di Lavoro, at the villages of Alife and Piedemonte. The only other country of Europe in which epidemic meningitis was prevalent to any considerable extent during this period (1845-48) was Denmark. It broke out first in the spring of 1845 in the sanitary district of Frysenborg (province of Aarhus, Jutland), where it showed an epidemic character and received the name of "hjernfeber" (brain fever). Many cases of it were seen at the same time in other parts of Jutland, as well as in Fiinen, Lolland, and Seeland (especially Copenhagen). It reappeared in the winter of 1846, this time mostly in Iceland; and there were similar accounts of it from various parts of the kingdom! in the winters of 1847 and 1848. In other parts of Europe meningitis occurred during this period in merely isolated epidemics or in small groups of cases. From Spain there was mention of a slight epidemic at Gibraltar in 1844; it was almost entirely among the townspeople, only a few cases having been seen among the troops. In the winter and spring of 1845-46, it was seen in several Irish workhouses, including those of Dublin, Bray, and Belfast ; and occasional cases of it occurred at the same time in Liverpool. In the summer of 1850 it reappeared in Dublin, and con- tinued into the winter, although of a very mild type ; and there were a few cases of it at Rochester the same year. For Germany also, there are references to few slight epidemics of "encephalitis" and "acute hydrocephalus," which in all probability relate to the form of menin- gitis here in question : one of these was at Meiningen in 1834, others in the spring of 1835 at Barmen, Bergheim, and Mimstermayfeld in the Rhine country, and another in the summer of 1843 at Steinheim in the circle of Hoxter, Westphalia. A number of typical cases of meningitis epidemica were seen at Wurzburg in June, 1851 ; perhaps that was also ETIOLOGY. 5 the nature of the epidemic which was prevalent in the summer of 1853 at some other places in Lower Franconia (Uffenheim, Ochsenfurt Aub), although Hirsch is unable to speak positively about it. During the second period, epidemic meningitis again became very prevalent in the United States, having been epidemic from 1842 until the winter of 1849-50. The malady was seen first at the beginning of 1842 in the county of Rutherford in the heart of Ten- nessee, and at Montgomery, Alabama. We hear nothing of it in 1843 and 1844; but in the autumn of 1845 it appeared at Mount Vernon, the chief town in Jefferson County, 111., and at other places in the south of that State ; in the winter of 1846-47 in the counties of Ben- tonville and Union, Arkansas ; at the beginning of 1847 in Vicksburg, Miss. ; and the same year in Hardman County, Western Tennessee, at Rocheport in Boone County, Mo., and at New Orleans among a regiment of recruits who had come from Mississippi. In the spring of 1848 it reappeared in Montgomery, and extended to the plantations in the neighborhood; the same season it was very destructive in the extreme west of Pennsylvania, in Beaver County on the Ohio. In March, 1848, it was seen in the towns of Millbury and Sutton, in Worcester County, Mass., and there were a good many cases among negroes at New Orleans in January and February of 1850. Third Period. — This begins with the outbreak of the disease in 1854 in Sweden, a country hitherto quite free from' it but now destined to most serious visitation lasting more than ten years. Early in 1854, epidemic menigitis was seen at Gottenburg, and toward the end of that year in Blekingelan and Kalmarlan, but only in somewhat scattered cases. It was not until the first six months of the year following (1855) that it attained to epidemic prevalence in these centers; and durjng the same season smaller foci of it were established here and there in the provinces of Christianstad, Jonkoping, Bohus, and Soder- manland. In its -progress northward from the southern extremity of the country it went no farther than the town of Kalmar by the end of the season. During the last six months of 1855 the epidemic was extinct; but it broke out anew in January, 1856, and now spread northward from its former seats through the northern part of Kal- marlan and the provinces of Jonkoping and Oestergottland ; meanwhile small epidemics appeared here and there in Blenkinge, Bohus, Gotten- burg, Elfsborg, Oerebro, and Wermland. That year its northern limit was Philipstad in Wermlandlan. In May the epidemic had died out everywhere, to reappear at the beginning of the following year. Its distribution-area was now a wide zone including the eastern shore of Lake Wenerand, the northern parts of Skaraborglan, the country 6 EPIDEMIC CEREBROSPINAL MENINGITIS. north of Lake Wetter as far as the southern part of Oerebrola, both shores of Lake Malar with the northern division of Sodermanland, the southern part of Westmanland, and the districts of Upsala and Stock- holm. That season the epidemic died out in June, having extended as far as the latitude of 61° N. It was in the year 1858 that epidemic meningitis reached its greatest height in Sweden. It was most severe in the provinces of Upsala, Westmanland, Oerebro, Wermland, Stora- Kopparborg, and Gefleborg. It reached that year to the latitude of 63° N., which has been its northernmost limit in Sweden. In the following season (1859) a considerable decline of the epi- demic was remarked, both in the number of its several foci and in the number of cases in each. The only considerable epidemics were in Stora-Kopparborg and Gefleborg; in the districts of Upsala and Skaraborg there were smaller epidemics, as well as a certain number of cases in the southern provinces. In I860 the disease was confined within still narrower limits, being of more considerable extent only in Oerebrolan at the northern extremity of Lake Wetter. From 1861 to 1864 there were merely occasional cases at a large number of places. In 1865-67 slight epidemics sprang up once more in the provinces of Upsala, Halland, Malmohus, Stora-Kopparborg, Elfsborg, Kalmar, Jonkoping, Oerebro, Sodermanland, Oestergottland, and Gottland. Since that time no epidemics of meningitis have been seen in Sweden. The number of deaths from the disease officially returned in 1854-60, and 1865-67 was 4577. Norway has remained almost exempt. Only twice has the epidemic been in that country : viz., a very malignant form of it during the first three months of 1859 in the village of Opdal (Hedemarken) ; and the year after, to a slight extent, in the village of Rangsaker in the same province. In Denmark, too, there was only one epidemic during this period in a few villages of northern Jutland during the winter and spring of 1875. Another of the principal seats of meningitis epidemica during its third period was Germany, where it reached its height in 1864 and 1865. The disease had been already seen in 1863 in a few localities of Silesia (Liegnitz and particularly in the valley of the Neisse) ; but in the winter and spring of 1863-64 it broke out almost simultaneously at a number of points in East and West Prussia, Posen, Brandenburg, and Pommerania. and was epidemic therein until the end of the fol- lowing winter. The same season witnessed its first outbreak at Leipzig and at a number of places in Thuringia. In South Germany its chief seats were the Bavarian departments of Central, Lower, and Upper Franconia. ETIOLOGY. 7 By the end of 1866 the disease in Germany had lost its epidemic character ; and in after years it was seen only in sporadic cases, unless in a few limited epidemics : such as those of Danzig and Konigsberg in the winter of 1869-70, and those of Berlin, Bonn, Mannheim, and Munich, in the winter and spring following. In Austria and Hungary epidemic meningitis had a very limited diffusion, so far as we can gather from the scanty records of it furnished by these countries. In the spring of 1863 it was prevalent in the orphanage of Vienna ; in the winter of 1865-66 in the Hungarian county of Gomor; and in the winters of 1866-67 and 1867-68 at Pola and other places in Istria, and at Trieste and some adjoining villages (St. Vito, Servola, St. Giacomo) . In Russia it was first seen in the spring of 1863 in the government of Kaluge ; and next year in the Caucasus ; it was also in the summer of 1864 that the first cases appeared at St. Petersburg, where the disease lasted until the summer of 1868 without becoming epidemic to any considerable extent. To the same period be- longs its earliest epidemic outbreak in Russian Poland; the first cases were seen at Kolo in 1865 ; it came to Warsaw in January and Feb- ruary, 1866, and about the same time it was in the neighborhood of Konin, Paryszew, and Minsk (Lithuania). From 1867 to 1869 it be- came more general in these provinces, and broke out also at a number of points in Galizia. Early in 1866 there had been many cases of it in Moscow ; and in the winter of 1867-68 an epidemic of meningitis de- veloped in Simferopol which spread over the whole of the Crimea and was especially severe in the towns of Bakchi-Serai, Alushta, Sebastopol, and Eupatoria. From Roumania we have an account of a slight epi- demic at Jassy in the winter of 1869 ; the same year the disease appeared in Turkey and at Magnesia near Smyrna ; and the year after in Smyrna itself. In Greece it was first seen in 1863-64 in the epharchy of Phthiotis, during the winter of 1868-69 in Nauplia and Milos, shortly in Argos, Tripolis, Athens, and other places, spreading so widely in that and the two following winters that no province of the country except the Ionian Islands escaped. The south and west of Europe were but slightly affected during this period. In the winter of 1866-67, epidemic meningitis occurred a second time in Dublin and other parts of Ireland, particularly among the soldiers; and on English soil in a village near Lincoln the same season. In the Netherlands it was seen in the winter of 1860-61 in the garrison of Arnheim ; and in the spring of 1867 a slight epidemic sprang up in the village of Giethorn (Overyssel). In Switzerland occasional cases were seen at Basel in 1859, and again in 1870; but in 1871 it was more extensively epidemic there and in a number of Bernese 8 EPIDEMIC CEREBROSPINAL MENINGITIS. villages. In France there were some cases among the Bordeaux gar- rison during the winter of 1867-68, and a small epidemic among the troops in Strassburg in the spring of 1868. In Italy it was seen at Bologna for the first time in 1873, and at Rome in the winter of 1873-74. In the spring of 1874 it spread for the second time widely over Southern Italy, especially in the vicinity of Naples and around Spinazzola, Minervino, Castelana, and other places in the province of Terra di Bari, in the district of Salerno, and in the provinces of Foggia, Capitanata, Apulia, and Campania, where it continued to be prevalent until the winter of 1875-76; it was epidemic also around Cremona in the summer of 1875. From, Portugal we hear of it in the winter of 1861-62 on the hilly ground along the right bank of the Tagus near the Spanish frontier, especially among the villages of M on forte, whence it extended in the directions of Oporto and Lisbon. In Asia, besides the outbreak of the disease already mentioned near Smyrna, it was reported at Jerusalem in the spring of 1872, the cases having been merely occasional, and in Persia in 1874 and 1875. In Africa there was a slight epidemic in January, 1868, at Setif in Algiers in a company of Algerian tirailleurs. The United States was again the chief seat of epidemic meningitis in this its third period. From 1857 to 1875 scarcely a year passed without its being seen over a larger or smaller area, its diffusion from first to last covering the whole of the country. This series of epidemics begins with outbreak of the malady in 1856-57 in two regions far apart, one of them being North Carolina, whence we have details of it in Salisbury (Rowan county), and the other New York State, where its visitation was mostly in the western and central counties of Onondago, Chemung, and Madison. During the Secession War of 1861-63 the sickness became more widely spread. In the winter of 1861-62 it appeared in the army of the Potomac en- camped near Washington; at the same time in Livingston county, Mo., among both soldiers and civilians ; in that and the following winter among negroes sent by the Confederates to Memphis ; and in the winter of 1862-63 among the troops encamped in and around Newbern, Craven county, N. Carolina. In the winter of 1863 a severe epidemic arose at Philadelphia and other places in Pennsylvania ; in that and the fol- lowing year it spread over a large part of the State, and was still going on in Philadelphia as late as the winter of 1865-66. In the winter of 1862-63, simultaneously with the outbreak in Pennsylvania, it appeared in LaGrange and other places in the north and south of Indiana, in Norfolk, Va., among the Confederate troops, in Iowa, at Newport, R. I., in the military school, making its first visit, and at Mobile. In ETIOLOGY. 9 the winter of 1863-64 it was epidemic in the southern and central parts of Illinois, in a few localities of New Jersey, in Vermont and along the Connecticut river, in Springfield county and some parishes of Licking county, Ohio, at Washington in two hospitals and an orphanage (having been imported from the seat of war), at Mobile and in Green county, Alabama, and in the spring of 1864 in Frederick county, Maryland. In 1865 the sickness would appear to have been in abeyance, if we may judge from the absence of all reference to it. But in the winter of that year it broke out anew in various parts of Illinois; in the spring of 1866 in Breckenridge county, Kentucky, and once more in Mobile; and in the winter of 1866-67 at Philadelphia. For the winter and spring of 1867-68 we have accounts of the prevalence of epidemic meningitis in Huntingdon county, Pa. ; in New York, where it was confined to one block of houses ; and in Findiey, Ohio. In 1869 we hear of it in various places in Indiana. In the winter of 1869-70 it reappeared in Green county, Alabama, and at Albion, in Erie county, Pa. : in the summer of that year it occurred in several parts of Virginia ; and toward the end of the year in the south of Mississippi State. In 1871 it became widely diffused in Minnesota and in Pennsylvania ; and in the latter it continued prevalent for two years longer in a number of places, such as Philadelphia and counties of Lancaster, Huntingdon, Lehigh, and Schuylkill. Coincident with this general prevalence in Pennsylvania was the outbreak of epidemic meningitis in 1872 in New Jersey, in New York City, and Brooklyn, and in some other parts of the State, such as Westchester and Onondaga counties ; also in Mon- treal, Canada ; in Edwardsville, Crawford, and places in Illinois ; and in a number of localities of South Carolina. In 1873 Massa- chusetts had a severe visitation, after an immunity of many years. The same year the malady was prevalent in the vicinity of Lake, Indiana ; toward the end of the year an epidemic sprang up in Michigan, which overran several counties and was particularly severe in Monroe county. Subsequent to 1874 the United States authorities are silent about epi- demic meningitis; so that the disease as a widespread malady would appear to have ended for the present on American soil with the extinc- tion of the epidemic last mentioned. Therewith also' ends the third in the history of the sickness. Fourth Period. — The last period in the annals of meningitis epi- demica, according to Hirsch's classification, embracing the years 1876-84, shows the malady retreating within narrower limits, so much so that it nowhere retains the character of a prevalent disease of the people. In 1876 there was a small epidemic at Birmingham ; another in the winter of 1884 at Galston near Glasgow; and many cases at 10 EPIDEMIC CEREBROSPINAL MENINGITIS. Dublin 1885-86 (Brit. Med. Joum., June 26, 1886, p. 1216). From Germany we hear of an epidemic in 1879 at Reichenbach in Silesia The disease appeared also in some parts of Poland: as at Proszowice in the winter and spring of 1876-77, at Plozk in the spring of 1879, and in the following winter in Sxydlowiec and vicinity, and at Plonsk. In the spring of 1879 it was prevalent at several parts of Galizia, such as Chrzanow, Podgorze, and Cracow; and at Bekes and Papa in Hungary. The latest news of it in France shows it to have been epidemic in the spring of 1880 at Castres, and in the winter and spring of 1881-82 at Cherbourg, both times in the garrison exclusively. It reappeared in Sicily from January to April, 1883, at Misterbianco near Catania; and in Greece, from 1879 to 1881, there were several slight epidemics, as well as cases in more sporadic diffusion, at a number of places both on the mainland and in the islands. PREDISPOSING CAUSES. Epidemiology. — The preceding outline of the history of epidemic meningitis shows that it has invaded practically all of Europe, including France, Germany, Italy, Sweden, Ireland, Russia, Denmark, Austria, Hungary, Greece, Roumania, Turkey, England, the Netherlands, Switzerland, and Scotland. In the East, it has occurred principally in Asia Minor, Syria, and Persia. In Africa, Algiers has been the prin- cipal center. The most extensive and severe epidemics have occurred in the United States, affecting all of the states and spreading to Canada. Mexico, Central America, the West Indies, and South America have so far been practically free from the infection. The disease can be found in sporadic form in nearly all of the large cities of the United States during the cold months. Epidemics are periodic, especially in the United States, recurring at irregular periods. Thus, in this country epidemics have been recurring since 1808. The first period was be- tween 1808 and 1816; the second period between 1842 and 1850; the third between 1857 and 1873. During these periods the disease affected different parts of the United States, spreading from state to state, in the succeeding years. In 1872, 1881, 1883, the disease was epidemic in New York City. In 1896, there was a large epidemic in Boston. In 1904-5, New York City was again invaded most extensively by this infection. In 1907-8, there was another severe epidemic in New York City and in the New England states. Since then, except for sporadic cases, this territory has been practically free from the disease. In 1910. there was quite an extensive epidemic along the Pacific Coast, especially in California. In October, 1911, a very severe epidemic occurred in the ETIOLOGY. 11 Southwestern states, affecting principally Texas, where 2,800 cases were reported. Epidemic cerebrospinal meningitis is an acute, infectious, contagious disease caused by the Diplococcus intracellularis meningitidis. The immediate exciting agent, the meningococcus, is with us always, being present in the noses and throats of a varying number of healthy persons Why do epidemics occur and recur at different times ? This should be analyzed from two viewpoints of the question : first, as to a common predisposing agent that would affect equally a great many persons; second, as to the immediate exciting factor. A study of epidemics in this country, with reference to a common predisposing agent that would affect many persons over widely scattered areas, would immediately exclude agencies like food, water, clothing, and would direct attention to an agency like climatic change, which affects equally rich and poor and all races in various parts of the country. Given a susceptible com- munity with reduced resistance, possibly caused by climatic conditions, the other important factor necessary is the immediate exciting agency, the bacterium, which must be of sufficient virulence to attack the indi- vidual. Undoubtedly both factors are necessary to produce an epi- demic. In analyzing previous epidemics in this country we find that the disease occurs in large areas that have been exposed to similar climatic changes. It is conceivable that changes in weather to which persons have not been accustomed, and which induce general nasopharyngeal catarrh, may so reduce their resistance that they may succumb to an infection by an organism that thrives in the nose and throat, and under conditions of reduced vitality, invades the system. Dopter states that it is really an epidemic of rhinopharyngitis with which one deals — an epidemic complicated at times by meningitis, which develops in a number of persons who are susceptible to cerebral invasion. By a virulent organism we mean one that can cause disease. Many organisms classed as belonging to the same group, as judged by mor- phology, staining, and cultural reaction, do not have this power. This is well illustrated by the diphtheria group of organisms. The same is true in every group of organisms, including the meningococcus group. A virulent organism usually retains its virulence if it keeps passing through an animal body, especially if it causes general disease. A non-virulent organism may assume virulence if it be inoculated in sufficient dose to cause disease or death in an animal. There are exceptions to this rule, but in most cases it holds true. A virulent organism may be kept active in a community between epidemics by the development of an occasional sporadic case. With suitable predis- posing agents, the organism may be disseminated freely and gradually 12 EPIDEMIC CEREBROSPINAL MENINGITIS. start an epidemic. It is more probable, however, judging from the causes and dissemination of different epidemics, that a virulent organism is carried from an infected country to other parts, which if sufficiently predisposed also become infected. Our study of the mode of trans- mission of the meningococcus will show that the infection can thus be transmitted over large areas and that a small local epidemic may be the focus for a large general epidemic widely scattered over many miles and followed by infection of one country after another, gradu- ally including the susceptible countries of the world. Indeed, it is claimed that meningitis originated in America, spread over its own country, then infected Europe. This brings us to the question : What accounts for the periodic outbreaks of epidemics? Our present knowledge of immunity is too meager to allow of anything but theory in answering this query. As I have indicated, the proper "soil" is necessary before a bacterium can take root. In the case of meningitis, this predisposition is climatic in origin. We know, however, that epidemics after a time die out even with apparent continuance of the predisposing climatic change. This resistance to< infection may be explained by the production of natural immunity, e. g., as the body is exposed to changes of climatic irregularities, it protects itself after a time by developing a resistance to the infections that accompany these changes. If the irregular climatic conditions cause general nasopharyngeal catarrh, local immu- nity or resistance develops after a time in the nose and throat, protecting them against the invasion by bacteria. Therefore, as general resistance against disease is developed in a community, the disease will die out except for occasional sporadic cases. After a lapse of years, if climatic conditions have returned to the normal, it is reasonable to suppose that the acquired resistance against conditions accompanying the previous climatic irregularity will gradually disappear. If, after a number of years, irregular climatic conditions recur and a virulent organism be again introduced, possibly having been carried over by a healthy person from the previous epidemic or carried from a recent epidemic in another country, the cycle may again be started, causing the "periodic epidemic." A study of the Texas epidemic in 1912 shows how these factors may work. The most recent epidemic began in October, 1911. The last previous epidemic, as near as could be ascertained, occurred about fifteen years before. Since that time, except for some sporadic cases each winter, the country had been free from the disease. The summer before the recent outbreak had been very dry. The winter was un- usually rigorous and was accompanied by many sudden climatic changes. This naturally occasioned a great deal of nasopharyngeal ETIOLOGY. 13 catarrh. By whom or how the virulent organism was introduced could not be learned. A rather severe epidemic of meningitis had occurred in California the previous winter. Other epidemics were occurring in Europe, especially in Greece. It is very probable that healthy carriers introduced the organism from these epidemics, most probably from California. One case, in a negro, developed in Dallas, Texas, in October. No history of exposure to the disease could be learned. Eleven cases occurred in November, eighty cases in December, one hundred and eighty-five in January, and two hundred and fifty more cases in February, March, April, and May. The disease appeared simultaneously in other large cities of Texas — in Fort Worth, Waco, Houston, Galveston, El Paso, San Antonio — gradually increasing in numbers and affecting all classes. Epidemic meningitis cropped up later in every part of Texas as well as in other Southwestern and Middle- Western states. In many instances it appeared in small towns of a few hundred inhabitants. Here no* distinct exposure of those infected to patients with the disease could be traced. The reason for this unusual dissemi- nation of the disease will, I believe, be satisfactorily explained under the discussion on "Carriers." Age Incidence. — The disease occurs at all ages. In most epi- demics, children up to fifteen years of age have been the greatest suf- ferers. Striking differences as to incidence of the disease at different ages have occurred in different epidemics. On the whole, it would appear that children under ten years are most susceptible to the disease. In some epidemics, adults seem to have been more susceptible. This was possibly due to the fact that they were more exposed to the pre- disposing agents and also that the ability to resist the disease depends upon the virulence of the infecting organism. Of 1,267 persons who died of epidemic meningitis in Sweden from 1855 to 1860, 889 were under fifteen years, 328 from sixteen to forty, and 50 were above that limit. In an epidemic at Kdnigsberg in 1865, of 779 cases, 737 were persons up to< fifteen years of age, 16 between fifteen and twenty years, and 26 over twenty years. In Thuringia in 1865, of 180 patients, 160 were not over twenty years old. Of 2,180 cases in New York City in 1905, 67% occurred in children under ten years of age. 15% occurred in persons under 1 year 29% occurred in persons from 1 to 5 years 23% occurred in persons from 5 to 10 years 18 % occurred in persons from 10 to 20 years 14 EPIDEMIC CEREBROSPINAL MENINGITIS. 12% occurred in persons from 20 to 50 years 1% occurred in persons over 50 years In 1906 in New York City, of 993 cases, 65% were children ten years of age. 16% occurred in persons under 1 year 30% occurred in persons from 1 to 5 years 19% occurred in persons from 5 to 10 years 19% occurred in persons from 10 to 20 years 16% occurred in persons over 20 years In 1907 in New York City, of 828 cases, 68% were children under ten years of age. 20% occurred in persons under 1 year 33% occurred in persons from 1 to 5 years 15% occurred in persons from 5 to 10 years 15% occurred in persons from 10 to 20 years 17% occurred in persons under 20 years In other epidemics, however, patients over twenty years of age out- numbered the children. According to Hirsch, this happened in the Italian epidemics of 1831-41 and 1845, at Strassburg and Avignon in 1840, at Toulouse in 1842, at Milford, Conn., in 1811-12. At Mont- gomery, Alabama, in 1848, of 84 patients, only 10 were under ten years, 23 between ten and twenty years, 27 between twenty and thirty years, 13 between thirty and forty years, and 12 above forty ears. Likewise in the epidemic of Brookfield, N. Y., in 1857, in Norway in 1859, in Berlin in 1864-5, and in Munich in 1865. In Councilman's cases in the Boston epidemic, most of them occurred between the ages of twenty-six and thirty. Sex. — There is no striking difference in the number of cases that have occurred in the two sexes. Of 1,026 cases in New York City in 1906, 611 were males, 415 females. In Texas in 1912, of 2,575 cases collected by Dr. Steiner, State Health Officer, there were 1,598 males and 977 females. Race and Nationality. — In cosmopolitan cities these conditions probably have no bearing, per se, except in so far that certain classes are more affected by sudden climatic changes than others and that their social status and unhygienic surroundings predispose them more to all infections. In the epidemic at Algiers, natives and Europeans suffered alike. In the New York City epidemic of 1905, 15% of the cases developed among the Italians. Excluding the Americans, the Italians formed 44% of the remainder, the Russians coming next, and then the Irish. In some of the epidemics in the United States, the ETIOLOGY. 15 negro race was visited with particular severity. Of 85 cases treated by Ames at Montgomery, Ala., 23 were whites and 63 negroes. In the New Orleans epidemic of 1850 and in Memphis 1862-3, the disease was confined principally to negroes. The same happened in the epi- demics of 1862-3 in Mississippi, in 1864 in Maryland, in 1865-6 in Mobile, 1867 in Philadelphia, and in 1873 in South Carolina. In the Texas epidemic, for some inexplicable reason, there were many more cases among the whites than among the negroes. Of 2,135 cases tabulated by Steiner, 1,600 were whites and 535 negroes. Seasonal. — In the Eastern Hemisphere, epidemic meningitis has extended from Russia and Sweden, 63° N., to Jerusalem, Persia, and Algiers, 30° N. Thus, it has been confined to temperate and sub- tropical latitudes. To some extent it has penetrated the cold zone, a small epidemic having been reported during the winter months in Dawson, Alaska; while the tropics and practically all of the Southern Hemisphere have escaped it altogether. Nearly all of the epidemics prevailed in the winter and spring seasons. As classified by Hirsch, most of the Russian epidemics took place during the winter and spring. This is also true of the epidemics of North and South Germany. In Austria, Galizia, and Hungary, they occurred only in the winter or spring. In Great Britain and Ireland, 11 of 12 epidemic outbreaks fell in those seasons. Of 63 French epidemics, 24 occurred in winter, 17 in winter and spring, and 9 in spring. In Italy all of the epidemics took place in winter, excepting that in 1843-4 in Sicily, which began in spring and was protracted through the summer. In Greece all of the epidemics occurred in winter. In Asia Minor and in Jerusalem, they prevailed in winter and spring, as was likewise the case in Algiers. Of 85 epidemics in the United States up to 1873, 37 raged in winter, 18 in winter and spring, and 23 in spring. The disease has been epidemic in this country almost constantly since 1904 and has occurred during the winter and spring seasons. The very extensive New York City epidemic of 1904 began with a few cases in March, reached its height in May, declined markedly in June, and practically disappeared with the hot weather in July. It reappeared in 1905, many cases having occurred one month earlier than the previous year, reached its height in March, and died out as in the preceding year. In the last Texas and Southwestern epidemic, the disease appeared in the latter part of October and was at its height during the months of January, February, and March. It began to die out rapidly in April and was almost gone by the middle of May. That low temperature, by itself, is not the only predisposing agency, is seen by the fact that a number of epidemics have occurred in mild 16 EPIDEMIC CEREBROSPINAL MENINGITIS. winters, while others have begun or have grown worse with the onset of the warmer weather. Thus, the disease occurred during mild win- ters in the epidemics of 1839-40 at Metz, 1839-40, 1840-41 in Italy, 1862-63 in Indiana, and 1866 in Kentucky. It has also been prevalent in normal, warm springs, as at Gibraltar in 1844 and Castres in 1880. Epidemics have appeared with summer, as at Bordeaux in 1839, Tou- louse in 1842, Dublin in 1850, and near Cracow in 1874. Then, too, epidemics have increased with the rise in temperature, as seen at Nancv in 1841, in Sicily in 1843-44, Massachusetts in 1873, Edwardsville, 111., in 1872, New York in 1872, and Southern Italy in 1874-76. Most epidemics and the height of epidemics, however, have been undoubtedly associated with unusually cold weather. Sudden, marked temperature changes, to which a particular community is not accus- tomed and which would cause widespread nasopharyngeal catarrh, would appear to be even a more important influence. This factor could explain the occurrence of the disease in warm climates. We know that common colds occur extensively, at times, even in warm weather. The sudden temperature change could explain this apparent irrelevancy. The large New York City epidemic occurred during a wet, damp, cold winter. In the last Southwestern epidemic, the country had been ex- posed to a drought for three previous hot summers. The winters for a number of years had been very mild. The winter of the epidemic was an unusually severe one and in Texas was characterized by marked, sudden changes in temperature coining with the Texas "northers," so that one day would be mild spring, the next, cold winter. The spring- also was much delayed. With the onset of uniformly warm weather, however, the epidemic disappeared. Similar conditions existed in Kansas City where there were many cases. Here, in addition, the weather was very damp and wet, and a great deal of snow had fallen. Influence of Overcrowding and General Hygiene. — Gaste, in writing of the outbreak of the disease in the garrison at Metz in 1839-40, believed that he could trace the epidemic to the overcrowding- of the barracks at the time, and he was successful in abating the epi- demic by sending part of the troops elsewhere. Similarly the majority of the French military surgeons, both in France and in Algiers, came at length to the conclusion that overcrowding of barracks was one of the most material factors in producing epidemics of cerebrospinal men- ingitis and that it was the only discoverable cause at that time. The spread of the disease in garrisons was noticed in the United States among the Federal troops at Newbern in 1862-63, when the disease was epidemic only in those regiments that were quartered in crowded and ill-ventilated barracks. Observations on epidemics in cities also . ETIOLOGY. 17 show that the disease has been most prevalent among the poor who lived in crowded dwellings situated in narrow, filthy streets. This was apparent in the epidemics in Rochefort, Versailles, Toulon, Strassburg, and Argues-Mortes, in Geneva, and in the epidemics of Germany and other countries. In the 1904 epidemic in New York City, 76% of the patients lived in tenement houses where crowding and unsanitary conditions were at their worst. In the recent Southwestern epidemic fully 75% of the cases were among the poor. Reasoning from our present knowledge of the portal of entry of the meningococcus and the mode of transmission of the disease, we can realize the very considerable influence of crowding and close contact with the sick or with healthy carriers who have mingled with the sick. A very striking illustration of this fact was demonstrated in the recent Texas epidemic. The Health Board had issued notices counseling the populace against collecting in crowds, attending mass meetings, or visit- ing places of amusement. For a time these precautions had been ob- served, and it was noticed that the cases were diminishing in number. In the month of March, a prominent gipsy preacher visited one of the principal cities and spoke to very large gatherings. Immediately the number of cases was increased, and the city was laboring under the worst period of the epidemic. The fact that more cases do not develop among members of a family where the disease has occurred simply proves that many persons can resist the infection. The reason for the greater spread of this disease, which is so much less contagious than the exanthemata, is that the exanthemata are transmitted principally by direct contact with the sick and that relatively few are exposed, even with lax quarantine, while in meningitis, contact with those stricken is unnecessary. There are a great many healthy carriers, estimated by some to be ten to twenty times the number of the sick. These healthy persons who harbor the organ- ism thus come in contact with a great many others. Only a very small percentage of persons who are exposed to the infection develop the disease. Bolduan and Goodwin reported about 5% of multiple cases in fami- lies in the New York City epidemic. In Texas, among 2,135 tabulated cases, Steiner's report was as follows : 2 cases of meningitis developed in 103 houses 3 cases of meningitis developed in 23 houses 4 cases of meningitis developed in 7 houses 5 cases of meningitis developed in 2 houses 18 EPIDEMIC CEREBROSPINAL MENINGITIS. Most physicians and nurses have fortunately been able to escape the disease. In the epidemic of New York City in 1911, two physicians developed meningitis. In Dallas two physicians and twelve nurses were stricken. i Dwelling Infection. — The low virulence and the resistance of the meningococcus against extraneous physical and chemical influences would certainly argue against this possibility. Bolduan and Goodwin found no evidence of house infection in any of the fifty-eight cases that they studied during the New York City epidemic of 1905. Previous Health and Fatigue. — All things being equal, good health will, of course, tend to protect and ill health to predispose to the disease. A great many persons who are in apparently good health at the time develop the disease during epidemics. In the New York City epidemic of 1904, only 6% of the persons were reported to be in poor health when they developed the disease. Fatigue appears to have some influence, as particularly evidenced in some of the epidemics in the army (such as those of 1839 in Ver- sailles, 1840 in Strassburg, 1847 in Orleans, 1848 in St. Etienne, 1845 in Dublin, 1861-62 in Portugal, 1847 in New Orleans), where the earliest as well as the most frequent of the cases occurred among the recruits who were unaccustomed to the strain of their new duties. Other Predisposing Factors. — Traumatism to the head. Such a history is but rarely obtained. The mode of infection, also, would speak against this as an important influence. Pure meningitis in domestic animals is uncommon. Many of the so-called cases of meningitis are toxemias, in which spinal and brain symptoms occur. This is seen especially in the "corn-stalk disease." Buchanan, in his book on "Veterinary Bacteriology," states that an organism, differing in no important particular from the meningococcus, has been reported by John Ostertag and others in epizootic or cerebro- spinal meningitis in horses. Ostertag succeeded in producing the dis- ease in horses by subdural injection of pure culture. Other organisms have been found in similar outbreaks by other investigators. Careful study of the relationship of these organisms to the disease must be made before conclusions as to their importance as an etiological factor would be justified. Hutyra and Marek, in their book, "Spezielle Pathologie nnd Ther- apie der Haustiere," come to« essentially the same conclusions. They mention that meningitis in the horse was- known as early as 1813 and that the disease occurs in oxen, sheep, and dogs. A number of ob- servers report cases of meningitis that were apparently due to a strepto- coccus organism. Wilson and Brimhall found the meningococcus in ETIOLOGY. 19 the central nervous system of a cow attacked by the disease. In other epidemics, the pneumococctis was found. In the Texas epidemic of 1912, there were vague reports, at dif- ferent times, of the disease among horses. Bacteriological confirmation of these reports could not, however, be obtained. Nevertheless, on general principles, it would be desirable, during epidemics, to exclude from the home household pets such as dogs and cats — animals known to harbor other organisms such as the diphtheria bacilli, causing disease among human beings. BACTERIOLOGY OF THE MENINGOCOCCUS AND ITS ALLIED ORGANISMS. Excellent work on the subject has been done by a number of workers. Many of the following notes on the bacteriology and agglu- tinating characteristics of this group have been obtained from the exhaustive work of Elser and Huntoon. The meningococcus, pneumococcus, and Streptococcus mucosus have been considered as being able not only to cause primary meningitis, but also to cause epidemics of meningitis. Other organisms, including the influenza bacillus and tubercle bacillus, produce primary meningitis. Many others produce secondary meningitis, these organisms being: namely, the tubercle bacillus. Streptococcus pyogenes, Streptococcus mucosus capsulatus, the pneumococcus, the influenza bacillus, the staphylococcus; less commonly the typhoid bacillus, colon bacillus . bacillus of bubonic plague and of glanders, Bacillus pyocyaneus, gono- coccus, and Micrococcus tetragenus. Weichselbaum, Netter, and others contend that the pneumococcus can produce, and has produced, epidemics of meningitis. A study of several of the reported small epidemics of pneumococcus meningitis has led many to believe that some of these epidemics, at least, were due to the Streptococcus mucosus and not to the pneumococcus. The fact that pneumococcus bacteremia is very common during the course of pneumonia and that the total number of cases of pneumococcus menin- gitis are so very few, surely speaks against the pneumococcus as having a special affinity for the meninges. In most cases of pneumococcus meningitis, the presence of a primary focus of infection can usually be established, frequently pneumonia, at other times endocarditis, and in some cases quoted by Elser, acute or chronic nephritis. Councilman re- ports twenty-eight cases of pneumococcus meningitis, in only two of which was there an apparent primary involvement of the meninges. 20 EPIDEMIC CEREBROSPINAL MENINGITIS. Libman reports six cases, all of which were secondary. In a series of several hundred cases of meningitis I studied, only about twelve spo- radic cases were due to the pneumococcus, all apparently being sec- ondary, usually complicating pneumonia. There is no record of any epidemic of pneumococcus meningitis in New York City. A careful study of several small epidemics of about sixteen cases, reported as being due to the pneumococcus, warrants the suspicion that, possibly, these were due to the similar organism, Streptococcus mucosus capsulatus. Elser believes that only two organisms — the meningococcus and Streptococcus mucosus capsulatus — apparently have a special affinity for the meninges, causing a primary involvement. While the influenza bacillus can and does cause a primary meningitis, cases are relatively uncommon, so that we may omit it from classification. A review of epidemics of meningitis leads one to< the conclusion that, while other organisms, principally Streptococcus mucosus capsu- latuSy may cause very small, occasional, localized epidemics, there is really only one organism, the meningococcus, which causes the out- break of repeated, large, serious epidemics, and the occurrence of nu- merous sporadic cases. The following studies, therefore, will deal exclusively with the meningococcus and its allied organisms. Classification of the Meningococcus and Allied Organisms. — The meningococcus is only one of a group of cocci, which have many characteristics in common, principally in staining reactions and gross morphology. We refer to this group as the group of Gram-negative cocci. It is extremely important to differentiate between these organ- isms, since all but the gonococcus are found in the nose and throat of many healthy people. The practical application of this fact would confront one, in attempting to determine the presence of menigococci in the nose and throat of the sick or healthy. This information, as I shall describe later, may be of invaluable assistance in controlling the spread of an epidemic. The members of this group are the following: I. Micrococcus intracellularis meningitidis (meningococcus) II. Pseudomeningococcus III. Micrococcus gonorrhoea (Neisser-gonococcus) IV. Micrococcus catarrhalis V. Micrococcus pharyngis siccus VI. Diplococcus mucosus ETIOLOGY. 21 VII. Chromogenic Gram-negative cocci Group I. Ferments dextrose, maltose, levulose, and saccharose. Group II. Ferments dextrose, maltose, and levulose. Group III. Ferments dextrose and maltose. VIII. Parameningococcus MENINGOCOCCUS. Morphology. — The appearance of a stained meningococcus varies considerably with the age of the culture or with the character of the exudate in which the organism is examined. In young, fresh cultures, 18 to 24 hours old, the meningococcus is usually biscuit-shaped, hemispherical, with the flat surfaces closely approximated. Some cultures show a spherical form predominating. Various strains of the „■.♦« ■#■■%'" QSei- Fig. I. Pure culture of meningococcus, 36 hours old. Note the irregular staining, the arrangement in pairs of the biscuit-shaped organisms and the approximation of the flat sur- faces of the individual bacteria. Note that the division between the individual cocci cannot be determined in many instances. organisms display considerable difference in size, some being very large, others very small. Ordinarily they are a little smaller than the Micro- coccus catarrhalis, and distinctly larger than the gonococcus. They usually occur in pairs, sometimes in tetrads and small clumps. Acci- dental chain formation has been described. I have only rarely seen this happen. In older cultures, over 48 hours, many degeneration forms are seen, the organism showing indistinct borders and failing to take the stain. In still older cultures, the cocci are entirely disintegrated. The morphology of the meningococcus in the cerebrospinal fluid in the early stages of the disease corresponds to that in young cultures. 22 EPIDEMIC CEREBROSPINAL MENINGITIS. In chronic cases, especially those treated with serum, the organisms frequently have an appearance that I refer to as clumping, the indi- vidual cocci often being so closely adherent that no dividing space can be seen. In addition, degeneration forms are seen as in the older cul- tures. Staining. — The meningococcus is a Gram-negative organism. If this important fact had been recognized, much of the confusion, arising from the classification of the Jager coccus, and other so-called menin- gococci that present variable reaction to Gram stain, would have been prevented. The meningococcus stains well with all of the ordinary aniline dyes — very well with methylene blue. By Gram stain it is readily decolorized, and is Gram-negative. The Gram stain is done as follows : Make a thin smear of the sediment or culture. After drying, fix hy quickly passing two or three times through flame. (All of the following stains are used in rapid succession. It is not necessary to allow for the usually described interval between the stains. — Mt. Sinai Hospital Labora- tories.) Fresh saturated solution aniline oil — gentian violet. Gram's iodin. Decolorize completely — 95% alcohol — two or three washings with alcohol lasting from one-half to one minute are usually necessary. Wash in tap water. Aqueous fuchsin, 12%. Wash in tap water. Dry with blotting paper. I have examined a great many strains of meningococci and have always found the meningococcus Gram-negative, the Gram-positive organisms having proved to be other bacteria. Older cultures, as de- scribed, retain the stain poorly. When stained with Lofifler's alkaline methylene blue, the menin- gococcus is usually only slightly stained, but has a brightly stained central spot, called metachromatic granule. These granules are similar to the bodies found in other organisms, notably in the diphtheria bacilli. They vary in size, number, and distribution, and depend, to a certain extent, upon the media on which the organism is grown, appearing best when grown upon media containing maltose and glucose. They disap- pear as the culture ages. These bodies are found in the other members of the Gram-negative group of cocci, but less regularly and in smaller numbers. They are usually absent in cultures of gonococci, but have been reported to be present in the pus of acute, fresh cases of gonor- rhea. Capsule stain fails to demonstrate a capsule in the meningococcus. ETIOLOGY. 23 Culture. — The meningococcus grows luxuriantly upon a number of different media. It grows very well upon solid media, but poorly upon fluid media. It is almost an obligatory aerobe. Elser prefers for his stock cultures, ascitic glucose agar, in which the end-reaction is about .8% to phenolpthalein. Among the serum-free media, those containing glucose were most favorable. He also used agar prepared according to Thalmann's method, particularly for his gonococci, and believed that this medium was more suitable for their growth, especially after adding glucose. Thalmann's agar is prepared as follows : Boil over free flame for 15 minutes, 500 grams chopped beef and one liter distilled water. Filter through cotton. Add 1% peptone; .5% salt. Bring to a boil, cool, and filter. Add 1.5% agar. Boil 45 minutes over free flame in bath containing 40% solution of salt. Now render mildly alkaline to litmus by means of a saturated solution of sodium carbonate. Then cool to 50° C, and clear in the usual way. At the Rockefeller Institute, sheep serum 2% glucose (beef infu- sion) agar, made neutral to phenolpthalein, is used for stock cultures, and serum-free glucose agar for immunization purposes. In the Research Laboratories, New York City, we obtained best results by using beef or veal-infusion agar, made neutral to phenol- pthalein. After the usual autoclave sterilization, a 10% glucose solu- tion in distilled water is added under sterile precautions. The glucose solution is prepared by adding, while hot, 10 grams of glucose to 100 c. c. of sterile water, then sterilizing by steam for 10 minutes. This is an application of Elser and Runtoon's work with the carbohydrates to be described in this chapter. In this method I found there was less change in the end-reaction of the medium, and growths seemed to be better. Ascitic or sheep serum 1 :6 is added. For our stock cultures, this has proved a very reliable medium, giving very uniform results. McNeil, of the Research Laboratories, found, in the course of some studies, that simple salt-free agar plus glucose, neutral to phenol- pthalein, makes a very fine medium. Undoubtedly very luxuriant growth occurs on this medium. I riave not, however, used this medium because I did not know how much it might affect the organisms for immunizing purposes. The ability of the meningococcus to grow at the wide range of alkalinity is very striking. The meningococcus grows well at incubator temperature, very well at 37° C. We have found, however, that a slightly lower incubator temperature favors the growth. The cultures, after 24 hours or longer in the incubator, continue to live much better at the incubator temper- ature than at subsequent room temperature. 24 EPIDEMIC CEREBROSPINAL MENINGITIS. Cultural Appearances. — The typical growth and characteristic colony formation are best observed on the solid media. On an optimum plate medium of glucose, ascitic, or sheep-serum agar, the colonies appear, after 24 hours, as discrete, flat, circular discs, with smooth and usually distinct outlines, ordinarily about 2 to 3 mm. in diameter. Older colonies, especially, often appear nucleated with a darker central zone. By reflected light, colonies appear grayish-white and moist; by transmitted light, they appear opaque, grayish-white, the edges fre- quently being more translucent. As colonies grow older, they attain a larger size, often reaching a maximum of 3 to 5 mm. in 48 to 72 hours. They usually remain discrete. In culture slants, where a heavy subinoculation has been made, the growth appears as a heavy mucoid, grayish (viscid) smear. The consistency is usually moist and viscid, sticking to the surface of the medium. Most cultures wash off easily when bathed in a fluid medium, though some cultures adhere in long strings. After prolonged cultivation, the cultures grow very luxu- riantly, even as profusely as coli or staphylococcus. In young cultures of serum-glucose agar, neutral to phenolpthalein, there is usually no clouding of the medium, such as is seen with strep- tococcus, staphylococcus, etc. On sugar-agar media, reacting up to one acid to phenolpthalein, I have occasionally met organisms that cause a distinct milky-white clouding of the media. Libman observed a similar condition. I have never met a gonococcus or catarrhalis organism that caused this phenomenon. In very old cultures, Albrecht and Ghon, Elser and Huntoon, and others have noted a brownish discoloration of the medium. This is rather easily demonstrated. Pigment. — Elser and Huntoon speak of some cultures producing a greenish-yellow discoloration of their medium, appearing after the culture had been exposed to incubator temperature for several days. The results are variable with the different specimens of the glucose medium. They believe that, possibly, the presence or absence of certain derivatives, resulting from the cleavage of the sugar in the process of sterilization, may explain the divergent results obtained in the use of samples of medium prepared at different times. I isolated one pigment-forming strain of meningococcus from a case of epidemic meningitis that responded very promptly to serum treatment. This organism produced a distinct greenish-yellow pigment of the growth proper, and after some months, still retained this property to a slight extent. There was no discoloration of the medium. Crystals. — After 24 hours of incubation, coarse, irregular crumbs often appear on the surface of meningococcus colonies, principally con- fined to the central portion, and becoming smaller and less numerous ETIOLOGY. 25 toward the periphery. After a growth of 48 hours, the coarse granules may cover the greater part of the colony, and in addition, crystalline deposits make their appearance, becoming more numerous after 72 hours. These crystals vary considerably in different strains. They are also seen in some strains of gonococcus and are, therefore, of no diagnostic significance. Other Media. — Plain Bouillon. — Very poor growth ; frequently no growth. Glucose Bouillon and Glucose-Serum Bouillon. — Slight growth, mostly near the surface. It is uncommon to obtain a sufficiently good growth to cloud the medium. No pellicle. Milk. — No coagulation. Very slight growth. Litmus Milk. — No coagulation. No acid. Poor growth, frequently no growth. Gelatin, — Frequently no growth. No liquefaction. Potato. — No growth usually. Fermentation Reactions. — Elser and Huntoon did some very elaborate and complete work on this subject. They established the fact that many of the irregular results reported in fermentation tests, not only for the Gram-negative group of cocci, but for all organisms, were due to the splitting of the sugars during the process of the regular, intermittent sterilization. They therefore recommend that the sugar used be prepared separately as follows : To make a 10% solution of the sugar, add 10 grams of the sugar, while hot, to 100 c. c. of sterile distilled water, and sterilize by steam for 10 minutes. This is now added to the sterile, melted agar, and is tubed. For testing the Gram-negative group of cocci, solid media are much better on account of the better growth. The medium used by Elser and Huntoon consisted of beef infusion, made sugar-free by bacterium coli, 1% peptone, .5% sodium chlorid, 1.6% agar. The reaction is made faintly alkaline to litmus. 1.5% of Kubel or Tiemann litmus solution was used. At times, where there was poor growth, 2 X A% agar was added. Meningococcus Ferments — Dextrose and Maltose. — Thirty- eight strains of meningococci, which we used for immunization, were carefully tested. Twenty-one of these were two to five years old, and all but four of them fermented dextrose and maltose ; one of the four did not ferment either sugar ; two fermented dextrose and not maltose, the other maltose and not dextrose. Of the remaining seventeen cul- tures that were from two 1 months to one and one-half years old, three strains did not ferment either sugar; two fermented dextrose and not maltose; and the rest fermented both sugars. Of those that did not 26 EPIDEMIC CEREBROSPINAL MENINGITIS. ferment either sugar, two were over six months old, and one culture was two months old. We have no record of the fermentation reactions of these organisms on isolation. These tests prove, however, that most cultures retain their fermenting properties for months and years ; that most ferment both dextrose and maltose; and that some few strains give irregular reactions. Viability. — The meningococcus is a very viable organism. Fresh cultures are often very difficult to cultivate. Exudates containing the organisms will frequently fail to give growth if the sediment is not inoculated within the first few hours after the removal from the canal. Direct smear of exudates, at different periods after removal from the canal, will, at first, often reveal many well-stained, well-formed organ- isms, while six hours later, the organisms will be poorly defined and poorly stained. Fluids 12 to 24 hours old will often show few organ- isms and those not sufficiently typical, by staining or morphology, for diagnosis. Old cultures of meningococcus grow luxuriantly, even without sugar, and are more resistant. While frequent transplantation is de- sirable — at least every four to seven days even in luxuriantly growing cultures — if protected from drying, they live much longer. Elser and Huntoon kept some strains alive in the incubator, by preventing their drying, for 282 days. Heat destroys the meningococcus readily, but the observations by different workers vary more or less. Some have found that moist heat, 50° C, will kill in five minutes, and 55° C. in three minutes. Others, including von Lingelsheim, Elser and Hun- toon, have found that 50° C. kills in one hour and 60° C. in ten min- utes. Room temperature is detrimental to the meningococcus, the organ- ism growing much better at the incubator temperature. The organism shows a tendency to- die rather quickly at room temperature, some ob- servers reporting death as early as five days, others 3 to 4 weeks. My experience has been that this factor depends upon the resistance of the various organisms, some dying as early as four days, others living- several weeks. The temperature of the room, of course, is also im- portant, an average room temperature of 67° F. being allowed. ICE Box. — The organisms die very quickly in the ice box, frequently in less than one week. Light. — Diffused daylight is very deleterious, killing in from 4 to 7 days. Sunlight kills in several hours. Elser and Huntoon found that it killed in from 2 to 8 hours. Dessicatton. — The meningococcus does not resist drying to any ETIOLOGY. 27 extent. The results reported by different observers have varied with the age of the culture and the media employed. Some report death in 24 hours. Elser and Huntoon believe that the organisms are some- what more resistant. Autolysis.— In his experiments on the biology of the meningo- coccus, Flexner proved that the meningococcus tends to die and dis- integrate quickly, not only on account of its poor vitality, but principally on account of an intracellular enzyme, which exerts a devitalizing influence on the organism and destroys it. This enzyme is accelerated by physical and chemical agents, which may kill the organism without affecting the enzyme, so that the organism can still undergo disinte- gration. The organism is killed at 60° C, but the enzyme still acts. Heating to 65° C. and higher affects the enzyme, and hinders its ca- pacity to cause dissolution of the organism. Salt solution is directly injurious to the meningococcus, but does not affect the enzyme. Dis- solution, therefore, occurs quickly in salt solution. Toluol also accel- erates autolysis, and makes the solution more complete. If to a strong salt suspension of the diplococcus toluol be added and the mixture kept at 37° C, the morphological changes indicative of autolysis begin to be evident in one hour, are pronounced in two hours, and are nearly complete in four hours. Potassium; cyanid has a restraining influence on the intracellular enzymotic activity. In 1 to 200 dilution, it kills the meningococcus, but no autolysis occurs even if toluol be added. The intracellular enzyme of the meningococcus also acts on other organisms, producing their solution. Among these organisms are the Bacillus pyocyaneus, typhoid, coli, and Staphylococcus aureus. Pathogenicity. — The pathogenicity of the meningococcus for laboratory-test animals has been tested principally on mice, guinea-pigs, rabbits, monkeys, goats, and puppies. Elser and Huntoon found the white mouse most susceptible ; Flexner, the small guinea-pig weighing from 175 to 200 grams. In the Research Laboratories, our work was done principally with guinea-pigs. The results of different observers with both guinea-pigs and rabbits correspond. The reaction to the large doses of meningococcus is very irregular. Not only do animals of dif- ferent weight show considerable difference in their response to large doses of living organisms, but also animals of the same weight. Of a few animals, for example, that may be injected with varying doses of live culture, some receiving the smaller doses may die, while others receiving the large doses may live. Even if uniform results be ob- tained one clay, entirely different results may be obtained the next. These animals frequently resist even very large doses given subcu- 28 EPIDEMIC CEREBROSPINAL MENINGITIS. taneously. Intraperitoneal^, a fatal dose kills in a varying length of time, in from 8 to 24 hours or longer, depending upon the dose. The fatal dose is determined by the virulence of the organism, recently isolated cultures usually being more virulent. The fatal dose also depends upon the size, weight, and resistance of the animal. Death in most instances is probably due to the liberation of the intracellular poison by the disintegration of the organism. This can be proved by injecting pure autolysate, which also kills, though in larger doses. Another factor, causing death of the animal, is the actual multi- plication of the organisms within the peritoneal cavity, with invasion of the blood stream. It is usually quite easy with most animals to demonstrate the local peritoneal multiplication of the organisms and their presence in the blood. While a true infection thus occurs in many tests, especially where large doses of culture have been injected, death, as has been explained, is probably, in most part, due to the intoxication by the liberated poison. In cases where one finds few or no organisms in the peritoneal cavities or heart blood after death, it is probably the sole cause of death. The visceral lesions in animals dying from intra- peritoneal injection show a peritoneal cavity containing a varying amount of purulent exudate, which usually reveals many organisms intra- and extracellular. At times, few or no organisms can be found. The intestines are reddened and distended. Flexner called particular attention to the hemorrhage in the mesentery, which he described as being distributed with great regularity, especially in the mesentery of the colon, below the pancreas, in that of the cecum, and in the central tendon of the diaphragm. Rabbits are more resistant to injections, though they can be killed if a large enough dose be given. Elser and Huntoon speak of the extreme emaciation that these animals de- velop after the injection, perhaps dying weeks later and at autopsy showing negative bacteriological findings and absence of definite organic lesions. They mention, however, the evidence of old focal hemorrhage in the gastrointestinal tract. The lesions have also been reported in man. While immunizing a number of rabbits for work on the "Strain Differentiation of the Meningococcus," we were struck by this marked tendency to rapid emaciation, death occurring frequently from exhaus- tion before the immunization was complete, and at autopsy, failing to show any bacterial invasion. I had a similar experience while immu- nizing a monkey. Elser and Huntoon experimentally established the fact that the meningococcus, when injected into animals, renders the mucous mem- brane of the gastrointestinal tract permeable for foreign bacteria. They concluded from this fact that it would seem probable that the heterolo- ETIOLOGY. 29 goiis agglutinins encountered by von L,ingelsheim and others, in animals immunized against the meningococcus, owe their presence to bacteria gaining access through the gastrointestinal tract, during the course of immunization. Experimental Meningitis. — Flexner was the first to produce meningitis in monkeys, which was similar to the disease in man, by injecting a large dose of living culture of the meningococcus into the subarachnoid space, by means of lumbar puncture. Later, successful experiments were reported by von Lingelsheim and Leuchs and others. The following is quoted from Flexner: A few hours after injec- tion of the culture, an inflammation was incited, the exudate of which accumulated chiefly in the lower spinal meninges and the meninges at the base of the brain, rarely occurring in equal amount over the con- vexity. Here, as in man also, were found encephalitis and abscesses, hemorrhage, proliferation of large cells of connective tissue in the tissue spaces, acute endarteritis, inflammation of the dorsal root ganglia, internal hydrocephalus, and purulent cerebrospinal fluid like in man. The nasal mucous membrane was found in many instances to be in- flamed and beset with hemorrhage. Smear preparations from the nasal mucous membrane, from the higher levels especially, showed poly- morphonuclear leucocytes, carrying diplococci, which morphologically and by stain presented all appearances of meningococci, which, how- ever, failed to grow. The excretion of the organisms through the nose in meningitis has not been definitely proved. Rubbing culture into the nasal mucosa has failed to produce the disease. Likewise intravenous injections of the organisms have failed. Conflicting results have been reported in attempts to produce the dis- ease in goats, by intraspinal injection. Weichselbaum produced acute meningitis associated with encephalitis in dogs, by subdural inoculation of live culture. Three dogs, trephined and inoculated subdurally with .5 to 2 c. c. of a fresh, live culture of meningococcus, died. Number 1 died in twelve hours, number 2 in three days, and number 3 in twelve days. In numbers 1 and 2 post-mortem disclosed hyperemia of the meninges and moderate encephalitis. Dog number 3 showed most pronounced changes. A reddish, purulent fluid was found be- tween the dura mater and the brain at the point of inoculation. In the brain itself an abscess had formed about the size of a hazel-nut, filled with yellow pus, while the abscess walls consisted of softened brain tissue, infiltrated with numerous hemorrhagic deposits. The ventricles on that side contained a cloudy, reddish fluid, with flocks of pus. Park notes that he obtained like results by injecting recent cultures 30 EPIDEMIC CEREBROSPINAL MENINGITIS. of the meningococcus into the spinal canal of very young puppies, but older dogs were not similarly affected. Cultural Characteristics of the Other Members of the Gram- Negative Group of Cocci. — Gonococcus. — After 24 hours on ascitic agar, the colonies appear as small, gray, translucent discs £4 to 1 mm. in diameter, with fairly distinct outlines. In the succeeding 24 hours, a slight increase in size occurs. Both in color and in general appear- ance, the colonies look like small meningococcus colonies. Grown on the same sample of ascitic agar, the gonococcus colony is almost in- variably smaller and more delicate than the majority of meningococcus colonies ; some meningococcus strains, however, also produce uniformly small colonies. Even after prolonged cultivation, the gonococcus never grows so luxuriantly as the meningococcus, and requires much greater care in cultivation, growing* very poorly or failing to grow on any but the optimum medium. The optimum medium for the gonococcus is serum-glucose agar. It grows very well on plain Thalmann's agar after cultivation, and also on salt-free agar plus glucose. Blood agar and glucose-serum bouillon are favorable media. In consistency, the meningococcus, while viscid, breaks up rapidly when transferred to a fluid menstrum. The gonococcus growth is more sticky, and when transferred to liquid, tends to form shreds that do not break up readily. I have met with a small number of meningococcus strains that also had this property. Microscopic Appearance. — The gonococcus colony is strikingly like the meningococcus. It appears as a small, faintly fawn-colored disc, with slightly irregular but fairly distinct outlines. ' The surface of the colony is covered with irregular, coarse crumbs, which are usually confined to the central portion, and are smaller and less opaque than the corresponding structures in meningococcus colonies. The periphery of the colony is colorless and almost structureless. Among fifteen strains of gonococci, Elser and Huntoon found one which showed crystalline deposits. Fermentation Reactions. — Reactions are not heavy on account of the light growth. Ferments dextrose — forms acid — no gas. No change in the other sugars. Arkwright states that he has had strains of gonococcus that also fermented maltose. Autolysis. — The gonococcus shows a disposition, similar to the men- ingococcus, to degenerate when grown on artificial media. It appears less prone to degenerate in exudates. PsEudomeningococcus. — The pseudomeningococcus, described by Kutscher in 1906, is rarely found in the nose and throat. It is not an important consideration in practical "carrier" studies. It cannot be ETIOLOGY. 31 differentiated culturally or morphologically from the meningococcus, but can be differentiated by the immune-serum tests. Micrococcus Catarrhaus. — This organism is a very common in- habitant of the normal nose and throat. When grown on serum agar, it presents two types of growth. Type 1 is the common type. The organism is usually larger than the meningococcus. The colonies appear as raised, opaque, grayish- white discs, about 1 to 2 mm. after 24 hours. The surface is some- what glistening and slightly irregular. With a low-power lens, nu- merous, irregular crumbs are seen on the surface. They are yellowish- brown in color, opaque, with abrupt, irregular, jagged edges. The most striking feature of this colony of brittle and mortar-like consist- ency is the fact that it does not adhere to the medium, but slides along its surface when one attempts to pick it up. These characteristics serve to differentiate -it from certain pseudodiphtheria colonies that it resembles in many respects. After 48 hours, the colonies become 3 to 5 mm. in size, and have irregular, jagged margins visible to the naked eye. It grows very well on all of the usual culture media, including ordinary agar, especially after a few generations of growth. It therefore presents very little similarity to the meningococcus or gonococcus. Type 2 is not as frequent as Type 1. It closely resembles a mini- ature meningococcus colony. After 24 hours, it appears as a flat, gray, translucent disc, J4 to 1 mm. in diameter. The outline of the colony is fairly distinct. The surface is smooth and glistens moderately. Its consistency is like the meningococcus. Very frequently, also like the meningococcus, the central portion is more opaque, and colored yellow- ish-white. Microscopically, it also resembles the meningococcus or gonococcus colony. It has fairly distinct, smooth outlines. The cen- tral portions are covered with a moderate number of coarse crumbs. The peripheral portion is almost homogenous in appearance. The crystalline deposits, described in meningococcus colonies, have never been observed. After continued cultivation, Type 1 assumes the char- acteristics of Type 2. During cultivation, the characteristic brittle consistency of Type 1 also disappears, so that neither type can morphologically be differen- tiated from, the meningococcus. The uniform emulsion seen on trans- ferring cultures of meningococcus to fluid menstrua is not perceived in the catarrhalis. Autolysis. — The Micrococcus catarrhalis seems to meet with more favorable conditions in the ordinary culture media, and degenerated forms, while not wholly absent, are far less numerous than in menin- 32 EPIDEMIC CEREBROSPINAL MENINGITIS. grows quite gococcus or gonococcus cultures of the same age. It luxuriantly upon the ordinary laboratory media. Fermentation. — This organism has no influence on any of the usual sugars tested. Pathogenicity. — It is only very slightly pathogenic for animals. Diplococcus Mucosus Capsulatus. — This organism is usually very easily differentiated. It forms very luxuriantly growing mucoid colonies, growing profusely on serum-free agar. It forms large, flat, smooth, grayish-white discs, which tend to become confluent. It grows readily at room temperature and has an easily demonstrable capsule. Chromogenic Group. — This group of pigment-forming organisms is divided into three groups, which, morphologically and culturally, resemble each other closely, but differ in their fermentation reactions on sugars, and in their immune-serum reactions. They all produce a greenish-yellow pigment, and form slightly adherent, small, circular, slightly elevated colonies, which appear greenish-gray by reflected light, and semiiopaque, greenish-yellow by transmitted light. Their consist- ency is very often like that of the catarrhalis, as they are brittle and can be moved about the surface of the agar. Microscopically, they also closely resemble a Micrococcus catarrhalis colony. They are irregular, circular in outline with rather abrupt margins, and brownish in color. On the surface there are a variable number of coarse crumbs, which are usually confined to the central portion of the colony. When first iso- lated, they closely resemble Type 1 of the Micrococcus catarrhalis, but after cultivation, they tend to assume the appearance of the meningo- coccus. The growth of pigment is especially favored by the presence of glucose, differentiating this organism from the meningococcus and catarrhalis. At times, however, the pigment formed may be very slight, or the organism may temporarily lose its power to form pig- ment, thus making the differential diagnoses from the meningococcus or catarrhalis more difficult. Group 1 ferments dextrose, maltose, levulose, and saccharose. Group 2 ferments dextrose, maltose, and levulose. Neither blood nor serum exerts a favorable influence on their growth. On artificial growth, they grow more luxuriantly, but in the main, the appearance of the growth remains the same. Group 3 closely resembles Group 1 and ferments dextrose and maltose. Micrococcus Pharyngis Siccus. — This organism is but rarely found. When first isolated, the colonies are smaller than the menin- gococcus colonies and can readily be differentiated from the latter by their consistency. They are very firm. It is almost impossible to ETIOLOGY. 33 break them up with a loop, and as a rule, they adhere very closely to the medium. In normal salt solution, they sediment spontaneously. They thus resemble in many respects, the Micrococcus catarrhalis colony. Fermentation reactions, however, readily differentiate them. Elser and Huntoon isolated organisms closely resembling those de- scribed and thus named by von Lingelsheim, but differing in their fermentative properties. Their strains fermented glucose, maltose, levulose, and saccharose, while von Lingelsheim's did not ferment sac- charose. They believed that, possibly, this difference was due to the fact that von Lingelsheim's observations extended only over twenty- four hours. Their observations were prolonged for one week. They also say that twenty-four hours is not always sufficient to establish the fermentative properties of the Gram-negative group of cocci. Parameningococcus. — Dopter, in 1909, described meningocoecus- like organisms that were not agglutinated by meningococcus serum, but that were fixed by complement fixation. In 1911, he described seven sporadic cases of meningitis in which he isolated this organism. He referred to it as the "parameningococcus." In view of the work that I shall describe under "Strain Differentiation of Meningococci," one must consider these organisms as most likely meningococci. Summary of Morphological and Cultural Differences of the Gram-Negative Group of Cocci. — While the Gram-negative group of cocci comprises a large number of different groups of cocci, their actual differentiation, as is necessary, for example, in meningococcus "carrier" studies, is usually not very difficult. The gonococcus is almost never found in the nose and throat. No absolutely authentic case of gonococcus meningitis is on record. Cases have been described, but have not been proved. It may, therefore, be discarded entirely in the practical study of "carriers." The organism is also quite easily differentiated from the meningococcus by its smaller size, more delicate growth, the less-marked tendency to spontaneous autolysis, and the different fermentation reaction. The chromogenic group is quite easily differentiated, especially if the precaution be taken to use glucose media. The Diplococcus mucosus grows more luxuriantly than the menin- gococcus, is more mucinous and succulent, and has an easily demon- strable capsule. The pseudomeningococcus cannot be differentiated from the menin- gococcus by cultural or morphological appearance alone. It is, how- ever, so rarely found in the nose and throat, that, for practical pur- poses, it may be excluded. The Micrococcus catarrhalis, especially the common type, and the 34 EPIDEMIC CEREBROSPINAL MENINGITIS. Micrococcus pharyngis siccus, are usually quite easily differentiated from the meningococcus by their morphology and structural appear- ance. The mortar-like consistency and the tendency to slide along the surface of the media are very characteristic. Fermentation tests and the tendency to rapid autolysis of the meningococcus establish the differential diagnosis. A Gram-negative extra- and intracellular diplococcus in the cerebrospinal fluid warrants the diagnosis of the meningococcus with- out other cultural confirmation. It is exceedingly uncommon for other members of this group of cocci to produce meningitis. Method for Doing Carrier Work to Isolate Meningococcus. — During the Texas epidemic, I thought it would be desirable to establish the presence of carriers in families where the disease occurred, and to keep up quarantine until the organisms disappeared from the nose and throat, as tested by culture. I shall speak of this in greater detail in the chapter on preventive measures in the treatment of epidemic meningitis. The method I suggested for doing this work is as follows: 1. Culture to be taken at quarantined homes. 2. Materials — Sterile throat culture swabs — Sterile test-tubes — Plates of glucose-serum agar — Tube of glucose-serum bouillon — Slides. 3. Method of Procedure. — Separate swabs used for nose and throat. Streak swab over surface of medium in the plate, then stir up swab in tube of glucose-serum bouillon, then make smear on slide. 4. Materials brought to laboratory as soon as possible and incu- bated. Incubate for about 12 to 18 hours, then examine the plates, pick off suspicious colonies and subinoculate on glucose-serum agar. I advised that the bouillon cultures be stained after incubation. One will thus, occasionally, see many Gram-negative cocci organisms that may be overlooked in the plates. If so, plate out from the fluid culture for meningococci. The slides, from direct smear from the nose and throat, are simply of interest, but mean nothing in the differential diagnosis of the Gram-negative cocci. An examination of the plates, after the first incubation, may enable one occasionally to make a fairly positive diagnosis, especially if the meningococci abound and the colonies are typical. It is desirable, how- ever, to examine the subinoculation on the tubes for further confirma- tion, as the character of the growth, the consistency, the absence of pigment, the typical colony appearance, the tendency to rapid autolysis, are all very important ; and while for practical purposes, in the control of quarantine, one may be able to make a fairly positive diagnosis of carriers within 48 hours, occasionally in 24 hours, it is nevertheless ETIOLOGY. 35 important to make further tests, especially fermentation tests. By systematizing the work, I believe carrier studies can be done on a large and practical scale, and be of tremendous assistance in the control of an epidemic. A simple method for diagnosis of carriers is that suggested by Hatchel and Haywood, who streaked the swabs directly on two or three slants of ordinary Loffler's media. After incubation, suspicious, discrete colonies were picked off, stained and streaked either over other slants or over glucose-serum-agar slants or plates. Another method, which has been suggested by Buchanan for differ- entiating the Gram-negative group of cocci, may be used also in the carrier studies. Petri dishes with Loffler's blood-serum, containing 1% of glucose with neutral red in the proportion of .5 in 10,000 as an indicator, are used. Streak cultures are made on the plate. Suspicious colonies are picked off and subinoculated. (Note. — The preceding method described is along the same lines, but simpler than this method.) A quicker method for diagnosis of carriers has been suggested. Pick off suspicious colonies of Gram-negative cocci after 24 hours' growth and do agglutination tests with a strong antimeningitis serum. It has been reported that 1-50, by some even 1-25, may be considered as a positive diagnosis. The technic is the same as for any agglutination test. Best results with agglutination tests in the Gram-negative group of cocci are obtained by macroscopic tests. Costa, 1911, recommends a quick macroscopic agglutination test done on a slide. (He claims to have obtained very reliable results by the method.) The irregular results that occur in agglutination tests between different strains of the various organisms, the cross agglutination be- tween different members of the Gram-negative group of cocci, render the agglutination test unreliable for rapid diagnosis. Specific Serum Reactions of the Meningococcus and the Other Gram-Negative Cocci. — Where the regular cultural methods do not establish a differential diagnosis between the various groups of organ- isms, it is desirable to do specific immune-serum reactions. As judged by Elser and Huntoon's conclusions, the agglutination reaction, which is the most practical serum differential test for bacteria, as in typhoid, coli, etc., in this group of organisms is surrounded by many difficulties, and is not a very reliable method for general use. The work on specific agglutinins in this group of organisms, done by Elser and Huntoon, was very painstaking and careful and is one of the most complete on the subject. The following is their description of the technic: 36 EPIDEMIC CEREBROSPINAL MENINGITIS. "We relied entirely upon the so-called macroscopic method for the deter- mination of these reactions. Preliminary tests in which the microscopic method was tried yielded less satisfactory results. The standard suspen- sions employed throughout were prepared with filtered and sterilized .85% salt solution. Each cubic centimeter of salt solution received .004 gram of moist bacteria, and was shaken up thoroughly so as to form a perfect sus- pension. The same standard loop was employed throughout for measuring the bacteria in preparing the standard suspensions. To secure wholly com- parable results, the tests were carried out and the results recorded through- out by the same individual. Various dilutions of the serum, graded in the customary manner, were prepared. Each tube in the series received the same amount of diluted serum, to which an equal amount of the standard suspension was added in a manner to insure a prompt mixing of the two fluids. The same suspension diluted with an equal amount of .85% salt solution served as a control. The series thus prepared was placed at incubator tem- perature for two hours and transferred to the ice chest (9° C), and kept at this temperature for twenty-four hours. Readings were usually taken after one, two, three, and four hours had elapsed, and the final control readings were made after the lapse of twenty-four hours. Particular attention was paid to the course of the reaction. It occasionally happened that no appre- ciable change in the appearance of the mixtures was noticeable after several hours had elapsed, whereas, after twenty-four hours, complete clarification of the fluids was noted, simulating a positive agglutination reaction in all dilutions. Whenever distinct progression in the reaction, both as to time and to dilution, was not apparent the tests were repeated, and we were not surprised to find quite different results. While a partial sedimentation in the control suspensions occasionally attracted our attention to the spurious nature of these reactions, such a sedimentation in the control tubes did not occur invariably. These experiences lead us to conclude that the normal salt solution control, which serves its purpose when less erratic organisms are being tested, is not a wholly reliable control in the case of the organisms under consideration. The tests here recorded were therefore controlled by the use of simultaneous tests with normal serum. In passing, we may mention that Eberle recommended centrifugalization of the suspensions at a reduced rate of speed. This caused a sedimentation of all coarser particles suspended in the fluid and, according to this observer, prevented the occurrence of pseudoagglutinations. The mixture showing the end-point of the reaction, adopted by us as the standard, presented the following picture: The vast majority of the cocci were clumped and found at the bottom of the tube. The supernatant fluid presented a degree of turbidity which was just appreciable when viewed at an angle and by a good light. We have recorded such a reaction as positive. Partial reactions were not utilized in comparing the effects pro- duced on different strains by the same serum for the following reasons: While at times a sharp distinction could be drawn between our end-point and the appearances in the succeeding dilutions, it very frequently hap- pened that partial reactions showing no appreciable differences were noted in several dilutions above this point. These peculiar results suggest that the individual organisms present in the same culture are not equally sensi- ETIOLOGY. 37 tive to the influence of specific agglutinins. When the end-point of the reac- tion is sharply defined or when a gradual but progressive decline in the effects of the serum is observed in dilutions above this point, we may as- sume that all the individuals enjoy the same degree of agglutinability, whereas numerous partial reactions in a series might be explained by the presence of very agglutinable individuals intermingled with others that are less agglutinable. Concerning the length of time required for the completion of the reac- tion, opinions differ. Most observers are agreed that the macroscopic test requires at least twenty-four hours. Dunham and Eberle found that the maximum reaction was not reached until forty-eight hours had elapsed. The results of our experiments bearing on this point also indicate that forty-eight hours are necessary in some instances to complete the reaction, but in the main the values obtained were not materially altered by post- poning the final readings to this extent. As a matter of convenience, there- fore, we adhered to the twenty-four-hour limit. The sera employed for these tests were derived from rabbits which were immunized by repeated intravenous injections of the organisms in question. As a rule the animals received weekly injections of bacteria suspended in normal salt solution, killed by exposure to a temperature of 65° C. for thirty minutes. We began by injecting .002 gram of moist bacteria and gradually increased the dose to .008 gram. While the immunizing procedure indicated above was generally followed, no effort was made to adhere to this rule. The dose, as well as the time of administration, was wholly determined by the general condition and weight of the animal after the preceding injections. Immunization with living cultures or with organisms killed by simple dessi- cation yielded less satisfactory results." General Summary and Conclusions Concerning Agglutination and Absorption Tests. — In reviewing the results obtained in con- nection with this phase of the work of Elser and Huntoon, the follow- ing facts deserve to be emphasized : 1. The unusual instability of the agglutinable properties of the meningococcus and the marked variations in the degree of aggluti- nability exhibited by different menigococcus strains in the presence of the same immune serum deprive these tests of much of their diagnostic value. Approximately 40% of the meningococcus strains studied were relatively inagglutinable. Recently isolated strains were on the whole less sensitive to the action of agglutinins than were older strains. 2. The presence of serum in the culture medium exerted a dele- terious influence on the agglutinable properties of meningococcus strains. 3. Passage through plain or glucose bouillon rendered some of the inagglutinable strains more sensitive to the action of agglutinins, whereas others were not influenced or were unfavorably affected by this treatment. 38 EPIDEMIC CEREBROSPINAL MENINGITIS. 4. Since spontaneous agglutination of these organisms may occur in various serum dilutions and be absent in the normal salt solution control suspension, parallel tests with normal serum should be under- taken in each instance. 5. Temperature exerts no marked influence on the end-results of these reactions. While incubator temperature and a temperature of 55° C. accelerated the reaction, the values obtained after the lapse of twenty-four hours were not materially higher than those obtained at room temperature. Attempts to render an inagglutinable strain more sensitive by exposing the tests to a temperature of 55° C, were un- successful. 6. For the completion of the agglutination reaction with these or- ganisms at least twenty- four hours are required. 7. Centrifugalization accelerates the clumping and sedimentation of agglutinable strains suspended in the corresponding immune serum. 8. In comparing the rate of the reaction occurring when an inagglu- tinable meningococcus strain was exposed to the action of the cor- responding immune serum with the velocity of the reaction occurring when a member of another group was exposed to the action of the same serum, it was observed that the meningococcus strains responded more promptly to the action of the immune serum than did the heter- ologous strains, although after the lapse of twenty-four hours both strains were clumped to the same extent. These differences in the rate of the reaction suggest differences in the avidity with which the substances interacting combine, or suggest fundamental differences in the substances participating in such reactions. 9. While the meningococcus, as a rule, fails to respond to the action of normal rabbits' serum diluted above 1-25, certain strains appear to be unusually sensitive to the action of such sera. A few strains were clumped in normal serum in dilutions of 1-250. 10. The agglutinogenic capacities of the meningococcus are very considerable. In the course of the work, meningococcus immune sera that agglutinated the homologous strain in serum dilutions of 1-25,000 were produced. The agglutinogenic capacities of the inagglutinable strains, though limited, were sufficient to produce immune sera of mod- erate potency when tested with ag'glutinable strains. Toward the ho- mologous inagglutinable strains they were ineffective. The failure to respond to the action of an immune serum on the part of certain strains is, therefore, not due to any peculiarities of the serum employed, but to reduced clumping capacities of the organisms. 11. A definite relationship between agglutinogenic properties and agglutinin absorptive capacities as a rule appears to exist. ETIOLOGY. 39 12. Failure to combine with agglutinins in a test-tube experiment does not signify a total loss of agglutinogenic properties. 13. What has been said concerning the behavior of the meningo- coccus toward the corresponding immune serum applies also to the behavior of the other Gram-negative cocci toward their homologous sera. 14. When properly controlled, agglutination tests serve to differ- entiate the various groups from each other, provided the strains tested are sufficiently agglutinable. Diagnostic difficulties may arise in con- nection with certain gonococcus strains. These are unusually sensitive to the action of normal and of group agglutinins and may yield higher values in the presence of a meningococcus immune serum than moder- ately agglutinable meningococcus strains. 15. Absorption tests served to differentiate the various groups of Gran>negative cocci from' each other and to establish the identity of the agglutinable and inagglutinable meningococcus strains. One gen- uine meningococcus strain, however, failed to absorb specific agglu- tinins from a homologous immune serum. 16. Meningococcus strains that were more or less inagglutinable exhibited reduced absorptive capacities, but a definite relationship be- tween the binding capacities of such strains and their agglutinability could not be established. 17. These tests also< revealed the existence of a group relationship between the meningococcus and gonococcus. 18. Judged by the results of absorption tests, the pseudomenin- gococcus group and the chromogenic Group I require a further subdi- vison. At least two varieties are represented in each of these groups. 19. A relationship of the Jager coccus and the Diplococcus crassus to the meningococcus could not be established by these tests. 20. Under certain conditions, centrifugalization of an immune serum causes a reduction of its agglutinating value. This alteration of the agglutinins has been attributed to the influence of discordant vibrations of the centrifuge. Since this cannot be wholly controlled, the necessity for a centrifuge control specimen is evident, if we clarify an absorbed serum by these means. Von Lingelsheim, 1906, Kutscher, 1906, Krumbein and Schatiloff, 1908, have described uniform results in agglutination, using menigo- coccus serum: plus meningococcus. (Von Lingelsheim used dead cul- ture.) The main objections to this test, as advanced by Trautmann and Fromme, 1908, Eberle, 1908, Detthorn and Geldermeister, 1907, Lieberknecht, 1908, Elser and Huntoon, 1909, are: first, the want of uniform reactions with different members of the same group ; second, 40 EPIDEMIC CEREBROSPINAL MENINGITIS. the fact that there is cross agglutination between meningococcus, gono- coccus, and other Gram-negative cocci. Dopter and Koch thought they could differentiate meningococcus and gonococcus by absorption tests. The objection to this, as advanced by Arkwright, is the fact that all the strains of either bacterium are not equally well fixed by all immune serumiof other organisms of their groups. Wollstein, 1907, was unable to differentiate between the menin- gococcus and gonococcus by opsonic tests. The same objections as for agglutination hold true for this test. The Precipitin Reaction has been advocated by Dopter and Koch, 1908, and Dopter, 1909, to differentiate between Gram-negative cocci. The work, so far, has been insufficient to warrant any conclusions. Complement fixation tests have given very widely varying results in attempts to differentiate the Gram-negative cocci. Vannod, 1906, and Krumbein and Schatiloff, 1908, considered this reaction specific for the meningococcus and the gonococcus. They used a polyvalent meningococcus serum and gonococcal serum. Watabiki, 1910, also maintained that the gonococcus could be differentiated from other Gram-negative cocci by this reaction. Arkwright, 1910, found no advantage or superiority of this reaction over agglutination. Woll- stein, in 1907, employed monovalent sera and could not differentiate between the meningococcus and gonococcus by this reaction. Colombo, 1911, used polyvalent sera, and had similar results. Arkwright in 1912 employed monovalent sera. He prepared an autolyzed antigen. He came to the conclusion that meningococci sera produce complement fixation as readily with some gonococcic strains as with extracts of some strains of meningococcus, while no reaction is obtained with some heterologous meningococcal strains. No satisfactory distinction can be made between the meningococcus and the gonococcus by means of complement-fixation tests. In 1911, Dr. Neal and I did some work on this subject in the Re- search Laboratories, New York City. The antigen was prepared in the usual way. The organisms were grown on plain glucose agar for 24 hours. The culture was then washed off in salt solution. Two different methods were used in the subsequent steps. The first was to add 2% toluol to the salt emulsion and incubate over night. The toluol was filtered off before it was used. The other method was to heat the salt emulsion to 50° C. for three hours and then place on ice for about 24 hours. The essential object in both methods was to produce good autolysis. Our results were essentially those of Arkwright. There was equally good cross fixation between meningococci and gonococci sera and antigens. ETIOLOGY. 41 McNeil, of the Research Laboratories, New York City, has prepared what he considers to be specific meningococci and gonococcic antigens, which do not give cross fixation. The antigen is prepared as follows : 1. Grow culture on slants of salt- free veal agar, neutral to phenol- pthalein, for 18 to 24 hours. 2. Wash off in distilled water. 3. Heat in water-bath for two hours at 56° C. 4. Centrifuge for about 20 minutes, take supernating fluid, throw sediment away. 5. Pass immediately through a Berkefeld filter, using, preferably, a filter of medium porosity. Berkefeld should be neutral. 6. Put in hermetically sealed capsules. Heat to 56° C. for half an hour, on two successive days for sterility. 7. Store in ice box. Keeps a long time — several months. 8. Before using, bring up to 9% tonicity, by adding one part of 9% salt solution to nine parts of antigen. 9. Titrate before using. The important thing to remember in preparing this antigen for specificity, is not to allow too long autolysis. The less time allowed for autolysis, the more specific the antigen. In a series -of tests done by McNeil, he found that sharp, high, specific fixation could be obtained with this antigen, and that the men- ingococcus and gonococcus could be so differentiated. Some experiments, instituted while I was in charge of the work, are now being performed in the Research Laboratories by Drs. McNeil and Neal. The object of this experimentation is to determine whether all the members of the Gram-negative group of cocci could be differen- tiated by complement-fixation tests using the specific bacterial antigens. Animal Test for Differential Diagnosis of Meningococcus from Other Cocci. — Dopter, December, 1910, has shown that if a mixture of antimeningococcus serum and of an emulsion of meningococci be introduced into the jugular vein of the guinea-pig, there is an imme- diate and profound effect with death, which he attributes to the serum destroying the cocci and liberating a toxin. By the saturation test, he has shown this test to be specific. He introduced likewise a technic similar to the Pfeiffer test for cholera, in order to distinguish the men- ingococci from other organisms. To a guinea-pig of 250 grams, one c. c. of a non-heated meningococcus serum is given peritoneally. Twen- ty-four hours thereafter, one-sixth of an agar culture, i. e., a non-lethal dose of meningococci, is given by the same route. The exudate is withdrawn, and the meningococci are found to be breaking Up. They finally disappear. 42 EPIDEMIC CEREBROSPINAL MENINGITIS. About this time, I was also doing some work along these lines. Antimeningitis serum, as has been proved by others, will protect smaller animals against lethal doses of culture. On this was based one of the methods for standardizing the antimeningitis serum. Administering the serum either before, at the same time, or even a little later than a lethal dose of live culture, will protect an animal. In performing some studies to obtain specific phagocytosis in vivo, I inoculated guinea- pigs, intraperitoneally, like Dopter, with serum and lethal doses of culture. Examination of the peritoneal exudate in 24 hours, revealed, as Dopter records, that the meningococci were breaking up. Very few TABLE I. Monovalent Serum of Strain 8 Plus Antigens of Different Strains. Serum Dilutions. hntlffens 10 SO 100 250 500 7^0 c 1 + + + + + + t -*• + + + 4 — It + + + + + + + + — 7 -»- + + + + + i i 1 - ¥ + + +• + + i i 1 — 9 + + + .+ + + + i 1 — 6 -f- + + + + + + + + 1 — Z + •+• + + + -»■ + +■ + + + + — 5 + + + +• + + +• + + + + + — 3 + + + + + + + + + + ♦ t — Z\ + + + -♦■ + t- + +- + + + — W t + + + — — — — ■ 19 + + + — — — — 1 + + + — — — — meningococci were present, and those were usually well phagocytosed. If the animal be allowed to live longer, to 3G hours, frequently no organ- isms can be found in the peritoneal cavity. Strain Differentiation of the Meningococcus by Complement- Fixation Tests. — Arkwright in 1909, performed some experiments on absorption and agglutination tests with different strains of menin- gococci and a monovalent meningococcus serum, and found that he could determine a difference of strains by this method. Torrey, in 1907, determined a difference in strains of the gono- coccus in his studies on agglutination, and later by complement-fixa- tion tests. Similar studies have proved differences in strains in the paratyphoid group, in the pneumococcus and streptococcus families, and in other bacteria. ETIOLOGY. 43 Com pigment-Fixation Tests by Sophian and Neal. — 1. Ma- terials. — Immune monovalent sera were obtained by immunizing rab- bits v/ith single strains of meningococci with increasing doses, first of dead culture, then of live culture. Immunization was continued for about six weeks. 2. Fourteen different strains of organisms were tested. 3. Antigens were prepared as described on page 40. 4. Wasserman hemolytic system used. 5. Guinea-pig complement. Technic of 7" est. — 1. Hemolytic system tested daily. 2. Antigen tested for anticomplementary action, and tested for fixation with a known positive serum. 3. Serum inactivated. Dilutions made in salt solution, e. g., 1-10, 1-00, 1-250, 1-500, 1-750, etc. 4. The various antigens were now each tested against the mono- valent serum to determine the degree of fixation. Discussion. — The above table shows that organisms, 8, 18, 2, 5, 3, 21, are fixed equally well by monovalent serum of strain 8. There- fore, these organisms all belong to the same strain. All of the other organisms were partially fixed by the serum, as one would expect, owing to the probable presence of a common group in the family of meningococci, which would be fixed by all sera of any member. The difference in strains might explain the therapeutic failure of the serum that is seen occasionally in favorable cases. It is very likely that each epidemic is caused by one particular strain of meningococcus. Resume of Bacteriology. — 1. The presence of a Gram-negative intra- and extracellular diploeoccus in the fresh uncontaminated sedi- ment of a specimen of cerebrospinal fluid may be considered as suffi- cient proof that the organism is a meningococcus. Only in very rare instances do the other members of the Gram-negative group of cocci cause meningitis. 2. The differentiation of the meningococcus from the other Gram- negative cocci is most important in "carrier" studies and can be estab- lished quite easily by the morphological appearance of the colony and by simple cultural tests. For further confirmation, fermentation tests are done. 3. The various serum reactions of the Gram-negative group of cocci will allow differentiation of the various members. Great care, however, must be exercised in the tests, as the different strains vary considerably in their reactions. Numerous controls must be employed. 44 EPIDEMIC CEREBROSPINAL MENINGITIS. Complement-fixation tests with a specific bacterial antigen appear to offer best results at the present time. 4. The meningococcus is made up of a number of different strains varying in their serum reactions. PORTAL OF ENTRY OF THE MENINGOCOCCUS INTO THE HUMAN BODY. It is generally accepted that the nose and throat are the portals of entry of the meningococcus and that nasopharyngitis predisposes to infection. Von Lingelsheim and E. Meyer were able to demonstrate a meningococcus pharyngitis before the occurrence of meningitis. Westenhoffer likewise says that every case of meningitis is first a case of meningococcus pharyngitis. He demonstrated an acute pharyngitis in each of a series of twenty-nine autopsies on cases of epidemic menin- gitis. Meyer reported a similar condition in a clinical study of thirty- two cases of meningitis, early in the disease, finding in twenty-four a well-marked inflammation of the nasopharynx. In one instance an acute meningococcus tonsillitis was definitely proved to precede the attack of meningitis. The fact that the condition appears so early in the course of meningitis, sometimes even preceding it, speaks probably for this condition as primary to meningitis rather than as occurring secondarily in the course of the disease. Those who at first suggested that the meningococcus reached the meninges from the nasopharynx maintained that the infection extended upward through the cribriform plate of the ethmoid. Subsequent inves- tigation, especially by Westenhoffer, von Lingelsheim, and Meyer, showed that, if direct extension does occur, its probable course is through the sphenoid bone. Westenhoffer demonstrated in his patho- logical study of twenty-nine cases that only two had inflammation of the ethmoid cells, while in 34% there was an inflammation of the sphe- noidal sinus. He suggested that after the sphenoidal sinus became infected the suppuration might readily extend through the thin lamina of bone over it. In cases that died early in the disease, the exudate was afterward localized at the base of the region of the hypophysis. Similar localization of exudate at the base of the brain has, however, been found in secondary meningitis, as from the ear and in tuberculous meningitis. Flexner also showed that there was a like localization in the experimental meningitis produced in monkeys by intraspinal injection of meningococcus culture. Westenhoffer found no evidence of any extension of the infection along the nerve-sheaths or along the lymphatics about the carotid ar- ETIOLOGY. 45 teries. There was, however, a constant enlargement of the cervical lymph glands. I believe that local inflammation is incited by the meningococcus before it invades the general system, but that attempts to prove the presence of nasopharyngitis due to the meningococcus are of question- able value. It is probable that many cases have a varying degree of nasopharyngitis before the meningococcus gains its entry to these pas- sages. It would be difficult, therefore, to determine whether the menin- gococcus was the causative agent, or was accidental, even though the culture at the time of examination revealed a preponderance of the meningococci. A great many meningitis cases also, at all stages of the disease, fail to show any marked evidence of nasopharyngitis. Pro- nounced local inflammation in the nose and throat would therefore ap- pear to be unnecessary to allow for the further invasion of the organism. Invasion by the meningococcus from the nose and throat is believed to be effected in one of two ways — by the primary invasion of the blood-current, causing a meningococcus septicemia with secondary localization in the meninges ; or by direct infection through the lym- phatics. The weight of pathological and clinical evidence is certainly in favor of the former channel. Examination of the lymphatics at the base of the skull and around the carotid arteries, in cases of meningitis, has disclosed no evidence of inflammation along this channel. Like- wise a microscopic examination of the nerves emerging from the base of the skull and of the spinal nerves failed to show any evidence of invasion along these paths. Most of the evidence points to the primary blood infection as the very probable channel. Clinically, as will be discussed in detail later, the very frequent occurrence of general septic symptoms before the appearance of meningeal symptoms bears this out. Likewise the early presence of the meningococcus in the blood, in a considerable number of cases, and the evidence of lesions in parts far removed from the cen- tral nervous system, found at the autopsy of individuals who succumbed to the disease within twenty-four hours of its inception, also appear to confirm this opinion. A number of observers, Solomon, Martini, Cecil and Rhode, Marcovitch, isolated the meningococcus from the blood be- fore the symptoms referable to the meninges were at all pronounced. The production of a primary, general infection by accidental inocu- lation through the skin, for example, as at an autopsy, is also worthy of consideration, although it is probably only a remote possibility. Summary. — The nose and throat are the probable entrance ways of the meningococcus. From there it probably invades the blood causing 46 EPIDEMIC CEREBROSPINAL MENINGITIS. a meningococcus septicemea with subsequent localization in the men- inges. DISSEMINATION OF THE DISEASE. In the 1905 epidemic, in New York City, of 2,180 cases studied, in only 6% had there been any direct exposure to other cases of cerebro- spinal meningitis, and in only a small number was there evidence of direct transmission of the disease. Drs. Bolduan and Goodwin investigated multiple cases in families and found eighty-eight cases, making in all less than one hundred in- stances of possible transmission out of over 1,500 cases. The meningococcus is found in the nose and throat of those ill with meningitis in over 90% of the cases at some stage of the disease. Von Lingelsheim, in 1906, found the organism in 93.8% of cases he studied. Fliigge found that the meningococcus usually disappeared from the nasopharynx of meningitis cases after the fifth day. This is in accord with the experience of other observers, who found that the organisms usually disappeared from the nasopharynx in from ten days to two weeks. ! Bochalli, 1908, described a very interesting regimental epidemic. As a result of his studies he noted : 1. During epidemics there are probably ten to thirty times as many healthy contacts who harbor the meningococcus as actual cases. 2. The cocci usually quickly disappear from the nasopharynx, but may remain four weeks or longer. 3. They are most numerous and virulent during the first week of their settling in the throat. Discharges from the nasopharynx, and frequently the saliva of meningitis cases during the first week of the disease, are therefore infectious and a serious danger. Even casual study, however, of pre- vious epidemics of meningitis and analysis of statistics show that only a very small percentage of meningitis cases could be traced to direct ex- posure to other meningitis cases. Cases of hospital infection are de- cidedly uncommon, and relatively few attendants in hospitals, including nurses and physicians, have been infected. In New York hospitals, meningitis cases, like many other acute infectious diseases, are kept in a general ward. This has its objections, especially in epidemics, as T shall discuss later. In Mt. Sinai Hospital, in looking over the records of the hospital for six years, during which time epidemic meningitis in a varying degree was almost always present in the ward, I could, however, find no record of infection in a doctor or nurse. Elser quotes ETIOLOGY. 47 the record of three nurses who developed meningitis while attending meningitis cases. In 1911, one physician in New York City, after performing an autopsy on a meningitis patient, developed meningitis with fatal results. In the Meningitis Hospital in Dallas during the epidemic of 1912, two internes and twelve nurses who were exposed to the disease became infected; all fortunately recovered. The contraction of the disease by physicians and nurses does not, however, give one a true idea of how directly infectious a disease is, since they ordinarily take the usual precautions while treating infectious disease. A more correct idea is obtained by studying statistics of multiple infections, where several members of one family became infected or where a history could be obtained in any case of exposure to another case. During the Texas epidemic, in 5% of cases two members of a family were infected and in one instance three members were stricken. The development of large numbers of cases, as seen during epi- demics, the spread of the disease over widely scattered areas, the ap- pearance of it in sections where no meningitis cases had ever been reported before, must be explained in some way other than by direct exposure to the disease. In 1901, Albrecht and Ghon first demon- strated that the memingococcus could be found in the nose and throat of healthy people. This was subsequently confirmed by a great many investigators, among them being Lord, Weichselbaum, Ghon, von Lin- gelsheim, Flugge, Kolle and Wassermann, Kutscher, Osterman, and a great many others. This fact is easily demonstrable. Later investi- gations revealed that the number of healthy meningococcus carriers, during an epidemic of meningitis, is relatively very large. Flugge estimated that the number is about ten to twenty times that of the cases of meningitis during the same period. He also estimated that about 70% of the individuals living in the immediate vicinity of menin- gitis cases act as meningococcus carriers. Flugge and Weichselbaum suggest the possibility that the meningococcus once established in the nasopharynx of healthy individuals remains there permanently. I do not agree with this statement, and believe that repeated examination of the nasopharynx secretion would easily demonstrate that most car- riers are only temporarily so. We have, however, many healthy people, who, having been exposed to the disease,' harbor the organism for weeks, months, or years. These we call the first carriers. They in turn transfer the organism to other healthy people who, in all proba- bility, had never been near cases of meningitis. We thus have the second class of carriers. It may be well to mention here, that, while most meningitis cases fail to show the meningococcus in the naso- 48 EPIDEMIC CEREBROSPINAL MENINGITIS. pharynx after the first two weeks, a small percentage also becomes carriers. During the height of an epidemic, the total number of carriers is very large, but there is a progressive diminution in numbers as the epidemic dies out, helping to establish the fact that the organisms are only temporarily present in the nasopharynx of most carriers. Organisms in Nasopharynx of Meningitis Patients. — Goodwin and Sholly in the Health Department Laboratories, during their studies of the nasopharyngeal secretions of those ill with meningitis, in the New York epidemic of 1905, found as follows : 1st week in 54% of cases 2d week in 33% of cases After 2d month in 6% of cases Von Lingelsheim found the organism in those ill with the disease, most often up to the fifth clay. The following figures were obtained in different cases examined at different times : 1st to 5th day in 66% of cases 6th to 10th day in 24% of cases 11th to 12th day in 11% of cases 21st day and la,teir in 4% of cases Netter and Debre found the organism as follows : 1st week in 78% of cases 2nd week in 60% of cases 3rd week in 50% of cases 4th week in 25% of cases Later in 15% of cases TABLE II. Examination of Secretions of Nose and Throat of Healthy People — When no Epidemic Existed. Observer. Total Examinations. Positive Carriers. Percentage of Persons Proved to be Carriers. Meyer and Collabo- 1911 soldiers once exam- 1.93% rators Furst, Wald- ined (sporadic cases had mann and Gruber occurred in the garrison every year). 1911 examined many times 47 2.46% (cases had likewise oc- curred in this garrison). Kolle and Wasser- mann, 1906 114 2 1.8% Drobe and Kucera, 1906 160 Kutscher 56 4 7.4% Huber and Kutscher 408 8 2 % ETIOLOGY. 49 TABLE III. Examination of Healthy Contacts During Epidemics. Observer. Goodwin and Von Sholly Dieudonne, 1906 Total Examinations. 45 68 contacts • Positive Carriers. Percentage of Persons Proved to be Positive Carriers. 11.1% 29 with rhinopharyngitis 9 13.3% Osterman, 1905-6 a. 24 close contacts 17 70 % b. 51 not closely exposed 2 4 % c. 10 not exposed Friese and Muller 60 contacts 28 46.6% 51 contacts 15 29 % Bochalli 16 close contacts 10 62.5% 114 little exposed 13 11.4% 355 no direct exposure 19 5.4% 40 not exposed in an- other garrison Bethege 187 contacts 60 3.2% Von Lingelsheim, 1908 387 contacts 28 7.2% 311 not exposed Bruns and Hohn, 1907 a. b. 609 close contacts 1786 not intimately ex- 224 36.7% posed 401 22.5% c. 380 not exposed 30 7.9% Herford 172 close contacts 43 25. % Trautmann 261 close contacts 24 9. % Hatchel and Hay- ward 97 contacts 15 15.4% Black 1912 801 close contacts 227 28.3% The work done by Meyer and his collaborators showed that the meningococcus was only temporarily present in the nose and throat in about 81% of the contacts they examined, and that most carriers are so, for only a short time. Of the remaining 19%, 12% are persis- tent carriers ; while 6% are periodic carriers showing periods when the organisms disappear apparently, as judged by culture. The proportion of carriers in an infected community bears a fairly definite ratio to the number of cases ill with the disease in the course of the epidemic. Brun and Hbhn's figures, as illustrated by the fol- lowing table of their studies, seem to bear this relative ratio out. 50 EPIDEMIC CEREBROSPINAL MENINGITIS. (Towards the end of the epidemic, the percentage of carriers becomes small.) TABLE IV. Table of Epidemic of 1907. Percentage of Number of Cases Number of Con- Number of Positive Healthy Month. of Meningitis. tacts Examined. Carriers. Carriers. March 148 120 37 30.0% April 278 841 152 23.7% May 327 730 113 15.5% June 188 644 88 12.0% July 146 616 53 8.0% August 68 403 22 5.5% The table compiled by Black during the Dallas epidemic helped to confirm this observation. He found that the total number of contact carriers became greater as the cases increased ; that during a temporary lull in the epidemic, there was a diminution in the number of carriers. Following this period, the weather again became cold, damp and very changeable, producing a large outbreak of fresh cases of meningitis with a relative rise in the number of carriers. TABLE V. Table of Dallas Epidemic, 1912. Total Per Cent Week. Examinations. Positive. 1st 148 47% 2d 210 26% 3d.. 159 16% 4th (Number of meningitis cases smaller) 64 4% 5th (Fresh outbreak of meningitis cases) 68 23% 6th 152 36% It is apparent, therefore, that a meningitis epidemic is produced essentially not by those affected with the disease, but by the healthy carriers who distribute the organisms over large areas, exposing a great many persons, only a very small percentage of whom actually become infected. One healthy carrier may, in turn, cause a number of other healthy carriers, thereby producing a vicious cycle of constantly increas- ing cases over widely scattered districts. It is easy to see how danger- ous a meningitis epidemic is, and how difficult it is to control. It is an epidemic where one must deal with the healthy. These healthy carriers can satisfactorily explain the course of an epidemic. The occurrence of the diseases where there is no direct history of exposure, the spread of it to widely distant areas, many miles away from the infected regions, can be so explained. In the 1912 Texas epidemic, ETIOLOGY. 51 most of the cases at first appeared in the larger cities, Dallas, Fort Worth, Waco, and Houston. As more cases developed in these cities, more cases began to crop up in small country towns in which there had never been any meningitis before and in which there was no history of direct exposure to other cases. In this way town after town became infected, small towns and large towns. In some there were but few cases, in others more. A good illustration of carrier transmission is the following: An interne in one of the New York hospitals developed meningitis. There had been no case of meningitis in the hospital for over a year, and he had not seen any outside of the hospital in months. At the time that he became ill, a large epidemic of meningitis was raging in Greece, a number of cases developing among the Greek immigrants on their voyage across the ocean. All Greek immigrants were therefore looked upon with suspicion as being possible carriers. We immediately thought of a Greek immigrant who had been admitted to the hospital some four or five days before the interne became infected. This im- migrant was suffering from some slight condition, not meningitis. Cultures from his nose and throat proved him to be a meningococcus carrier. Another very probable means of transmission of the disease, at least in the production of carriers, is the urine of meningitis cases. I shall discuss this subject in the chapter on "Symptoms," but will say here, that the urine of meningitis cases, early in the disease in many, and later where complications of pyelitis occur, shows the presence of meningo- cocci in abundance. Sufficient attention has not been called to this fact, which I believe to be a source of grave danger. The secretions from conjunctivitis and herpes incidental to menin- gitis contain the meningococcus in profusion, and here is another ele- ment of danger as a means of infection. Since this meningococcus is very viable to external influence outside of the body, it is improbable that transmission by inanimate objects, like clothing, occurs to any extent. .RESUME OF ETIOLOGY OF MENINGITIS, AS TO EPIDEMIOLOGY, BACTERIOLOGY, PORTAL OF ENTRY OF THE ORGANISM, AND MODE OF TRANSMISSION. 1. Meningitis is an acute, infectious, contagious disease occurring sporadically and in periodic epidemics. The most important predis- posing factor is probably unusual climatic change, to which people are 52 EPIDEMIC CEREBROSPINAL MENINGITIS. unaccustomed and are non-resistant, and which occasions general naso- pharyngeal catarrh. The immediate exciting factor is the meningococcus, which must be virulent and which is very likely carried over from some recent previous epidemic in the nasopharynx of some healthy person, being kept virulent by the occurrence of sporadic cases ; or it may be carried from a meningitis epidemic in some other country. 2. The meningococcus is probably the only organism that causes extensive epidemics of meningitis. It is one of a group of Gram- negative cocci from the others of which it can usually be easily differ- entiated by the ordinary morphological and cultural characteristics plus fermentation reactions. All except the gonococcus can be found in the nose and throat. Extremely rarely the gonococcus may also appear there. Other means of differentiation of the organisms are specific serum reactions. The agglutination reaction has a great many diffi- culties, though, if properly controlled, it is accurate. By complement- fixation tests, using McNeil's specific antigen, differentiation may be more definite and accurate. 3. Portal of Entry. — The meningococcus most probably gains entry to the body through the nose and throat, where it either may become implanted on an already existing nasopharyngitis or may cause a naso- pharyngitis. From there it probably enters the blood-stream, causing septicemia with subsequent localization in the brain. 4. Mode of Transmission. — The disease is transmitted partly by means of the secretions of the nose and throat of meningitis cases early in the disease, causing thereby a small number of carriers. The chief mode of dissemination is by means of healthy carriers who harbor the organisms in the nasopharynx for months or years and who transmit the infective agent to others and so scatter it over large areas. A small percentage of carriers contract the disease. CHAPTER II. SYMPTOMATOLOGY. Incubation Period. — The duration of this period is unknown and it will probably be very difficult to determine it definitely, since the meningococcus may be present for a variable length of time in the nasopharynx before it gains entry into the system. Some observers found that the interval between the sickening of the first and second case, where multiple infection occurred in the same family, varied con- siderably. In Glasgow, Wright found the interval to be from one to ten days; at Leith, Robertson reported the interval as being from two to thirty-six days. In the Texas epidemic, the intervals varied within very wide limits ; most often, however, secondary infection appeared in from. one to ten days. The following two sporadic cases are suggestive as to the probable incubation period. In 1911, New York City was free from an epidemic. But one was raging in Greece, and a number of cases were being brought over on the Greek steamers. Dr. A. who had not been previously exposed to any cases of meningitis performed an autopsy on one of the first Greeks who died on the steamer. Twen- ty-four hours later, he became infected by a malignant form of the disease. The second case is that of Dr. B. who contracted epidemic meningitis five days after he had treated a Greek immigrant for some febrile condition other than meningitis. Cultures of the nose and throat proved this immigrant to be a meningococcus carrier. Thus, in the above cases the incubation period was, in one instance, twenty- four hours ; in the other, five days at the outside. I believe that the incubation period probably falls in between these limits. Previous Health. — In this disease, as in others, poor general con- dition predisposes to the disease. In most cases, however, a history of distinct previous ill-health cannot be obtained. In the New York City epidemic of 1905, such history could be obtained in only 6% of the cases. Exposure to cold and wet, causing common cold, is a very important factor. Dr. Nash of Dallas noticed that a considerable num- ber of his female patients were menstruating when they developed the disease. I have likewise observed this in a number of instances. It may probably be explained by the lowered general resistance during the menstrual period. 53 54 EPIDEMIC CEREBROSPINAL MENINGITIS. I. INFECTIONS PRODUCED BY THE MENINGOCOCCUS PRECEDING MENINGITIS. Nasopharyngitis. — The meningococcus very probably in all cases first causes a nasopharyngitis, which in turn, in a smaller number, is followed by entry of the coccus into the general circulation with subse- quent development of meningitis. A certain degree of visible inflam- mation in the nasopharyngeal mucous membrane exists in most in- stances. Severe sore throat or rhinitis, however, is uncommon. Occa- sionally, in severe septic cases, there may be a very fetid, purulent, nasal discharge. General Septicemia — Ulcerative Endocarditis. — We have dis- dussed how epidemic meningitis, in most cases, is probably preceded by a primary bacteremia. A number of cases have been reported, in the literature, in which there was a true meningococcus septicemia with lesions in organs outside the meninges, occurring before the attack of meningitis ; in some instances, no meningitis subsequently developing. The earliest case was reported by Solomon in 1902. The patient, a woman of thirty, had chills, fever, with pain and swelling of the joints of her hand, elbow, and knees. Blood-cultures yielded the meningo- coccus. These symptoms persisted for two months, being in general the picture of a severe sepsis. She then developed meningitis (the meningococcus being found in the cerebrospinal fluid) with ultimate recovery. Andrews, 1906, reported a case with general sepsis and purpuric eruption which yielded meningococci by blood-culture. The patient died in a few days without developing meningitis, evidence of which was also absent at autopsy. R. L. Cecil and W. B. Soper, in July, 1911, reported a case of pri- mary meningococcus verrucous endocarditis, proved by blood-culture and autopsy, without the subsequent development of meningitis. The history of their case is very instructive. The patient, aged thirty-one years, dated the history of his illness back to two Aveeks before admis- sion to the hospital. He complained of sore throat, felt feverish, and noticed some pain and tenderness in the right wrist and elbow. He had headache, vomited a number of times, but continued to work until four days before going to the hospital when he. began to suffer with a dull pain across the front of the chest. Physical examination : General condition good. No meningeal symptoms. Heart showed presystolic murmurs at the apex. There were acute swelling and tenderness of a number of the large and small joints. The clinical diagnosis at that time was rheumatic fever with endocarditis. During the next ten days, SYMPTOMATOLOGY. 55 the patient became very septic; fever rising very high. He became irrational and delirious. Blood-cultures yielded the meningococcus, On the ninth day a few petechial spots appeared over the trunk; on the tenth day he died, without, however, showing symptoms of meningitis. Autopsy showed no meningitis, but verrucous ulcerative endocar- ditis and septic infarcts in spleen and kidney. This case of meningococcic verrucous endocarditis is especially in- teresting in that the patient was evidently subjected to an extremely virulent general sepsis, lasting for about a month, without developing meningitis even when his resistance was very much reduced. Other cases of meningococcic verrucous endocarditis have been reported as occurring during the course of meningitis. These will be discussed, including one of my cases, in the chapter on "Complications." Primary meningococcic pneumonia has been described by some authors. In the 1912 Kansas City epidemic, one case of pneumonia in a woman was treated for four days, during which time many menin- gococci were present in the sputum. She then developed epidemic meningitis. Another patient, a woman of thirty, developed what ap- peared to be acute articular rheumatism affecting a number of the large and small joints and causing considerable swelling and pain. There was little redness over the joints, however, and they failed to respond to salicylates. There was no previous rheumatic history. About three weeks later, while several of the large joints were still actively inflamed, the patient devoloped acute epidemic meningitis. Under serum treat- ment her meningitis promptly improved, and some of the joints cleared up. During her convalescence, one shoulder- joint which had been affected grew steadily worse ; became very tense and painful ; and caused high fever. Aspiration of the joint gave a purulent fluid in which were many intra- and extracellular meningococci. Antimeningitis serum was injected into> the joint cavity. Immediate recovery from the affec- tion of the joint which had persisted for about six weeks, followed. It is more than probable that the joint condition was due to the menin- gococcus from the very onset of the disease. II. ACUTE GENERAL DISEASES NOT DUE TO THE MENINGOCOCCUS, ACCOMPANYING AN ATTACK OF EPIDEMIC MENINGITIS. Meningococcus meningitis has occurred during the course of other acute infectious diseases ; vice versa, other acute infections have oc- curred during the course of meningitis. I saw one instance of typhoid fever in which meningococcus menin- 56 EPIDEMIC CEREBROSPINAL MENINGITIS. gitis set in at the end of the second week. The patient, a negro boy of nine, was admitted to the hospital with an indefinite history of about ten days' illness. He had high fever as well as all the active signs of meningitis ; marked Macewen's sign ; very rigid neck and Kernig's sign ; pulse rapid — 120 — intermitting; respiration irregular — 24; mentality clear, but very irritable and hypersensitive. Lumbar puncture gave a slightly turbid fluid, showing many meningococci and pus-cells. His nose and throat culture and urine also yielded meningococci. He was tapped in all four times, and serum was injected each time. The cere- brospinal fluid cleared up promptly with disappearance of the menin- gococci and pus-cells. The meningeal symptoms likewise improved. The neck became limber, and Kernig disappeared. The fever during the first week of illness was continuous and high between 103° and 104°. In spite of the improvement in his meningitis, the patient continued to run a high temperature, which now had become very remittent, ranging between 101° and 104°. His abdomen was distended, and he com- plained of occasional pain in the right iliac region, over which there was some rigidity and tenderness. His spleen was slightly enlarged ; the pulse was slower and dicrotic. I now became suspicious and upon the examination of his Widal found it positive in high dilution. The patient was then treated as a typhoid case and ran an uneventful course for another week when he reached the normal. It was interesting to note that the meningitis ran a very mild course, that the febrile course throughout was that of the typhoid and did not appear to be influenced at all by the meningitis. (See Chart I.) During the course of meningitis, other forms of pathogenic organ- isms have become engrafted in the meninges. Thus, I was told of a case — in the Babies' Hospital in New York City — of meningococcus meningitis in which, during the acute course, an influenza meningitis set in, both the influenza bacillus and meningococcus having been iso- lated. Similarly a number of cases of meningococcus meningitis during the acute stage showed the pneumoeoccus in addition. «A number of such cases were observed during the 19i2 Texas epidemic. Holdheim, Heubner, Hunter and Nuttall, Lenhartz, Frohman, and Netter have reported instances of tuberculous meningitis, in which an organism believed to be the meningococcus was also isolated from the cerebro- spinal fluid. In most of the cases reported, however, the meningo- coccus was not found in the original smear examined, but grew later. The cultural characteristics, likewise, did not coincide, in most instances, with that of the meningococcus, leading to the suspicion of a possible secondary contamination of the cerebrospinal fluid — an occurrence quite common. No authentic case of such mixed infection by the tubercle SYMPTOMATOLOGY. 57 > « P O « 1 J j S!!i S i! s: ■ V v. :? si t\ Si si i! ■1 f! S! S! !! i\ it !» |! Si 5 !! if o ^ °^ * £ *© ,-.- :s ^ --» ^ "" "" "" " i:::ai e :::":;;!i[:::::::::::::::::::::: ^ - ** ___-_„_.-_-_■ = - = 2 < ^ * ^ « ► -.„ e Ii:::si t> ^ ______ „ _.-'-* #s o _,_---■ v< * '~ ri "II "11 * ::_::::; =;: ^ * 3 --:=i *• ^i j|j © m „_,--• = = == = = = = = = = = == = k * *' s> "--,. 1 ~ ■<_" 2 _ 1 . _ .--. - = :: = : = _....- ._. -i Os "■ ._ J ___* h M - = _L_. ._._,, _!____ - _____^:::::;±; ;__:_: *> - ^-;;; ■ «r-* r I •■::::::::::::::":::J;!':!: ° > * .__.._*=»>. 1 4 •&:»:«;;«:« o __ __-£■■ 1 * v ^-'5<> _i_jv ;^?5)2' S '" > ^ """'i :::X . y 2 (k --«. ci * | „ ~-»r$ ■ra't*Ttr"->ir.>*l\u) A *y ">15 770 * : ::::::::: :::k::::::::: ^ * L_ ,!n ^a? • 1 >.>.f> s 4^' s '" ! __J „|„^ r ...._. U © © © o o '1 " " 5 8 S < * 5 * S K O Z "o 3 'E. Ph u 58 EPIDEMIC CEREBROSPINAL MENINGITIS. bacillus and the meningococcus has been reported in New York City. Elser and Huntoon examined a series of 25 cases of tubercu- lous meningitis, failing to find any other organism. Libman, too, examined 44 cases of tuberculous meningitis with no instance of mixed infection. I have examined the cerebrospinal fluids of over 200 cases of tuberculous meningitis proved by finding the tubercle bacilli in the cerebrospinal fluid and by animal inoculation. In no instance was there a mixed infection with the meningococcus. SYMPTOMS IN THE ACUTE FORM OF MENINGITIS. A. Accumulative Stage. (Stage of Invasion.) — The usual de- scription of epidemic meningitis is that it begins very acutely, coming suddenly without any previous symptoms, frequently causing severe convulsions, delirium or coma* and intense shock. The disease probably begins, in most instances, as a primary bac- teremia; then subsequently localizes in the meninges. The period of general primary bacteremia may last from a few to twenty-four hours or longer. Theoretically at least, one would expect a group of symp- toms that would correspond to this stage. While studying many cases in the 1912 Texas epidemic, I was impressed by the fact that one could commonly obtain a history of a group of symptoms preceding the severe outbreak of nervous symptoms, though the patient or family, unless carefully questioned, would usually date the disease, from the time of onset of the nervous symptoms. I believe one can secure this history in most cases. During epidemics, especially, it would be very important to be on the "lookout" for this stage and, if sufficiently defi- nite, to give the patient the benefit of an early lumbar puncture. In sporadic cases it would, of course, be very difficult to diagnose or sus- pect meningitis during this stage. This first stage corresponds to the presence of the meningococcus in the general circulation. Judging from the clinical course of cases, it would seem that symptoms of cerebral irritation occur only a short time after the onset of the general blood infection. The cerebral symp- toms appear to.be due to an increase in the quantity of the cerebro- spinal fluid, which at this period, is clear and usually entirely normal by chemical and bacteriological examination. The meningococcus has not yet localized in the meninges, but has irritated them probably through its toxic products. Thus, the first stage consists of a general sepsis plus increase in the quantity of cerebrospinal fluid. It seems that the nervous symptoms appear and grow worse with the increase in the accumulation of cerebrospinal fluid; and that after a certain SYMPTOMATOLOGY. ■ 50 degree of accumulation there is a violent outburst of meningitic nervous symptoms, corresponding to the second stage. The cerebrospinal fluid sometimes accumulates in large quantities very quickly, within a few hours, so that the second stage may set in only a few hours after the onset and entirely overshadow the first stage. I have referred to the first as the "accumulative" stage. Symptoms of Accumulative: Stage: — Diagnosis. — Many of the symptoms are of a general nature, being very much like those of influ- enza. The onset is acute, frequently with chilly feeling or a severe chill. The patient is feverish and soon begins to complain of painful throbbing frontal or vertical headache. He is restless, irritable, and vomits. The vomiting is repeated, somewhat explosive, and frequently is not accompanied by nausea. Physical examination shows a patient who may not appear ill. His mentality is perfectly clear, but he may be nervous and hypersensitive. The pupils are quite often dilated and may respond very sluggishly or fail to respond to light. Photophobia may be present. The neck usually shows no rigidity at first, but as the symptoms grow worse, some spasm appears ; though for several hours, it may be very slight and only present on anterior posterior flexion. Tenderness at the angles of the jaws may be quite marked. Herpes are quite often present, and a petechial eruption may occasionally be seen. The pulse and respiration may show no change, or there may be occasional intermitting in the pulse and the breathing may show slight irregularity especially if noted when the patient is asleep. Sigh- ing, deep and apparently uncontrollable, is quite' commonly encountered. The temperature varies considerably; sometimes it is very high from the very onset ; other times it may be low throughout. Careful exam- ination will usually enable one to demonstrate a moderate degree of hydrocephalus evidenced by the bulging fontanel in young children and by Macewen's sign in older children and adults. Macewen's sign is a dull, tympanitic note obtained on percussion of the skull at the fronto- parietal region. It is best obtained by raising the head a little, bending it slightly toward the side to' be tested, then percussing firmly over the skull with the finger. At the frontoparietal regions it is usually most clear. Both sides should be tested ; quite often it is more marked on one side. It indicates an increased collection of the fluid within the ventricles. It may be difficult to elicit this sign with any degree of certainty in older children and adults on account of the thickness of the skull. Blood examination at this stage will usually show a moderate leuco- cytosis and relative polynucleosis. After these symptoms have lasted for a variable length of time — 60 EPIDEMIC CEREBROSPINAL MENINGITIS. up to 24 to 36 hours, there is usually a violent nervous outbreak that sets in the active picture of meningitis. While some or even most of the symptoms described may be absent during the accumulative stage, one can ordinarily elicit some suggestive signs which would warrant performing a lumbar puncture. Rksumk of Important Symptoms. — 1. History of exposure to the disease, especially during an epidemic. 2. Violent headache unexplained by usual causes. 3. Repeated vomiting, explosive in character, not accompanied by any local evidence of gastrointestinal disorder, and uncontrolled by local treatment. 4. Eruption of herpes. 5. Eruption of petechia. 6. Photophobia ; hyperasthesia. 7. Dilated, sluggishly responding pupils ; sometimes failing to re- spond. 8. Tenderness at angle of jaws. 9. Signs of hydrocephalus. a. Bulging fontanel or Macewen's sign. b. Irregular pulse or respiration. A lumbar puncture at this stage will show, as a rule, a decided in- crease in the total quantity of fluid with corresponding increase in cerebrospinal fluid pressure. The fluid is usually perfectly clear and limpid, especially very early in the disease. Microscopic examination may fail to reveal any organisms or may show a few free meningococci which may be explained by the general sepsis. Cytology may be nega- tive or may show slight increase of lymphocytes. As the meningitis stage is approached, the fluid becomes slightly turbid, shows a few organisms and an increase in leucocytes. The essential impression of the fluid during this stage of the disease is certainly not that of a men- ingitis, but rather like that produced by a general toxemia. Cases of Accumulative Stage. — Case 1. Boy, aged two and one-half years. The brother had died of meningitis one day before. This patient had been in the same dwelling as his brother during the illness. Twenty-four hours after the death of his brother, the child abruptly developed a fever of 101°, vomited a number of times, became restless and irritable. The attend- ing physician could find no sign of meningitis but suspected it on account of the history of exposure. The boy was admitted to the hospital about five hours after the onset. Physical examination showed a well-formed, healthy looking child, temperature 99°, mentally clear and bright but hypersensitive. Pupils were dilated but responded well to light. The neck was not rigid. There was distinct tenderness on pressure at the angle of the jaws. Mac- ewen's sign was marked. No Kernig. No tache cerebrale. It was thought advisable to wait for further symptoms, which, about two hours later, suddenly SYMPTOMATOLOGY. 61 appeared in the form of convulsions. The temperature rose to 106°. All of the active signs of meningitis were now present. Lumbar puncture gave a turbid fluid containing many meningococci. Discussion. — The picture described on admission to the hospital cor- responded to the accumulative stage, showing all of the symptoms but no active meningeal signs. Puncture during this stage would have yielded, in all probability, a clear fluid under high pressure and treatment would have shortened the disease considerably, possibly have aborted it. Case 2. Girl, aged 19 years. No history of exposure to meningitis. On- set sudden, twenty-four hours before, with severe headache, restlessness, chilly feeling, slight temperature, which fluctuated during the day between 100° and 101°. She vomited repeatedly in an explosive manner. Physical examination the second day showed a nervous, hypersensitive patient; men- tality clear; small crop of herpes over lips. The neck was slightly spastic on bending forward; no lateral spasm; marked tenderness at angle of the jaws; Macewen slight; reflexes normal; no Kernig; no tache cerebrale. I believed that we were dealing with the accumulative stage. Lumbar puncture was performed, and 30 c. c. of faintly turbid fluid under high pres- sure were removed. Few Gram-negative cocci were found. Cells, mostly leucocytes, were slightly increased. Twenty c. c. of serum were injected. The patient made a rapid, uninterrupted recovery without further treatment, and was discharged as well four days later. Discussion. — This patient, when observed on the second day, was in the accumulative stage as it was passing into the explosive stage. Localization of the meningococcus in the meninges had begun, though the active signs of meningitis had not yet set in. Case 3. A woman, aged 50. Three days after she had visited a friend who was suffering from meningitis, she suddenly experienced a very severe chill, followed by high temperature. She vomited a number of times. Head- ache was very intense. Physical examination, twelve hours later, proved the patient to be in good general condition. She was irritable and hypersensi- tive, but mentalitjr was clear; Macewen uncertain; pupils dilated, responding sluggishly to light; very slight antero-posterior spasm in neck; tache cere- brale moderate; no change in pulse or respiration; very profuse petechial eruption all over the trunk and extremities; temperature 103°. Lumbar puncture gave a clear fluid (40 c. c.) under high pressure. 15 c. c. of serum were injected. Examination microscopically failed to show any bacteria or increase in cellular elements. Twenty-four hours later, all of the symptoms became more marked, and active meningeal signs developed. The cerebrospinal fluid was now turbid and contained many meningococci and pus-cells. Discussion. — This case was a typical illustration of the accumulative stage. The patient was suffering from symptoms of general sepsis plus some pressure signs. An important feature of this case was the fact that an ex- amination of the urine at the time of the first lumbar puncture yielded many meningococci and pus cells. B. Active Stage of Meningitis. — I. Symptoms op Sepsis. — Onset is acute with active symptoms, such as have been described in the accu- mulative stage. 62 EPIDEMIC CEREBROSPINAL MENINGITIS. Chills most often occur at the onset of the disease as severe rigors. The percentage of cases having rigors varies in different epidemics. About 20% of 185 cases I studied in Dallas had the initial chill. Re- peated chills are less common, occurring in less than 3% usually. The chill is most frequently experienced during the first few days of the illness. The following charts illustrate the irregular course of the disease in cases not affected by treatment. Name \gt Date 191 . / 2. 4 s i 7 z PuUe Reap. 2 6 iO 2 6 10 2 6 2 6 10 2 6 10 2 6 10 2 6 10 2 6 10 2 6 10 V •P 6 , >' ,5 J2 V' , \ \ &' K 4 V \ •l ,i m y v. 7 s An 3 W I '^l \ v A 1 1 g> "i ^4 1 i ■ NORMAL ■■ s 1 tA ^ 98 *M ,/« ». j \ .M \i \ JT \ r i> C D — . — ,. ., 96 95 Chart II. Child aged 6. A very fulminating case. Child died in 36 hours after the onset; for the most part the fever being sub-normal, at no time being over 99.8 degrees. Fever in meningitis is extremely irregular and of absolutely no diag- nostic significance. The most common curve is irregular, remitting, fluctuating between 101° and 103°. Very high pyrexia, so-called cere- bral temperatures of 105° or 106°, rising suddenly and dropping just as suddenly several hours later, are quite common. The characteristic feature of the fever in meningitis, treated or untreated, is the extreme irregularity of the curve, regardless of the course of the disease. T have not infrequently seen active meningitis in young, robust indi- viduals run afebrile for several days or longer at the onset, then run SYMPTOMATOLOGY. 63 a low, irregular curve up to 101° or 102°. Other times the temperature may remain afebrile for several days, the cases terminating in death. Some cases show this irregularity changing from afebrile periods to periods of moderate or high temperature without -affecting the prog- nosis per se. Others run a uniformly even temperature of 103° or 104° for days, coming down by lysis or crisis, depending upon the response to treatment. Older patients of sixty or over are very apt to run a subnormal course throughout. Children usually run a higher temper- ature than adults. Name Age Dab / 2, 3 4 s 4 7 * /O ' i 2 6 '0 2 6 10 2 6 10 2 6 10 2 6 "0 2 6 10 2 6 K ! 2 V 10 2 I 10 2 6 10. •« 6 10 106 — 4r# ( * Si f m<* 105 104 103 102 101 * M ■f'A J 1 i "5-- ■4—$-- rtm i=< H — -4 100 99 NORMAL 98 97 96 n — — 5 — i ^7 * - d 1 95 Chart III. Child aged 6. A septic case accompanied by septic irregular temperature which rose to 107 degrees before death. The course of the fever is very considerably influenced by specific serum treatment. In the chapter on "Treatment" are seen the curves in cases re- sponding to serum treatment. Eruptions of herpes are very common, especially in some epidemics. In the Dallas epidemic they occurred in about 50% of the cases. They usually appear at the very onset of the disease in small or large crops, most commonly over the lips and chin. Less often they are noted in other sites as over the cheeks, ears, neck, trunk, eyelids, cornea, over 64 EPIDEMIC CEREBROSPINAL MENINGITIS. the knees and anterior pillar of the fauces. The contents are at first serous, but later become purulent. Quite often a number of fresh crops develop, during the disease, at or near the original site. Other times repeated, successive crops of herpes develop over different parts of the body. Occasionally the new crops are accompanied by some fever and general constitutional symptoms. One patient, a girl of fifteen, who was convalescing from meningitis, suddenly developed high temperature — 104°, with restlessness, some general symptoms, but no aggravation of her meningitis. Examination revealed some enlarged, tender cervical glands. The throat, of which there was no subjective complaint, displayed a large crop of herpes over the anterior pillar of the fauces. The following day the temperature dropped to normal. A few days later the fever rose to 103°. This time there was a large crop of herpes over one knee. About three days later a fresh crop appeared over the same knee again accompanied by fever. Herpes is considered of favorable prognostic value in some diseases. There apparently is no such significance in meningitis. Petechia. — Petechial eruptions appear to be much less common now than formerly. In the Dallas epidemic only about 5% of 185 cases under my observation developed the eruption. The petechia are usually small, some of the spots having white centers. As a rule, the eruption is very profuse, though there may be only a few scattered spots. It appears very suddenly, and is distributed all over the trunk and ex- tremities. It is occasionally seen on the palms of the hand and the soles of the feet, and in a small percentage of cases in the eyelids. Petechia are probably bacterial in origin and indicate a bacteremia. Such is the case clinically. Petechial cases are very severe. The pa- tients are very septic and are very prone to run a rapid, fulminating course. Purpuric eruptions are much less common than the fine petechial ones. I saw them in less than one per cent of several hundred cases. They may occur in any part of the body, but are most frequently en- countered on the extremities. Erythematous eruptions, which may consist either of a diffuse erythema, or of a papular erythema, are occasionally observed. This type of eruption, distinct from that due to serum sickness, is very un- common in my experience and is of no particular diagnostic signifi- cance. Osier described a livid erythema, accompanied by vesicles filled with blood, as occurring sometimes on the extremities. Conjunctivitis. — Conjunctivitis is so common in meningitis, occur- ring frequently at the very outset of the disease, that it may be classified as in the regular symptom-complex rather than as a complication. It SYMPTOMATOLOGY. 65 may appear before the development of the active meningeal symptoms, but is usually seen a short time after the disease has become well es- tablished. The secretion is purulent and contains many meningococci, intra- and extracellular. This inflammation, unlike the gonococcus, is benign and subsides spontaneously. Mental Symptoms and Symptoms of Meningeal Irritation. — The important diagnostic symptoms in meningitis are the mental symp- toms, and those of meningeal irritation. They appear early in the dis- ease, and are very distinctive, and frequently enable one to establish a differential diagnosis between epidemic and other forms of meningitis. The usual, characteristic mental state is one of irritability and hyper- sensitiveness. The mind may remain clear throughout or may be dis- turbed by periods of delirium. Delirium is usually very active and in adults is frequently of the wild, maniacal type suggestive, at times, of delirium tremens. The periods of delirium are often very short, the mentality being perfectly clear in the interim. The whole mental pic- ture is thus one of hyperexcitability. This feature is even evident in the very late stage of meningitis. With the advance of the disease, frequently associated wth increase in hydrocephalus, stupor sets in and progressively increases. Even in the very deep stupor, how- ever, the patient responds and is hypersensitive when disturbed. A curious and somewhat unusual mental state is one suggestive of typhoidal insanity. I saw two striking cases of such disturbance which occurred late in the disease when the active meningitis was practically over. In both, this flighty mental condition persisted well into conva- lescence for several weeks, then suddenly cleared up. In each case there was a marked simple hydrocephalus. I am inclined to believe that the cause here, as in typhoid, is probably toxic, possibly aggravated by the simple hydrocephalus. Recapitulation, — In the early stages especially, the characteristic feature of the disease is a hyperactive, hypersensitive mental state, which is frequently undisturbed otherwise except for occasional periods of delirium. As hydrocephalus increases in the later stages of the disease, the patient becomes stuporous, later comatose. Even when very stuporous, however, the patient will respond upon being disturbed. The symptoms above described include some of the more important ones of sepsis in acute meningitis. The symptoms next to be consid- ered are those due to 1. Meningeal Irritation and 2. Hydrocephalus — Accumulation of Fluid within the Ventricles. Headache is constant and a very bitterly complained of symptom throughout the whole course of the disease. It is most often referred 66 EPIDEMIC CEREBROSPINAL MENINGITIS. to the frontal region or vertex. Sometimes, especially in women, it is localized in the occiput. The patient protests that his head is split- ting and begs for relief, even asking for lumbar puncture if relief had already been experienced by that means. Photophobia is a common and annoying symptom from the very onset. Convulsions are noticed most often in young children, in whom they may usher in the disease. They are absent in many cases of older children and adults. Where the disease is progressing unfavorably and is accompanied by a steadily increasing hydrocephalus, general clonic and tonic spasms frequently occur. At the onset of meningitis, convulsions are usually general and clonic in character. Later in the disease, local spasms affecting different parts of the body are more common. Here also clonic spasms are present, frequently followed, however, by tonic spasms lasting for hours. In children under one year of age, convulsions are of very significant diagnostic importance. If tetany can be excluded, one should be very suspicious of meningitis. Twitching is observed most often late in the disease, and acts very much the same way as the local convulsion. General bodily pain grippal in character is quite common at the onset. With the development of more active meningeal signs, pain is referred, principally to the back of the neck and along the spine. Rigidity of the neck is one of the most important diagnostic symp- toms. It is an early and constant sign, persisting throughout the en- tire course of the disease. In the very early accumulative stage, rigidity of the neck is absent, or there may be a little antero-posterior spasm on attempting to flex the head. As active meningitis sets in, the neck becomes rigid and fixed, and attempts to move the head in any direction are resisted and cause considerable pain and spasm of the posterior group of neck muscles. A good way to test this sign, espe- cially in young children, is to place the hand under the occiput and to raise the head gently. If rigidity be present, one can usually raise the head and trunk without flexing the neck. Varying degrees of retrac- tion of the head accompany the neck rigidity. At times, chiefly in the cases of posterior basic meningitis, there is extreme retraction of the head, the occiput almost touching the spine. The rigidity of the neck, the spasm and retraction of the head usu- ally subside with improvement in the disease. There is a "limbering- up" of the neck muscles, and the patient begins to move his head around, at first very cautiously, then freely. Not infrequently, how- ever, the rigidity of the neck with opisthotonos persists well into conva- lescence and disappears very slowly. There seems to be a considerable SYMPTOMATOLOGY. 67 element of fear that prolongs the spasms in these cases. In the last moribund stage of the disease, there is complete relaxation of the neck as elsewhere. Rigidity and bowing of the spine go hand in hand with the rigidity of the neck. Tenderness on pressure at the angle of the jaws is an early sign of some diagnostic importance. Kernig's sign, like the neck sign, is a very early and constant symptom and is of very considerable relative diagnostic significance though present in other forms of meningitis. It is of little value in children under two years. The test is made by flexing the thigh on the abdomen, then attempting to flex the leg on the thigh. In most normal individuals the legs can be fully extended, though in some this can be but partially accomplished. In such instances, however, one is simply unable to extend the legs fully, while in meningitis there is a sudden sharp spasm of the hamstring muscles, accompanied by acute pain referred usually to the back of the leg and thigh, sometimes to the lumbar regions. Thus in meningitis cases during the active stage, it is often impossible to extend the leg more than at right angles. I have tested this sign several thousand times in meningitis cases and have found it positive in 95% of the cases. As the disease declines, the sign becomes less pronounced. In the last moribund stages, there is relaxation here as elsewhere in the body. Vasomotor Phenomena. — Tache cerebrate is an erythema that ap- pears quickly on slight irritation of the skin, well obtained by gently scratching the skin. This sign is only of minor, relative diagnostic importance. Other vasomotor phenomena, such as spontaneous flush- ing and perspiring of different parts of the body, are quite commonly seen, especially in cases with marked hydrocephalus. Vomiting occurs in most cases at the onset. The characteristic feature is the fact that it appears causeless, that nausea and other evidence of gastrointestinal disorder are usually absent. As hydrocephalus increases, vomiting becomes projectile and almost uncontrollable. Bowels are often very constipated. Pupils are most often dilated, sometimes irregular, responding slug- gishly or failing to respond to light. Severer Pressure Phenomena. — Pulse. — The pulse rate in menin- gitis is very irregular and is apparently independent of the amount of intracranial tension, temperature, or general condition. At times, it is very slow at fifty or under. Most often, however, it is rapid, aver- aging over one hundred. It is astonishing how comfortable and in what seemingly good condition patients having a tacchycardia up to 68 EPIDEMIC CEREBROSPINAL MENINGITIS. 160, will appear. Irregularity and intermitting of the pulse are early signs of considerable diagnostic value. Irregularity in Respiration. — Respiration is most markedly affected by increasing intracranial tension. Many observers have studied this important change. Biot in 1878, described a type 'of respiration, which has since been called Biot's breathing, and which by older authorities had been called cerebral breathing. He considered the breathing to be characteristic of meningitis as against other cerebral conditions with respiratory disturbance. According to Biot, the "meningitis rhythm" lacks the rhythmical alterations of periods of apnea and periods of gradually increasing and decreasing respiratory movement, which is the essential feature of the Cheyne- Stokes type. The respiratory pauses occur at irregular intervals, and the individual respirations showed constant variability as to both size and rate. Connor and Stillman studied forty-three cases of meningitis, mak- ing graphic tracings of the respiratory movements. Thirty-two of the cases were tuberculous meningitis, and in all, respiratory irregularities were observed at some time during the illness, and usually during the greater part of it. Of the remaining eleven cases, six were of the epidemic type, four were secondaty streptococcus meningitis, and one was acute syphilitic basic meningitis. Two of the cases, both epidemic meningitis, failed to show the respiratory irregularities. One was a very mild case recovering in a few days ; and the other was a child who was very restless and had constant twitchings, making it impossible to get satisfactory tracings. According to these authorities, respiratory irregularities appear early in meningitis. They divide them into the 1. Cheyne- Stokes type. 2. Biot's meningitic type. 3. An undulatory type. Cheyne-Stokes type was observed in 53% of the meningitis cases. Biot's breathing also occurred in 27% of these cases. Biot's breathing is characterized by: 1. Periods of apnea of varying length and occurring at irregular intervals. 2. Constant irregularity in the rhythm and in the force of the individual respirations. 3. The frequent occurrence of deep sighing respiration. Biot's breathing was encountered twice as frequently in adults as in children, while the Cheyne-Stokes type was present almost twice as often in children as in adults. SYMPTOMATOLOGY. 69 They particularly called attention to the occurrence of deep sighing, saying that in their experience, it is rare in conditions other than menin- gitis. It was observed in a great many cases and was of consid- erable relative diagnostic significance. The undulatory type differs from, the other two types of breathing in that the apnea does not constitute a feature. This form of respira- tory disturbance was seen at some time in the course of almost every case. In discussing the diagnostic value of respiratory irregularities in meningitis, they state that irregularities occurred in 95% of cases of meningitis studied. Of the three types of arrhythmia, Biot's is un- questionably the most nearly pathognomonic of meningitis. In making tracings of several hundred patients, both adults and chil- dren, suffering from different diseases, they met it in only one case not meningitis. Most of the respiratory irregularities observed occurred when the patients were in a state of stupor or coma, but there were a number of exceptions to this rule. Incidence of Biot's type in the tuberculous cases was distinctly less than in the non-tuberculous cases, there being five instances of it among the thirty-two tuberculous cases, and four among the eleven non-tuber- culous. Biot's breathing was observed four times among the thirteen adults, or 30%, and five times among the thirty infants and children, or 17%. In a very large experience with epidemic, tuberculous, and other forms of meningitis, I have always considered respiratory irregularity as an important diagnostic and prognostic symptom. It has usually been absent in cases without appreciable hydrocephalus ; i. e., in cases with little fluid. I have found it to be one of the most significant signs of hydrocephalus, indicating lumbar puncture for relief of pressure. The most common irregularity occurring early in the disease has cor- responded to the undulatory type described by Connor. Biot's type, usually called cerebral breathing, is of very considerable prognostic importance. I have seen it frequently in all types of meningitis, but never in any other disease. It has occurred late in the disease and was usually indicative of a hopeless outlook. Of several hundred cases that I studied, I have record of only one case of epidemic meningitis that recovered after this type of breathing had developed. Bulging of the fontanel in young children occurs with hydroceph- alus and is the most important physical sign of this condition. The fontanel is full, sometimes extremely tense. Crying causes the fulness to become more pronounced. Regular pulsation may be present. Ex- ternal heavy pressure over the bulging occasions considerable pain ; if 70 EPIDEMIC CEREBROSPINAL MENINGITIS. continued, it produces stupor, convulsions, respiratory pressure symp- toms, and death. Macewen's sign is of the same significance as the bulging fontanel. 3. Symptoms op Meningitis Due to Local Nuclear Involve- ment. — The more extensive lesions due to nuclear involvement are sufficiently uncommon to be classed rather as complications. The more common paralyses occurring early in the disease are those of the eye muscles. Strabismus, due to paralysis or spasm, is of very frequent occurrence, sometimes being one of the early subjective symptoms, as evidenced in the patient's complaint of double vision. It is usually divergent and very transient, though it sometimes persists after re- covery. The appearance and disappearance of the squint seems to depend upon the degree of hydrocephalus. Slight facial palsy is also quite common, but likewise very transient. Other combinations of paralyses will be described under "Complications." Reflexes. — Reflexes are very irregular. The knee-jerks and ankle- clonus are frequently exaggerated early in the disease, and later, lost, Exceptions are very common, however. The plantar reflex is usually lost. A somewhat constant feature is the loss of the abdominal reflex — a fact that has been explained as due to early involvement of the lower part of the cord. Oppenheim's sign has been said by some to appear regularly in the disease. I have found it to be of very irregu- lar occurrence and of no diagnostic significance. The Babinski reflex is not obtained usually. It occurs sometimes late in the disease, espe- cially in posterior basic meningitis. Absence of Babinski's sign is thought to be due to anemia of the cord caused by hypertension of the cerebrospinal fluid. Brudsinskr 's Sign. — Two forms of this are described. The one is called "reflex contro-lateral identeque." In this, when the patient is supine with both legs extended, it is found that on flexion of the leg and thigh of one side upon the abdomen, the other leg follows suit the moment the thigh touches the abdominal wall. If this is not obtain- able, the second form, "reflex contro-lateral reciproque," may be found. In this case, one leg and thigh being flexed as before and the other extended, it is found that when the flexed limb is lowered to the ex- tended position, the opposite limb undergoes, in turn, flexion on thigh and abdomen. De Lepinay describes a clinical test called the "Signe de la Nique." To obtain the reflex the neck is bent forward and it is found that the lower limbs at the same time become flexed at the knees and on the abdomen. This sign is said to be present in 97% of the cases. Tt is, however, only of relative diagnostic importance. In forcibly flexing SYMPTOMATOLOGY. 71 the neck which is painful and stiff from any cause, there is also this tendency to flex up the lower extremities. Classification of Acute Form of Meningitis. — I. Usual form. II. Abortive form. III. Fulminating form. 1. The usual form of epidemic meningitis seen is a composite pic- ture of the symptom-complex described. Collective Description — History. — The history may be of ex- posure to some other cases of meningitis or to a possible carrier. Previous Disease. — Frequently, an immediately preceding common cold ; alcoholic debauch sometimes ; other times no history of previous illness. Onset. — The onset is acute, with chilly feeling or real chills and fever, general bodily pain and vomiting. Headache is frontal or re- ferred to the top of the head, is constant, and becomes more and more severe. As the disease progresses, vomiting becomes more frequent and may be more projectile. The patient complains of vertigo and sometimes of double vision. He becomes restless and irritable. This symptom-complex conforms to the first stage. Examination at this period will show a patient with normal, clear mentality, frequently restless and irritable. Herpes is common, and petechial eruption may be present. Pupils are frequently dilated, respond poorly or not at all to light. Diplopia is rather common. Macewen's sign or bulging fontanel can be determined toward the end of this stage. There is often distinct tenderness on pressure at the angle of the jaws. There is tenderness on percussion of the skull. There may be no> neck rigid- ity, or later there may be a little antero-posterior spasm. Tache cere- brale is present. No Kernig ; reflexes are usually increased. Leu- cocytosis is present. Lumbar puncture gives a clear fluid under high pressure. The fluid may show nothing else abnormal or may exhibit a slight increase in cellular elements or a few free bacteria. Temper- ature as described is usually very irregular; most often it is elevated. These symptoms gradually, ofttimes abruptly, merge into those of the second stage. Second Stage. — The patient may suddenly develop general, re- peated convulsions. He becomes much more hypersensitive and irri- table, and is irrational at times. Sudden, complete unconsciousness, accompanied by extreme restlessness and delirium 1 , may set in. Head- ache is marked and unbearable. Vomiting ma}^ be repeated. He now complains of severe pain in the back of his neck, his spine, and his legs, as well as stiffening o>f the neck and inability to move it. Pho- 72 EPIDEMIC CEREBROSPINAL MENINGITIS. tophobia may be marked. He becomes very weak and intensely pros- trated. Physical Examination. — Physical examination shows a greatly prostrated, extremely irritable, hypersensitive patient, at times actively delirious with deep stupor. But even in this stuporous condition, he usually responds upon being disturbed. He lies with his head re- tracted. Has expression is anxious, and color frequently cyanosed. His neck is very rigid and resists movement of the head in any direc- tion. There is pronounced tenderness on pressure over the posterior cervical muscles. Pupils are usually dilated and either respond poorly Fig. II. Patient actively ill six days with epidemic meningitis. She was apathetic but otherwise clear and responded to questions. Note the anxious expression; the retraction of the head; the dilated pupils; the right facial paralysis; right external strabismus, and the sordes on the teeth. or fail to respond to light. Very commonly strabismus (external rectus) is present. Tenderness on pressure at the angle of the jaws is distinct. Macewen's sign or bulging fontanel is pronounced. Ten- derness is exquisite on percussion of the skull. Tache cerebrale is prompt and marked. Kernig's sign, often at 90°, is very evident. Ab- dominal reflex is frequently missing. Deep reflexes are most often absent, other times accelerated. Respirations are frequently slowed and irregular, usually showing in early stages, the arrythmia described by Connor. Pulse is usually rapid ; other times very slow and fre- quently shows distinct irregularity. Partial deafness is rather common at this period, probably due to hydrocephalus. Other palsies described SYMPTOMATOLOGY. 73 may be present. Temperature may be very high and septic. It may be high continuously, or low, ranging only a little above the normal. Blood-pressure is usually raised. Lumbar puncture and laboratory examination show the typical condition described. As the disease subsides, vomiting ceases, headache and vertigo improve, and the general condition becomes wonderfully changed. Pressure signs and signs of meningeal irritation rapidly decline. Type Acute Cases. — Three members in one family. Case 1. Mother, aged thirty. Acute onset with severe chills; violent, frontal headache; vomiting and high fever. After a few hours she began to Fig. III. Boy of eleven, ill forty-eight hours with epidemic meningitis. He was ac- tively delirious so that he had to be held for the photograph. Note the posture. The head markedly retracted, back bowed. complain bitterly of pain in the back of her neck, in her back and legs. Physical examination on the second day revealed a very hypersensitive, slightly delirious patient; head retracted; neck very stiff; Macewen's sign marked; pupils dilated, irregular, with no response to light; large crop of herpes over lips; tache cerebrale marked; Kernig marked; abdominal reflex, plantar reflex, and other deep reflexes not obtainable; pulse 120, irregular; temperature 100°; marked tenderness to pressure at the angle of the jaws. Lumbar puncture proved the diagnosis. Serum was administered. There was prompt improvement in all symptoms. Temperature continued at nor- mal after the third day. She was discharged as well two weeks after ad- mission. Case 2. Son of above patient became ill four days after his mother. The attack was very acute with a violent chill, marked prostration and symptoms of collapse. Cyanosed; pulse rapid, weak; vomited repeatedly; complained 74 EPIDEMIC CEREBROSPINAL MENINGITIS. of intense headache and of abdominal and general bodily pain. A few hours later he became very delirious. He was admitted to the hospital in collapse; pulse 140, weak, intermitting; neck very rigid; Macewen very marked; pupils very widely dilated and fixed; ptosis of left upper lid, slight external strabismus; marked tenderness at the angle of the jaws; respiration, deep, sighing, slow and irregular; Kernig marked; reflexes lost; skin was covered with a widely scattered, profuse petechial eruption; herpes over upper and lower lips; temperature 105°. There was gradual response to serum treatment. A simple hydroceph- alus, accompanied by high intermitting temperature, persisted for a month after the infective meningitis cleared up. Fig. IV. Alcoholic patient, ill thirty-six hours with epidemic meningitis. Violently delirious and deeply stuporous at intervals. Note the blank expression and the rigidity of the neck. Case 3. Father of above case, aged 40. He had insisted upon visiting his family and, in addition, had been imbibing regularly to drown his misery, he said. One afternoon on visiting the hospital, he was somewhat under the influence of liquor, but otherwise seemingly well. Twelve hours later he was found unconscious and wildly delirious in his home. He was promptly admitted to the hospital. Physical examination showed a maniacal, delirious patient whom it was impossible to hold. He kept shouting and fighting for a number of hours. Head was retracted and very rigid. The pupils were irregular, dilated, and fixed. Macewen's sign could not be determined. He was acutely tender at the angle of the jaws. There was a slight left facial palsy. Pulse was rapid, occasionally intermitting. Kernig and tache cere- brale were marked; knee-jerks very much exaggerated; abdominal reflexes lost; temperature 104°. This man also promptly cleared up under treatment. SYMPTOMATOLOGY. 75 He was up and about a week later, though he had a number of inflamed joints that somewhat retarded convalescence. Case 4. Man, aged 40. On the day before the onset had attended business but was not entirely well. He felt chilly, had headache, complained of gen- eral bodily pain and pain in the back. He had been suffering from a cold for some time, and attributed the symptoms to grippe. He was restless during the night, and toward early morning suddenly became violently delirious. He was at once removed to the hospital. Examination showed a wildly delirious patient. The neck was markedly rigid. Pupils were widely dilated, no re- sponse. Macewen's sign could not be determined. There was distinct ten- derness at the angle of the jaws. Kernig was pronounced. All reflexes were apparently lost. Pulse was 140, intermitting. Respirations, during quiet Fig. V. Patient violently ill with acute epidemic meningitis. Markedly stuporous and delirious ; head retracted and very stiff. intervals, were slower and showed long periods of intermission. Temper- ature was 105°. Lumbar puncture gave a turbid fluid under very high pres- sure and showed many meningococci. Serum was administered. The follow- ing day the patient was rational, but complained of severe headache, vertigo, and double vision. He was punctured that day and on the two succeeding days. All the symptoms subsided, and the patient was up seven days after admission to the hospital. During convalescence he complained of intense weakness and, for a time, continued to lose flesh. These late symptoms are frequently observed during convalescence. Abortive Epidemic Meningitis. — The abortive form of menin- gitis has had but scant attention in the meningitis literature and for very good reasons. Positive diagnosis in epidemic meningitis can only 76 EPIDEMIC CEREBROSPINAL MENINGITIS. be definitely made by finding the meningococcus in the cerebrospinal fluid. In most cases, one is inclined to postpone lumbar puncture until meningeal symptoms are distinctive. Thus, diagnosis is confirmed only in definite, clinical cases that run the usual course. An abortive form of epidemic meningitis may be described as a form in which the disease is spontaneously checked, before it becomes advanced and causes the usual severe symptoms. These cases undoubtedly exist in epidemic meningitis just as they do in the similar condition of poliomyelitis. In a classification of an abortive form we must include only those forms that have been checked before the development of active meningeal symptoms. In meningitis, judging etiologically at least, this stage must be during the period, and only shortly after, the meningococcus septi- cemia has set in. The first stage corresponds very well with the description of the "Accumulative Stage." Theoretically, there is every reason to suppose that cases of menin- gococcus septicemia, without subsequent severe involvement, occur. Clinically, a case which I shall cite, will, I believe, bear this out. To recapitulate, the symptoms of abortive cases are those of mild, general sepsis with possibly some signs of meningeal irritation. Case 1. Woman, aged thirty-five, had an acute onset with chill and moderate fever. She vomited several times and had a severe headache. In a tew hours she began to complain of pain and discomfort in the back of the neck and spine. There was, however, no impairment of motion in her neck. About twelve hours after the onset she called her physician, who suspected epidemic meningitis and performed a lumbar puncture, removing a few cubic centimeters of clear fluid under slightly increased pressure. No serum was injected. A few free' Gram-negative cocci that failed to grow were reported as being found in the fluid. She was sent to the hospital about an hour after the puncture. Examination at this time showed a well-nourished woman; general condition good; mentality clear; no irritability; slightly hypersensi- tive; pupils slightly dilated. There was a little spasticity of the neck antero- posterior^, but it could be moved after the first slight spasm. Macewen could not be determined; tenderness marked at the angle of the jaws; no Kernig; reflexes exaggerated; no tache; pulse and respiration normal; tem- perature normal. Nose culture yielded the meningococcus. She was dis- charged from the hospital 48 hours later, no further symptoms having de- veloped. Discussion. — This was undoubtedly an abortive case of epidemic menin- gitis. A study of this history will show that these cases may easily be over- looked as grippe during an epidemic. The following case belongs to the abortive type of meningitis, but must be classified as "aborted" meningitis, since it was serum treated. Case 2. Man, aged twenty-two. Sudden onset about 18 hours before ad- mission to the hospital with severe chill, violent headache, and repeated vomiting. Temperature was 104°, in the course of the day dropped to 101°. SYMPTOMATOLOGY. 77 The patient complained of general bodily pain, localized after a number of hours especially in the back and legs. On admission, the general condition was good. He suffered from very severe headache, was irritable and restless. Complained of nausea and dizzi- nsss on turning from side to side or on attempting to sit up, together with rapid lateral nystagmus. Macewen was present. Pupils were slightly dilated, reacting well. Marked tenderness at angle of jaws; very slight anteroposte- rior spasm of the neck; pulse and respiration negative; no Kernig; slight tache cerebrale; reflexes active; few petechial spots over trunk; physical examination otherwise negative; temperature 101°. Lumbar puncture gave clear fluid (30 c. c.) under moderately increased pressure. 20 c. c. of serum were injected. Examination of the cerebrospinal fluid yielded a few free organisms — no adventitious cells. On the following day there was a sub- sidence of symptoms. The temperature was 101° but dropped to normal in 48 hours, when the patient felt well with the exception of slight headache and vertigo upon turning from side to side. Nose and throat culture was positive. After local treatment and uro- tropin internally, it became negative. He was discharged from the hospital four days after admission still complaining of occasional, slight vertigo. This corresponds to the accumulative stage. Diagnosis was proved by finding the organisms in the cerebrospinal fluid. It is a question whether this case might have aborted spontaneously or whether the serum aborted the disease. I am inclined to the latter view, principally because there was evi- dence of considerable local and meningeal irritation as judged by the large quantity of cerebrospinal fluid. An interesting feature was the symptom of vertigo on turning the head from side to side. Hydrocephalus was probably the cause. Fulminating Type. — This is the most malignant form of menin- gitis. It runs a very acute course and kills the patient frequently in from a few hours to a day. The picture of this disease is not so much that of a meningitis, but rather of a violent general sepsis that utterly overwhelms the patient, causing complete collapse. Clinical observa- tion and postmortems bear out the fact that it is the general sepsis that kills ; the local meningitis process may be very mild. This group is made up, in greater part, of the petechial and purpuric cases. The onset is very acute with chills and very rapid progression of symptoms, the patient looking and becoming very septic and rapidly going into collapse. The patient is frequently very cyanosed, the skin mottled, cold, and covered by a very profuse petechial and purpuric eruption. Pulse is weak and very rapid; respiration rapid and labored. Menin- gitic symptoms may be very mild. In many of the petechial, fulmi- nating cases that were sent to the hospital, lumbar puncture had to be postponed for a number of hours while the patients were being actively stimulated. I have noticed that if these septic, petechial, fulminating cases can be tided over the first 24 or 36 hours, they will respond and then run the course of the average case of epidemic meningitis. It 78 EPIDEMIC CEREBROSPINAL MENINGITIS. would appear that if the patient can survive the immediate shock of the overwhelming bacteremia that he may overcome the bacteremia in a very short time. This is analogous to the bacteremia seen in lateral sinus thrombosus, in which a blood culture will show plates overgrown with the streptococcus ; and after the operation of opening and draining the sinus and possibly tying off the jugular, the bacteria in the blood will disappear almost immediately, so^ that a blood culture only one-half hour after the operation will yield only a few colonies or be entirely sterile. Case 1. Eoy, aged eighteen, laborer, strong and robust, had gone to work in the morning, thinking he had grippe. He felt worse during the day, but kept at his work. In the afternoon, about seven hours after the onset, he suddenly collapsed. Examination showed a cyanosed intensely septic-looking patient in complete collapse. He vomited a few times. Pulse was 180, very weak. Respirations numbered 34 and were regular. He had a very profuse petechial eruption all over the body; a number of petechia were in his lower eyelids, a few in the buccal mucosa. His neck was only slightly rigid. Ker- nig was slight. In spite of all treatment the patient grew rapidly worse and died in one hour. Lumbar puncture gave a faintly turbid fluid, moderately increased in quantity and showed a few meningococci and pus-cells. Case 2. Child of six. History and course were very much like that of the previous case. She died twelve hours after the onset. Post mortem showed only a very slight meningitis. Case 3. An old woman of sixty became ill at nine in the morning and died four hours later. She was intensely septic and in severe shock. She was covered with a profuse petechial and purpuric eruption. Had practically no meningitic symptoms. She acted throughout as if she were suffering from a severe general sepsis. Post-mortem puncture gave almost a clear fluid in which were a. few meningococci. Case 4. Wife of physician became acutely ill with chill, severe headache, some fever and vomiting. The symptom-complex at first was believed to be due to grippe. After eighteen hours, however, she was very acutely ill and in decidedly poor condition. Physical examination revealed a patient in poor general condition; conscious but irrational; cyanosed; extremities cold and clammy; pulse rapid and weak, but regular; respiration accelerated, but regular. The trunk and extremities were covered by a very profuse petechial eruption, which the husband insisted had not been there two hours before at his examination. The neck was slightly spastic antero-posteriorly, no lateral fixation, no Kernig, reflexes active. Faintly turbid fluid was obtained under moderate pressure. There was a moderate increase in leucocytes, but no definite meningococci could be found, although there were a few suspicious- looking cocci in the smear. Her urine, however, had a number of pus-cells and was loaded down with meningococci. The patient was actively stimu- lated. Twenty-four hours later, the general condition was very much im- proved, although meningeal symptoms were much more evident. The neck was appreciably more rigid, and Kernig was marked. The fluid now was SYMPTOMATOLOGY. 79 turbid and contained many meningococci. She progressively improved under serum treatment. Discussion. — When first seen, this patient was a fulminating petechial case. She was evidently suffering from a violent general sepsis, so that even her urine contained many organisms. No active meningitis had yet set in. After twenty-four hours there was a clearing up of the general sepsis with marked general improvement, even though localization had occurred in the meninges and she was suffering from a pronounced meningitis. CHRONIC MENINGITIS. This stage of meningitis is simply a continuation of the acute stage and similarly has a group of symptoms due to sepsis, menin- geal irritation, pressure symptoms, and local paralysis. It is char- acterized principally by its slow, irregular, lingering course, the tendency to gradual but steady aggravation in the condition, ex- treme emaciation, and severe cerebral pressure symptoms. ■ This form of meningitis was the classical type of the disease formerly described in textbooks. Since the advent of specific serum therapy, it is relatively uncommon, and occurs now usually in untreated cases or in incompletely treated cases. It is a great pleasure to see this dreadful picture of meningitis becoming less and less fre- quent as we learn more about the clinical and pathological picture of meningitis and the methods for employing the specific serum in the disease. Septic phenomena are very much less active in the chronic stage. The general experience with epidemic meningitis is that the septic phenomena either kill quickly or subside quickly. This is borne out by examinations of the cerebrospinal fluid, which shows few organ- isms and little change in cytology in the chronic condition. The symptoms of sepsis are thus mild and irregular. Fever is extremely irregular in this condition. It may be en- tirely absent or subnormal. It may remain normal for days or weeks at a time, then suddenly rise very high and run an irregular, intermitting curve for a few days, coming down to normal again. Other times there is an irregular curve, running daily between 101° and 103° for weeks. One case, under my observation, ran a tertian malarial fever curve up to 104° every third day, reaching normal in twelve hours. Malaria was ruled out by repeated examinations. Chills may occur irregularly. Emaciation is the constant feature of this stage of the disease. It is curious to note that the general nutrition, as a rule, remains remarkably good during the acute stage. As the disease continues, 80 EPIDEMIC CEREBROSPINAL MENINGITIS. however, evidences of the most profound nutritional disturbance develop. Patients will take large quantities of nourishment and apparently digest the food well, but appalling wasting continues steadily, reducing previously well-nourished bodies to skin and bones within a short period of days. This state, however, does not necessarily intimate a fatal issue. It is astonishing to see patients reduced to skeletons and who appear as a living death, linger for weeks at a time and ultimately recover. I shall never forget one Name Age_ Date 191_ Chart IV.-A. Man aged 50. Illustrates the very irregular febrile curve in a lingering subacute case of meningitis ultimately terminating in death. The febrile curve was no index at any time of the patient's general condition. patient, a girl of seven, whom I saw several years ago. She was in the advanced chronic stage of meningitis, suffering from severe hydrocephalus and pressure symptoms. She was almost completely unconscious and terribly emaciated. She continued in this condi- tion for weeks. It was sometimes difficult to determine whether she were still living. After a time, the nurses and doctors in attendance prayed that she be released by death. This patient ultimately recovered. SYMPTOMATOLOGY. 81 It is difficult to explain this profound, nutritional disturbance except by some vital affection of the centers of the central nervous system. A similar tendency to emaciation is not infrequently seen in acute cases of meningitis during convalescence. Hydrocephalus, caused by an excessive collection of only mildly infected fluid, is the principal pathological condition met in chronic meningitis. It causes a varying degree of pressure symptoms, which have a tendency to gradually become worse. It may be divided into two groups : Age Date 191_ Name. 10 II IX 13 //■ /* /7 /* Pulse Reap. 2 10 2 6 10 2 b 10 2 6 10 2^ m 6 10 2 6 10 2 6 10 2 6 10 2 6 10 1 75 d ,y 1 ^ r. £ ft • ZS su >. rt v ^i X ZI c <*V » >cs «L 104 Jh \ _(^ * 1 /> / 1 » \ A / Jf \ /\ Zl N /^ \ Q / \ rS ~z ri zr >A / c ^L » rz z£ & zt si / J o tz y/ It zt s A < 1: V II It V <.S T X r ZI ± V It 3 it ZI 101 JL 1 \>, j it 1 n i 3l ZI /> *- iVr IT s " ZI "LB \ / ^ i_ _j -i S Zj K fik \ / t / / s 1^ izz 13 j tz ZI r ZJ / A ZJ 1 H tz Zt Jt ZJ^ / > ZI t zt 551 / u. fc / 3 5P lJ 1 (^ fc / s « 1 -^ ±] J VI _& n : h I r ±L f 3t iS ^ H I A > *»[ ± J Jt ^k_ II I / v It ' 4R 1/ NORMAL 4? JL f % „ tn 95 Chart IV-B. I. Usual form, where there is free communication between the ventricles and subarachnoid space through the basal foramina. II. Posterior basic meningitis, where there is shutting off of the communication between the ventricles and subarachnoid space with encapsulation of the fluid within the ventricles. I. Symptoms of Chronic Meningitis with Usual Form of Hydro- cephalus. — The symptoms of this condition are simply an aggra- vated picture of the pressure symptoms' described under the acute form of meningitis. 82 EPIDEMIC CEREBROSPINAL MENINGITIS. Rigidity of the neck and Kernig sign are very variable. They may be as marked or more marked than in the acute condition, but both may be very much relaxed for days at a time, to recur irreg- ularly, especially with recurrence of the 'fever. Mentality is very much more obscured than in the acute condi- tion. The patient is drowsy and stupid, sleeping most of the time. There are also periods of extreme restlessness, crying, and delirium. The condition similar to typhoidal insanity, which has been de- scribed under the acute form, is very apt to occur here, the patient Name Ag< Date 191 If Xt> XI .5 ^ r \ ^ 3 , \ /* s. ^ / I / Ti m» *•? i< 1 r- t| # 1 t: V \ 2% n tz ) J _J £ ■ f ZJ IT ZJ . I I 1 'v ZI I. C 1 j zt r fc Z3 ZZ1 s rt 1 37 ZJL .>! it ^ i ' >^ X _ZJ ifl u y: 45 /r \ ^ ■ 1 x: ^ r \ ZJLZ 4Z f \ JZ jr — j .. t: « mi / . ^ tz ^i JUl zt J II! \ t: ? I J 5; V 1 ft / 1 1 1 3 \j 1 :£ L o 3 *, J V 1 ^ JZ V i a *i .. 100 tz r si 1 A ^ v \ , t f -U ^ , V 5 ^ — | \r V \ \j ^/ 60 20 1 96 95 T 46 " — »8- Chart IV-C. being irrational, childish, and having many delusions. This may be accompanied by intervals of hours of perfect rationality. The "hydrocephalic cry" (crie hydrocephalique), a purposeless, high- pitched, anxious, wounded cry, which appears to be utterly auto- matic and independent of pain, is encountered in extreme hydro- cephalus. Complete coma occurs in the final stages. Convulsions are quite common, occurring occasionally as gen- eral clonic convulsions or persisting as tonic spasms of some or all of the extremities, interrupted at times by clonic spasms. SYMPTOMATOLOGY. 83 Twitchings are observed irregularly all over the body. Vasomotor phenomena are frequent. There is flushing of the face and body with irregular perspiration. Trophic disturbances are common ; extensive, deep, sloughing bedsores occur. Respirations are usually slow, irregular, deep sighing with long periods of intermission. They conform at first to the undulatory type described by Connor, later Biot's breathing occurs. Pulse is most often very rapid, weak, intermitting, or may be Name . . — Age Date 1 Jl. - l* M 27 if *? 3.0 31 3X 33 Pulse Reap. 2 6 , 10 2 6 -10 2 6 2 6 10 2 6 ' 10 2 6 iO 2 6 10 2 6 10 2 6 10 { i A lV ■ 75 ri H u * -i . - / t / nJ „v n :* 60 n X ' 2_ r V ■j IfM A J IU4 ^ [A Z) J V \ zt e / ^r \ 7$ T ^ f / y T k nr ^ J IB j _/_ \ i J V 1 '£ ', i& JZ \J f \ _X \v t: T. ■ 1 $J t tz I TZ LZ I t: t 1 4^l3 \ 3J \ 3] i -M V mi • V .__ .- IJJ W 110 35 99 . NORMAL CA ._ % pO " ._ 95 - —I 4— Chart IV-D. irregularly rapid. At other times, it is very slow, full, of high ten- sion, irregular and intermitting. Vomiting occurs several times daily, as a rule. It is explosive and sudden, the so-called "projectile vomiting" of large quantities of food that is usually well digested. Immediately after a vomiting spell, the patient will be able to eat a large meal. Bowels are usually very constipated. Macewen's sign or bulging fontanel is very pronounced. In young children with open sutures, the head becomes distinctly en- 84 EPIDEMIC CEREBROSPINAL MENINGITIS. larg*ed. The veins over the scalp, especially over the temporal region, become very much distended. In young children there is a wide separation of the sutures. Eyes are wide open, expressionless. Sometimes patients are actually blind. Other times they see, but it is difficult to deter- mine whether vision is present. Pupils are widely dilated, often irregular, and respond very sluggishly or fail to respond to light. Lateral nystagmus is very common. Strabismus is usually present, most often divergent. Reflexes superficial and deep are absent, or very sluggish. Babinski is frequently obtained. Involuntary passage of urine and stool is the rule. Urine is usually scanty. Fig. VI. Patient ill eight and one-half months with epidemic meningitis. This pho- tograph illustrates the chronic stage of epidemic meningitis frequently seen before the intro- duction of the serum treatment. This patient had not been treated with serum. She was unconscious during the last seven months of her life. Note the painful, blank, sardonic expression ; the retraction of the upper eyelids ; the retraction of the head ; the extreme emaciation ; the retracted boat-shaped abdomen ; the enlarged knee joints and the flexure of all of the joints. She succumbed ten days after this photograph was taken. Swallowing may be very difficult, so that food may have to be given altogether by gavage. Palsies and all the other complications to be described under "Complications" are very common in this stage. General Appearance of the Patient in Advanced Condition. — The patient usually lies on his side, head retracted. Most of the larger joints are flexed, the forearm on the arm, the legs on the thighs, the thighs on the abdomen. He shows a varying degree of emaciation. The face is pinched and anxious and frequently has a characteristic appearance. It is expressionless, fixed, immobile, and at times, is disturbed by the automatic, hydrocephalic cry. The abdomen is very retracted and "boat shaped." The flexed joints become stiff, frequently swollen, and contractures occur. The color SYMPTOMATOLOGY. 85 is either a ghastly pallor or cyanotic. The skin is mottled and cold. Bedsores are common. The tongue is dry, tremulous. The lips and gums are covered with sores. The patient lies in the same position for hours. He looks like a living death. At times, it may be difficult to determine whether the patient is alive. He does not appear to hear or see. This condition may suddenly change, and the patient may become brighter and appear to hear and try to answer questions as well as take his nourishment better. CASES. Case 1. With recovery. Mr. U., aged sixty-five, developed typical acute attack of meningitis. He was punctured, and serum was administered on three different occasions, with considerable improvement; but some of the symptoms continued, and the cerebrospinal fluid obtained at the last puncture still showed extracellular meningococci and pus-cells. For some reason (I believe that it was objec- tion by the family to further puncture) treatment was discontinued prema- turely. His temperature remained normal for a week, but he was suffering from some pressure symptoms. He continued to have some headache, vomited occasionally, and was irritable and stupid. A week after the last puncture all signs became very pronounced. Headache was very intense, ac- companied by severe vertigo. Vomiting was repeated. The patient became more stuporous, restless and anxious. His neck became more rigid and Kernig more pronounced. He complained of double vision and his hearing became impaired. The fever rose to 104°. Lumbar puncture showed a marked hydrocephalus. The fluid, however, was only slightly infected, only an occasional meningococcus could be found in smear; culture was sterile. There was immediate relief after the puncture, but treatment was again dis- continued for the same reasons. Some of the symptoms as before were still present. A week later the same symptom-complex again was present. The temperature again rose from the normal to 103°, staying up for 72 hours. After lumbar puncture all of the symptoms promptly improved. The patient ran this irregular course for six weeks. He became very much emaciated, but he ultimately recovered under continuous treatment. Case 2. Extreme case with death. Girl of fourteen had been ill with meningitis for three weeks in her home, but lumbar puncture had not been, performed nor serum administered. On admission to the hospital she presented the following picture: She was terribly emaciated, looked wizened and about thirty years old. Her face was gaunt and immobile. At times she uttered a shrill hydrocephalic cry. She was very stuporous, almost in coma. She appeared to be blind and failed to respond to questions. Pupils were dilated, no response. Her neck was only slightly rigid. Mecawen's sign was marked. Her pulse was 160, weak, flut- tering, and irregular. Respirations were, at times, very superficial and irregular; other times, deep, stertorous, sighing, and irregular. All of the larger joints were flexed; attempts to extend them caused considerable pain. Her abdomen was very much retracted; abdominal reflexes were gone; Ker- nig was marked; deep reflexes lost; Babinski present. There was constant 86 EPIDEMIC CEREBROSPINAL MENINGITIS. incontinence of urine and stool. She had to be fed by gayage. Over one buttock was a large, deep, sloughing bedsore. There was a right facial paral- ysis, together with divergent strabismus and ptosis of the right upper lid. After a number of lumbar punctures with relief of pressure signs, there was considerable improvement, so that a week later she appeared to hear at times and answered some questions. She swallowed nourishment and looked more animated. These periods of temporary improvement, however, were followed by relapse into her former condition. She continued for two weeks in this extreme condition. She then began to develop occasional, gen- eral convulsions. Her extremities were held in constant tonic spasms. She ultimately developed pneumonia and died. II. Posterior Basic Meningitis. — Gee and Barlow, in 1878, first described this form of meningitis in young children, calling par- ticular attention to the marked retraction of the head that occurs in these cases. The etiology, at that time, was not known. They considered syphilis as a possible factor, but believed that there was probably some relationship to epidemic meningitis. Still described a number of cases in 1898. He found a Gram- negative coccus that resembled the meningococcus but different from it, he believed, in some minute details. He attempted to further draw the distinction between these cases and epidemic men- ingitis by stating that these cases occurred sporadically but not in epidemics. Houston and Rankin, Taylor, and others believed that this organism differed from the meningococcus isolated in epidemics, as proved by agglutination and opsonic tests with the serum of men- ingitis patients. In reference to the difference found by various workers between the organism present in this condition and in epidemic meningitis, one need only refer to the later work on the meningococcus group of organisms, as described in the preceding chapter, to explain away these slight differences. We know that the meningococcus, like the gonococcus, is made up of a number of different strains, which give different serum reactions. They, however, are all meningococci. I have isolated these organisms both during epidemics and in sporadic cases, and have found no cultural difference from the usual meningococcus. One strain. that I tested with complement-fixation gave equally as good fixation with the serum of an organism iso- lated from an epidemic case as with the autogenous serum. These cases occur, like the usual epidemic meningitis, both spo- radically and in epidemics. I have met them in epidemics like the usual epidemic meningitis. Furthermore, as my discussion later on will prove, any case of epidemic meningitis may, during its course, SYMPTOMATOLOGY. 87 develop into a posterior basic case with closure of the basal fora- mina. The condition is simply one of the possible pathological lesions produced by the meningococcus, but is and should be con- sidered epidemic meningitis and due to the same organism. . In this form of epidemic meningitis in which there has been a collection of plastic exudate at the base of the brain, the communi- cation between the ventricles and the subarachnoid space is shut off. The subarachnoid space communicates with the general ven- tricular cavity of the brain by three openings, one of these is in the middle line at the inferior boundary of the fourth ventricle where an opening in the pia-matral covering of this cavity, the foramen of Magendie, exists and permits the passage of fluid from the one space to the other. The other two communications are the extrem- ities of the lateral recesses of the fourth ventricle behind the upper roots of the glossopharyngeal nerves. They are named the foramina of Key and Retzius. It is stated by Merkel that the lat- eral ventricles also communicate with the subarachnoid space at the apices of their descending horns. The essential feature of this lesion is the encapsulation of the inflammatory process within the ventricles. This is the condition that causes the symptoms and ultimate death. The inflammatory process in the subarachnoid space usually promptly subsides so that one ordinarily is unable to obtain any fluid from it by lumbar punc- ture. If a little fluid be withdrawn, it is most frequently sterile. Posterior basic meningitis may develop primarily at the onset of the disease; but in most cases, it develops during the subacute or chronic stage of meningitis. It may develop very suddenly, appar- ently in a few hours, while a case is under observation, or it may appear more slowly with a gradual shutting off of the communica- tion. I believe the latter is more commonly encountered. The two principal forms of this condition are : 1. Fluid in the ventricles is entirely sterile. 2. Fluid in the ventricles is infected with meningococcus, most often only slightly infected, sometimes very purulent. Note. — The fluid in the subarachnoid is usually sterile, but may be infected. In all forms of this condition, however, the symptoms, like in Type I of Chronic Meningitis, are due chiefly to pressure except in the form with very purulent fluid in the ventricles. This condition, as mentioned, develops usually in the subacute or chronic stage of meningitis. It sometimes arises during the ap- parent convalescence from an acute attack of meningitis when one 88 EPIDEMIC CEREBROSPINAL MENINGITIS. is congratulating one's self on the drop in temperature and the disappearance of organisms from the cerebrospinal fluid. It may be noticed, however, that the patient is very quiet, is somewhat stupid, and sleeps a good part of the time. The neck still remains stiff and retracted. Gradually the pressure symptoms become more marked. Sometimes posterior basic meningitis develops acutely during the course of the usual case of epidemic meningitis. Things may be progressing fairly well. All symptoms of meningitis are present, but the symptoms are principally those of meningeal irritation and sepsis. Large quantities of purulent fluid may be obtained by lum- bar puncture. It is suddenly noticed, possibly only a few hours after lumbar puncture, that the patient has become very stuporous, that all pressure signs are marked and that opisthotonos has be- come more pronounced. Lumbar puncture results, however, either in 1 or 2 c. c. of fluid or a dry tap, showing that pressure signs are due to an encapsulated collection of fluid. More often, however, the closure is less abrupt. Pressure symp- toms develop more slowly, and there is a gradual diminution in the quantity of fluid obtained by lumbar puncture before a dry tap ensues. Symptoms in this condition simulate those in a mildly infectious hydrocephalic case seen in Type I of chronic meningitis. Signs of sepsis are very much the same, being usually mild. Where the fluid in the ventricles is very turbid, the more acute symptoms of sepsis occurring in meningitis, may be present. Emaciation is progressive and extreme. Pressure signs are even more marked than in Type I, in which there may apparently be an equal degree of hydrocephalus. Espe- cial attention may be called to the following group of symptoms : Opisthotonos with rigidity of the neck occurs in its most ex- treme form in this condition, so that it is not uncommon to see cases where the occiput touches the spine. The mental state is one of apathy and stupor, which, however, is different from the stupor seen in tuberculous meningitis. In the latter condition, the patient appears to be overpowered by sleep as if he were under the influence of some powerful hypnotic. In basic meningitis, the patient looks wide-awake. The eyes are open and staring. He looks as if he had been struck speechless in a hypnotic state. Respiration shows marked pressure symptoms and is very irreg- ular. Pulse, too, indicates the influence of pressure. SYMPTOMATOLOGY. 89 Convulsions are very common. There is usually a continuous tonic spasm of the upper and lower extremities which are very rigid in full extension. The wrist is firmly flexed, and the fingers are tightly flexed into the palm. The feet and toes are in a state of complete extension. Clonic, general or local convulsions and twitchings of different parts of the body are likewise frequently seen. Vasomotor symptoms of marked flushing or blanching of the skin and irregular perspiration are very striking. Macewen's sign, bulging fontanel, and dilated scalp veins are very marked. All or any of the pressure phenomena, vomiting and reflex changes, and palsies may occur in this condition as in Type I. The appearance of the patient is characteristic and will often first suggest the diagnosis. The patient lies very still. The eyes are wide open and staring. The lids are retracted. In addition, some exophthalmos is present, giving a bulging expression to the eye and allowing a large part of the ocular conjunctiva to be seen. There is marked opisthotonos with bowing of the body. The ex- tremities are rigid, in tonic spasm, in the manner described. The patient does not respond. The pupils are widely dilated and he appears to be blind, often not reacting to light. He does not appear to hear. Course. — Patients can remain in this condition for several weeks. One case lingered six weeks. Practically every case, with the ex- ception of a very occasional one that responds to treatment, termi- nates fatally. Out of about thirty-five cases, I know of only four that recovered after developing this lesion. Differential Diagnosis Between Posterior Basic Meningitis and Type I Chronic Meningitis (Chronic Infectious Meningitis), in Which There Is Free Communication Between the Ventricles and Subarachnoid Space. — Both conditions have a marked pressure symptom-complex, though in posterior basic meningitis it is more pronounced and presents a somewhat more characteristic clinical picture. By lumbar puncture, chronic meningitis, Type I, with free com- munication between the ventricles and subarachnoid space yields a large quantity of cerebrospinal fluid, while posterior basic menin- gitis gives either a dry tap or only 1 to 2 or 3 c. c. of fluid. Brain ventricular puncture, however, gives large quantities of fluid. 90 EPIDEMIC CEREBROSPINAL MENINGITIS. CASES. Case 1. K. N., aged twelve years, developed a typical meningococcus meningitis infection. Patient was being treated by repeated subdural admin- istration of antimeningitis serum with slow improvement. On the twenty- first day of the disease, after a period of considerable improvement, both in the general condition and in the condition of the cerebrospinal fluid, the patient suddenly began to complain of severe headache, and in a short time, became delirious and violent, then apathetic and stupid. She vomited a few times and respiration became much slower. Temperature displayed no ap- preciable change. When I saw the patient a few hours after these symptoms became manifest, it was immediately apparent that some vital change had occurred. She lay very still and did not respond to questions. Her face was immobile, mask-like; her pupils were dilated and did not respond to light; her lids were retracted so that her eyes had the appearance of exophthalmos. Fig. VII. Patient ill six weeks with epidemic meningitis. Posterior basic meningitis developed four weeks after the onset. Note the extreme ophisthotonos. The appearance of the face is characteristic — the blank, staring expression ; the prominent, wide-open, staring eyes ; the retraction of the upper eyelid, giving the appearance of extreme exophthalmos. Note the emaciation and the tonic spasm of the upper and lower extremities. Breathing was very irregular, slow, deep, sighing. Head was more retracted; neck more rigid; Macewen was marked; slight left facial palsy; pulse rapid, irregular; Kernig and tache cerebrale marked; occasional clonic spasm of arms and legs which in the interim had been extended — rigid in a tonic spasm; reflexes absent. The symptoms of meningeal irritation had therefore all become aggravated with the addition of severe pressure symptoms. The diagnosis was consequently apparent, a sudden increase of intraventricular pressure, indicating urgency of lumbar puncture, both for therapy, to relieve pressure if possible, and for confirmation of diagnosis. A lumbar puncture was performed in the usual site. The cerebrospinal fluid that had been present in the many previous punctures, in large quantities up to 100 c. c. and under considerable pressure, now dropped very slowly under low pres- sure, in all only 2 c. c. (Note. — Subsequent examination proved the specimen to be sterile.) I now made the diagnosis of posterior basic meningitis with closure of the basal foramina and retention of a large quantity of cerebro- SYMPTOMATOLOGY. 91 spinal fluid within the ventricles. This was a case of acute closure of the basal foramina, the condition having developed, at most, within twelve hours. Case 2. A man, aged twenty-three, had the usual history of epidemic meningitis on admission to the hospital. Lumbar puncture revealed a con- siderable quantity of thick, purulent exudate containing many meningococci. Serum administered in large doses daily had some slight beneficial effect on his general condition, but caused marked and striking improvement in the cerebrospinal fluid, the exudate diminishing rapidly after the first adminis- tration of serum, becoming clearer and showing a rapid disappearance of organisms. On the fourth day the cerebrospinal fluid, of which only about 4 c. c. could be obtained under low pressure, was clear and contained no pus or bacteria. Corresponding improvement in his symptoms, however, was not manifest. Temperature continued high. The patient was very restless and delirious, then became more stupid and did not respond to questions. His face began to assume the mask-like appearance; his eyes were fixed, wide open and staring; the lids were retracted, showing more of the conjunctiva. In addition, there was some exophthalmos, more in the left eye. He had divergent strabismus and left facial paralysis. Rigidity of his neck and opisthotonos were marked. Kernig and tache cerebrale were pronounced. Respirations were slow and irregular. Pulse was irregular. On the fifth day no fluid was obtained on lumbar puncture, and the clinical picture was that of a very severe, active meningitis with moderate pressure signs from internal hydrocephalus. In view of the findings by lumbar puncture, I made the clinical diagnosis of posterior basic meningitis with closure of the basal foramina. On account of the presence of active signs of infection with high temperature, live meningococci within the ventricles could be strongly suspected. A small trephine opening was made in the skull, and ventricular puncture was performed, revealing large quantities of turbid cerebrospinal fluid containing many organisms. After the evacuation of large quantities of exudate, serum was introduced. The process was repeated for several days with some temporary improvement, especially in the pressure signs, but the patient succumbed in a few days. This case appeared to be one of gradual closure of the basal foramina. The fluid from the subarachnoid space had become sterile, but was considerably diminished in quantity. Ac- tive symptoms continued. Ventricular puncture confirmed the diagnosis. Here there was a sterile subarachnoid fluid and an infected ventricular fluid. CLINICAL DIFFERENTIAL DIAGNOSIS BETWEEN EPIDEMIC AND OTHER FORMS OF MENINGITIS. Epidemic meningitis must be differentiated from other forms. of meningitis, from tuberculous meningitis and other pyogenic forms of meningitis due to the streptococcus, influenza, pneumococcus, or any of the other pyogenic bacteria, from infantile paralysis with pronounced meningeal symptoms, and from meningeal irritation, called meningismus, which occurs during other acute infectious diseases and is considered to be due to toxemia. 92 EPIDEMIC CEREBROSPINAL MENINGITIS. TABLE VI. (A) — Obseevation on 180 Clinical Cases. From the Research Laboratory, New York City. Clinical Diagnoses Reported by Attending Physician Final Diagnosis Established by Combined Clin- ical and Laboratory Examination Epidemic Meningitis. . . .71 Cases Epidemic Meningitis 27 Tuberculous Meningitis 17 Ac. Suppurative Meningitis, due to: Pneumococcus 4 Streptococcus 7 Streptococcus mucosus capsulatus. ... 1 Influenza 1 Unidentified Gram Coccus (no growth) 1 Enteritis 1 Bronchopneumonia 2 Cerebral endarteritis 1 Intestinal Intoxication 2 Delirium Tremens 1 Gastrointestinal Acidosis 1 Measles 1 Simple Chronic Internal Hydrocephalus. 1 No Meningitis (undetermined diagnosis) 20 Epidemic Meningitis 8 Tuberculous Meningitis 10 Poliomyelitis or Polioencephalitis 13 Enteritis 3 Bronchopneumonia 11 Lobar Pneumonia 4 Hysteria 2 Purpura Hemorrhagica 1 Intestinal Intoxication 2 Cerebrospinal Lues 1 Fractured Skull 1 Spastic Paraplegia 1 Tuberculous Meningitis 23 Epidemic Meningitis 1 Streptococcus Meningitis 2 Undetermined Diagnosis, but no Tuber- culous Meningitis 2 Poliomyelitis or Polioencaphalitis. ...... 6 Epidemic Meningitis 1 Meningitis unclassified .7 4 Tuberculous Meningitis 28 Poliomyelitis or Polioenceph- alitis 7 SYMPTOMATOLOGY. 93 TABLE VI. (B) — Summary. Total Cases Reported by Attend- ing Physician Total Cases in Which Final Knowledge Was Obtained by Combined Clinical and Laboratory Examinations ♦Epidemic Meningitis.. 71 Meningitis, unclassified 74 Tuberculous Meningitis 28 Poliomyelitis or Polioenceph- alitis 7 Epidemic Meningitis 37 Tuberculous Meningitis 50 Acute Suppurative Meningitis, due to : Pneumococcus 4 Streptococcus 9 Streptococcus Mucosus 1 Influenza 1 Unidentified Gram Coccus (no growth) 1 Poliomyelitis 8 Polioencephalitis 11 Enteritis 4 Intestinal Intoxication 4 Bronchopneumonia 13 Lobar Pneumonia 4 Hysteria 2 Gastrointestinal Acidosis 1 Purpura Hemorrhagica 1 Measles 1 Delirium Tremens 1 Cerebral Endarteritis 1 Cerebrospinal Lues 1 Fracture of Skull 1 Spastic Paraplegia 1 Simple Chronic Internal Hydrocephalus. 1 No Meningitis (undetermined diagnosis) 22 'Due to Meningococcus. During an epidemic, of course, the great majority of cases are due to the meningococcus. In periods free from epidemics, tuberculous meningitis, especially in large cities, is much more common than sporadic epidemic meningitis. The differential diagnosis between epidemic meningitis and its allied condition by clinical methods alone, is often extremely difficult. While in charge of the Menin- gitis Department in the Research Laboratories of New York City, I had opportunity to see a great many cases that were reported by physicians as epidemic meningitis but which we proved to be men- ingismus, tuberculous, or other forms of meningitis. The preced- ing tables illustrate the true diagnoses as compared to the reported clinical diagnoses. 94 EPIDEMIC CEREBROSPINAL MENINGITIS. From a study of the table, it is evident that of the true inflamma- tions of the meninges, tuberculous meningitis is the most common form and is most often confused with the other forms, especially with epidemic cerebrospinal meningitis in the absence of an epi- demic. Of the conditions simulating meningitis, I found broncho- pneumonia in children, particularly those forms with apical lesions, gastroenteritis, other acute infections such as typhoid, other condi- tions of the central nervous system such as cerebrospinal lues, and anteriar poliomyelitis most often mistaken for meningitis. Tuberculous meningitis can, I believe, in the majority of cases be diagnosed clinically, for the clinical picture is, as a rule, definite and distinct. The patients are often well nourished and usually under two years of age, though it is not an unusual disease in later life. Frequently a family history of tuberculosis can be obtained. The onset is insidious, of two weeks or longer duration. The child is apathetic ; there is a little fever and occasional vomiting. Younger children frequently have convulsions — older children complain of headache. The mother often calls attention to the symptoms that are most important in making a differential diagnosis. She com- plains that the child does not seem to recognize her, is stuporous and sleeps most of the time. This condition of apathy, stupor, and impaired mentality is characteristic ; the children are stupid, expres- sionless, do not notice their surroundings, and respond very slowly and indifferently to external stimuli. Almost the same symptoms are encountered in adults. I recall one patient, a man of twenty- two, who was brought to me in the early stages of the disease, complaining only of severe hiccough. The symptom that im- pressed me was the marked stupidity, listlessness, and indifference of the patient. Upon closer examination, finding some evidence of cranial nerve involvement, slight facial paralysis and pupillary ir- regularity, a temperature of 100° F., and a few signs of probably old, healed lesions at one apex, I made a tentative diagnosis of tuberculous meningitis. Two days later, he developed rigidity of the neck, convulsions and stupor increasing to coma. Cerebrospinal fluid showed tubercle bacilli. Other signs of importance are marked internal hydrocephalus, indicated by Macewen's sign in older children and a bulging fontanel in the younger. Convulsions and local palsies, principally facial paralyses — paralysis of the eye muscles — or paralysis of one arm and leg are more common in tuberculous than in other forms of meningitis. The transitory nature of these palsies is particularly worthy of note. A palsy one day will be gone the next day and may reappear as suddenly. Vaso- SYMPTOMATOLOGY. 95 motor change, indicated by frequent, marked flushing of the face or body, and tache cerebrale are common. Considerable irregularity of the pulse, and slow, deep, sighing, irregular respirations are often seen. Rigidity of the neck and Kernig are only moderate as a rule. The reflexes are irregular ; at the onset of the disease usually exag- gerated, later diminished or absent. Pupils are frequently irregular and may respond sluggishly or not at all to light. The temperature early in the disease is only moderate up to 101° F. to 102° F. in the evening, but as the disease progresses may go up to 104° or 105° F. and may show the marked intermittency of meningococcic menin- gitis. Demonstration of tubercles in the choroid is, of course, con- clusive. Tuberculous meningitis runs an acute course, death usually occurring from two to four weeks after definite symptoms appear. Epidemic cerebrospinal meningitis presents a distinctive symp- tom-complex. The children, on an average, are older. The onset is more acute with rigors, high temperature, prostration, and pro- jectile vomiting. The cerebral condition is often the direct opposite of that in tuberculous meningitis. In place of apathy, indifference, impaired mentality, there are hypersensitiveness, irritability, con- stant crying and complaining, and objection to any disturbance. Mentality, though disturbed by periods of delirium, is often, except in the last stages of the disease, unimpaired for hours. Retraction of the head, tenderness in the back of the neck and Kernig are usually marked. Palsies are often entirely absent. Bulging fon- tanel or Macewen is usually marked, but often to a lesser degree than in tuberculous meningitis. The pulse and respiratory changes are not so great except in cases with marked hydrocephalus, usually in the advanced stage of the disease. Petechial eruption and herpes are frequently present. The temperature is often high, and while continuous high temperature occurs, the usual picture is that of a high intermitting curve. The so-called cerebral temperatures up to 106° F. are not infrequent. From -the above description, it is apparent that the conditions of cerebrospinal and tuberculous meningitis, while frequently easily differentiated, may sometimes so closely resemble each other clin- ically, especially in the late stages of epidemic or in the early stages of tuberculous meningitis, that it may be impossible to make a clin- ical differential diagnosis. The following case illustrates this point. An Italian boy, six years old, had an acute onset with high tempera- ture, rigors, vomiting, delirium, apathy, stupor, stiffness of the neck. On the twelfth day, when I saw the patient, he was extremely 96 EPIDEMIC CEREBROSPINAL MENINGITIS. apathetic, stuporous, almost comatose, but was irritable and resist- ant when disturbed. Orientation was greatly impaired, but he did respond occasionally. Neck was markedly rigid ; Kernig and tache cerebrale marked; frequent flushing of the face; pupils irregular, fixed; left facial palsy; Macewen marked; pulse rapid, irregular; respiration, deep, sighing, slow, irregular; temperature 105° F. Here the history pointed to a cerebrospinal meningitis, but the marked stupor and apathy with evidence of extreme internal hydro- cephalus, local palsy, and vasomotor disturbances made me very suspicious of tuberculous meningitis. The irritability and restless- ness, slight response to questions even at the late advanced stage of the disease, the marked rigidity of the neck and Kernig, made me, however, lean more to the cerebrospinal diagnosis. Lumbar puncture demonstrated a very severe form of epidemic cerebro- spinal meningitis. The other acute forms of meningitis, as Streptococcus pyogenes, Streptococcus mucosas capsulatus, pneumococcus, influenza, present almost the same symptom-complex as epidemic meningitis. The history of previous disease, such as otitis media, may be of some help, but the diagnosis can only be definitely established by lumbar puncture and examination of the cerebrospinal fluid. It is import- ant to note here that in pneumococcus meningitis, as well illus- trated by Holt in two of his cases, the cerebrospinal fluid may be sterile, due to a localized cortical meningitis. Meningismus complicating other acute infections, while some- times difficult to differentiate from epidemic meningitis, can, as a rule, be diagnosed. First, the presence of the primary infection must be established, very often bronchopneumonia or one of the other conditions mentioned in Table VI. The mental symptoms of restlessness and irritability are not accompanied by the anxiety, constant crying and complaining of the usual epidemic meningitis. Unless delirium is present, the patient is usually bright and intelli- gent and responds readily to questions. Rigidity of the neck is only moderate, can often be relaxed, and while opisthotonos is present, the patient will still be able to turn his head from side to side with ease. Kernig is also only moderate or absent and the Macewen sign or fontanel bulging may be present to a lesser degree. With the subsidence in temperature and the improvement in the original infection, the meningeal symptoms disappear. Oseki states that cases of meningismus, occurring during infec- tious disease, have been considered and found in most instances to be free from any apparent anatomic change in the meninges or SYMPTOMATOLOGY. 97 brain. Definite meningitis and encephalitis have also, however, been found in such conditions, giving similar symptoms to those cases without anatomic lesions. Oseki, studying this group of cases, found that in some cases with clinical signs of meningitis, the post- mortem examination showed no gross changes, except perhaps a moderate amount of edema, sometimes also a little opacity of the membranes. On microscopic examination, there were found acute inflammatory changes most pronounced about the small blood- vessels with leucocytic and lymphocytic infiltration in the men- inges and brain substance, sometimes associated with small foci of necrosis in the brain and spinal cord. In some of the cases, also with clinical meningitic symptoms, there was found only encephal- itic change but no change in the meninges. He encountered cases of pneumonia, in which meningitis and encephalitis were found on postmortem, but of which there were no symptoms during life. Thus, meningitis and encephalitis may be latent; e. g., in cases with definite symptoms there may be only microscopic but not macroscopic findings, and vice versa, cases may occur, as in pneu- monia, in which symptoms may be absent and definite microscopic changes be found postmortem. In the cases classed as meningis- mus, gross examination alone is not sufficient to exclude meningitis or encephalitis. Careful microscopic examination must be done. Poliomyelitis and polioencephalitis, especially the latter, present distinct meningitic symptoms during the acute stage. A careful study of the history and clinical course will usually enable one to establish the diagnosis even without lumbar puncture. The symp- toms are most severe in the cerebral form of infantile paralysis. In the ordinary form of poliomyelitis, the premonitory meningitic symptoms may be so very mild as to be overlooked. The following description applies principally to the cerebral form : The onset is acute with high temperature, vomiting, frequently symptoms of common cold, with headache and general bodily pain, or symptoms of mild or severe gastroenteritis. In young children, less commonly in the older, convulsions may be present. Cerebral symptoms are usually distinct. The patient is restless and irritable and frequently complains of pain in the back of his neck and spine. Vomiting may be repeated. Examination shows a patient who is apathetic and stuporous but who, on being roused, is clear and intelligent. In con- tradistinction is the disorientation of epidemic meningitis with the more marked irritability, restlessness, hyperesthesia, and constant complaning. This I consider an important point of difference. Pupils usually respond, at first sluggishly or not at all. Neck shows 98 EPIDEMIC CEREBROSPINAL MENINGITIS. anteroposterior rigidity, frequently no lateral rigidity but neither, as a rule, so marked as in epidemic meningitis. Macewen or bulging fontanel may be marked. Kernig varies, usually is slight. Tache cerebrale may be marked or slight. Pulse and respiration may show irregularity from the onset, the pulse being rapid with some inter- mitting, the respiration deep, sighing, slower. These signs may continue for a few days, during which time pressure signs from in- creasing hydrocephalus may become emphasized, as shown by in- creasing stupor, more marked Macewen, or fontanel bulging and more marked changes in pulse and respiration. Temperature may drop to normal during the first two days or gradually by lysis. The palsies may first be noticed four or five days or longer after the onset of symptoms. It is important to remember that the patient will frequently not complain of or notice the palsy. Occasionally, the palsy may be so slight, especially the face and other cranial nerve palsies, that even older children and adults cannot appreciate them. The palsies depend entirely upon the brain involvement. Thus, we see the facial palsy, varying degrees of ophthalmoplegia, mono- or hemiplegias. In poliomyelitis, one sees the usual flaccid paralysis affecting the limbs. These mild cases, especially, are characterized rather by partial palsy than complete paralysis, the patient still retaining considerable power in the affected parts. The affected limbs are more flaccid, the spasticity in cerebral cases, if the extremities be affected, frequently not appearing until later. Reflexes on the affected side are often exaggerated, though they may be absent at first. Bladder and rectal involvement are quite common. At the time that palsy appears, the temperature is apt to be low or normal, the stupor decreases, and the general symptoms become less marked. Ataxia is frequently first observed in this stage when the patient attempts to sit up. This form of the dis- ease, according to Wickman's classification, may be a distinct type and may be the only symptom noticed, following the prodromal symptoms, which also may be very mild. These cases, as classified by Wickman, should really correctly be considered under the polio- myelitic group, as degenerative changes in Clark's column have been demonstrated in some. In all of the cases I have observed, however, Macewen's sign of hydrocephalus was marked. In one case considerable fluid under high pressure was. removed by lumbar puncture. I am inclined to believe that in some cases the ataxia may, to a very ' great extent, be explained by the hydrocephalus, especially in the instances of quick recovery. The differential diagnosis, therefore, from epidemic meningitis is SYMPTOMATOLOGY. 99 the absence of the active cerebral symptoms, especially of disturbed sensorium and of marked pulse and respiration change even with evidence of a considerable hydrocephalus; the greater tendency to early stupor, the less-marked neck rigidity and Kernig, the early appearance of palsies, which may be extensive as a hemiplegia. While palsies occur in epidemic meningitis, they ordinarily do not appear early in the disease, nor are they, as a rule, extensive. I have, however, seen exceptions to this rule. The temperature, gen- eral constitutional symptoms, and many cerebral pressure signs often clear up in this disease when palsies appear, while in epi- demic meningitis, if palsies occur, showing graver involvement, all of the symptoms become more marked — the temperature rises, pressure signs become more pronounced, and the general constitu- tional symptoms bcome worse. Differential diagnosis of tuberculous meningitis from these milder cases should be less difficult. The acute onset in polioen- cephalitis is important as well as the early high temperature that rapidly comes down to normal, as against the low temperature at the onset of tuberculous meningitis, with later high temperature. Then, too, there is the rapid progression of symptoms with early appear- ance of palsy in polioencephalitis, which may be extensive, as against the transient, usually not extensive paralysis in tubercu- lous meningitis. With the drop in temperature in polioencephalitis, the general constitutional symptoms, headache, backache and many of the pressure signs clear up, while in tuberculous meningitis, the very opposite is the case, for with the evidence of more extensive involvement all of the symptoms become worse. Lumbar puncture, of course, is the method of more exact differential diagnosis. I have found it unnecessary, however, in many cases where the his- tory and symptoms were carefully weighed. The group of cases already alluded to contain many of consid- erable interest, and some of the more striking types are recorded in the following pages : Case 1. School-girl, aged eight. Previous history good; onset sudden. Five days before child seemed to have grippe.. She complained of headache, coryza, cough, pain in the back of the neck, and high fever. Vomited several times. She became more stupid and on the third day was markedly apa- thetic. Temperature came steadily down by lysis, reached normal on the fourth day. At the same time she became brighter, was less apathetic, but still complained of headache and pain in the neck. Physical examination on the fifth dav showed that the patient was apathetic, but answered questions readily. Macewen was marked. Neck was moderately rigid antero-poste- riorly, no lateral rigidity; pupils equal, reacted promptly; some coryza; 100 EPIDEMIC CEREBROSPINAL MENINGITIS. herpes present; tache cerebrale present; pulse irregular — 80 (physician stated that the pulse and respiration had both been irregular since the first day of the illness); occasional sighing respiration; distinct but not marked left hemiplegia, there being slight flatness on the left side of the face; some weakness of the left upper and lower extremities. This had not been noticed by either patient or mother. Reflexes were increased on the affected side. Summary. — The characteristic diagnostic symptoms in this case were, therefore, the acute onset, the rapid progression of symptoms, the early ap- pearance of palsies, the clear sensorium throughout the illness, even with apathy, the drop in temperature and clearing up of general constitutional symptoms, when in epidemic or tuberculous meningitis one would expect the symptoms to become worse. Note the presence of herpes. Lumbar puncture was not performed. I did not consider it necessary for diagnosis. Case 2. Man, aged twenty-two. Past history negative. No similar dis- ease in the neighborhood. Onset sudden one week prior to examination by me. He complained of moderate headache, some nausea, some fever, general malaise, pain in spine and legs. After two days he felt so much better that his physician allowed him to get up. He then began to feel worse. Tem- perature was 99° P. to 103° P. daily. He complained of severe headache and pain in the back of his neck. Stupor and apathy developed so that the family physician suspected typhoid. Patient, though stuporous, was at all times perfectly clear and intelligent, not very irritable. On the seventh day physical examination: Temperature ranged from 100° F. to 102° F.; patient was perfectly clear; complained of headache; neck showed slight antero- posterior rigidity, but could be easily turned from side to side; eyes, distinct left ophthalmoplegia; distinct left facial palsy; slight Kernig; slight tache cerebrale; knee-jerks not obtained; no pulse or respiratory change. Summary. — My clinical diagnosis was polioencephalitis, the clinical picture being a typical one and the differential diagnosis being identical with Case 1. Lumbar puncture was performed at the request of the family physician. Cerebrospinal fluid — 60 c. c. of clear fluid — high pressure. Cytology — Cells moderately increased in number; lymphocytes 85%; polynuclears 15%. Bacteriology — Spread negative; no t. b. c; culture sterile. Globulin— Negative. Fibrin — Very slight increase. One week later, the patient was entirely well; paralyses gone. Aseptic meningitis is an irritative, purulent meningitis, which is sterile of bacteria. It is considered to be a reactive meningitis pro- duced by a neighboring tissue infection, most often succeeding a local bone infection, such as follows after mastoiditis and suppura- tions of the sinuses of the head. In one case in Mount Sinai Hos- pital, necrosis of the petrous portion of the temporal bone was found at autopsy in a patient who had had recurrent attacks of sterile, purulent meningitis. Other cases occur after infection of the frontal and ethmoidal sinuses. On account of the etiological SYMPTOMATOLOGY. 101 agent that is sometimes inaccessible to treatment, such as in the necrosis of the petrous portion of the temporal bone, these cases are usually very severe. They may recover spontaneously and recur a number of times following a relapse of the old bone disease. Clinically, these cases may present an active picture of menin- gitis such as is seen in epidemic meningitis. A history of preceding bone disease can, however, be elicited. Lumbar puncture estab- lishes the differential diagnosis, showing a sterile, very purulent fluid. It may be well to classify under this heading cases that show a turbid, purulent fluid containing many pus-cells, but sterile, occur- ring after a repeated, simple lumbar puncture. Sladen cites two in- stances in which a perfectly clear fluid was obtained at the first puncture, but the second puncture twenty-four hours later, yielded a purulent, sterile fluid. This change was considered to be a reac- tion after the first puncture. In this group may be mentioned cases showing clear fluid on lumbar puncture but with clinical symptoms of meningitis sufficiently suspicious to warrant the intraspinal ad- ministration of serum. Such cases will frequently give a turbid, purulent, sterile fluid at a later puncture also as a result of the reac- tion set up by the serum. No damage, however, results in such cases, as the fluid clears up in a few days with no after effects. RELAPSES. True relapse occurs in this disease as it does in typhoid and other acute infections. Ker reports relapses in from 15% to 20% of his cases. Some of his cases suffered four or five relapses. One physician reported as many as thirteen. In my experience, true relapse after complete recovery is de- cidedly uncommon, occurring in less than 5% of the cases. Most of the cases of apparent relapse, coming under my observation, had symptoms of a varying degree of hydrocephalus at the time of their apparent recovery. We know that hydrocephalus, even when ac- companied by a slightly infected fluid containing many meningo- cocci, as is seen in the study of the chronic cases, may give a very irregular picture. Fever may be absent for a week or longer. Pres- sure symptoms may be very mild, but severer symptoms recur irregularly with high temperature and marked pressure signs. This is well illustrated in the last case described where the patient was comfortable for a week and then developed severer symptoms. It is important not to confuse an aggravation of the already existing 102 EPIDEMIC CEREBROSPINAL MENINGITIS. hydrocephalus, which may or may not be due to an infected fluid, with a true recurrence of the disease after recovery as occurs in relapse. I believe that most of the cases reported as relapses are not true relapses but are rather the condition I have described. The patient is not altogether well at the time of his supposed con- valescence. He very often has distinct objective evidence of hydro- cephalus, though subjective symptoms may be very mild. His cerebrospinal fluid, at the time of his discharge, may be clear, but we know that these clear fluids especially during convalescence or in chronic meningitis, contain a very few meningococci, which can be grown by careful culture. Thus, a patient with this condition is discharged. He begins to walk around and to exercise. After a week or longer, the hydrocephalus becomes more marked. The few meningococci may multiply, causing a more turbid fluid and he develops active symptoms of pressure with fever. To casual ob- servation it appears that he has had a relapse, instead of which he has had a recrudescence. Symptoms of relapse though similar to those in the acute attack are usually milder. As a rule, the septic phenomena are not so pronounced, while hydrocephalus with its pressure symptoms, as previously described, is more marked. Under proper active treat- ment, these cases usually clear up within a few days. If they be prematurely discharged, however, the same condition will recur. The warning these relapse cases sound is not to discharge menin- gitis patients too hastily, to be quite certain that hydrocephalus is no longer present or rapidly vanishing and that organisms have dis- appeared from the cerebrospinal fluid. Case 1. Boy, aged six, had an acute attack of epidemic meningitis. He was punctured on the second day, and a large quantity of cerebrospinal fluid was withdrawn. Serum was administered on three successive days. At the last puncture the fluid was almost clear and failed to show any meningococci in the smear examination, but culture gave a growth of meningococci. There was such marked improvement in every way that it was decided not to sub- ject the boy to further lumbar punctures. His mentality was again per- fectly clear. The rigidity of his neck and Kernig had disappeared. Pulse and respiration were normal. Temperature was normal. He had a marked Macewen's sign, however, and his pupils were still moderately dilated and responded sluggishly to light. He continued in this condition with normal temperature for ten days, at times, however, complaining of dull headache and vertigo on moving his head, and of occasional double vision. He con- valesced very slowly. On the tenth day his temperature rose to 104°. He vomited a number of times, suffered from intense headache and vertigo, and complained of diplopia. His neck was more rigid and he was very restless, irritable, and hyperesthetic. Macewen's sign was very marked. Pupils were SYMPTOMATOLOGY. 103 widely dilated and did not respond to light. Lumbar puncture yielded 80 c. c. of clear fluid under very high pressure. Smear was negative, but culture gave growth. There was prompt relief in all symptoms. He was punctured on two more occasions and recovered fully after two weeks. The histories of most cases of relapse read very much like the above. CHAPTER III. LABORATORY DIAGNOSIS OF MENINGITIS. A study of the clinical history, symptoms, and course will usually enable one to diagnose inflammatory meningitis, and frequently to differentiate the bacteriological type of meningitis. Positive diagnosis, however, can only be made by examination of the cerebrospinal fluid. Once a clinical diagnosis of meningitis is made, a lumbar puncture should immediately follow, first to prove the diagnosis, and then, if indicated, to use a specific immune serum. The laboratory examination for diagnosis of epidemic meningitis may be classified into : I. Cerebrospinal Fluid. a. Chemical examination b. Bacteriological examination c. Serological examination d. Animal inoculation II. Blood a. Leucocytosis b. Blood culture c. Serological tests III. Other examinations a. Urine b. Conjunctival secretions c. Herpes d. Other suppurations as middle ear I. THE CEREBROSPINAL FLUID. The examination of the cerebrospinal fluid yields the most impor- tant information in all forms of meningitis, as also in other cerebral conditions, such as infantile paralysis, syphilitic disease, fracture of the base of the skull, brain tumor, cerebral hemorrhage. The data to be studied in a cerebrospinal fluid are : 1. Pressure of the fluid during withdrawal by lumbar puncture. 2. Quantity of fluid as compared to the normal. 104 LABORATORY DIAGNOSIS OF MENINGITIS. 105 3. Color. 4. Chemical examination : Globulin Albumin Sugar 5. Fibrin content 6. Cytology 7. Bacteriology 8. Animal inoculation 9. Special serological tests I. Pressure. — The usual method of obtaining the cerebrospinal fluid pressure is by measuring the height to which the cerebrospinal fluid rises, in a glass tube of one mm. bore. A number of instruments have been devised for the purpose ; some have used mercury manometers. The simplest instrument consists of an ordinary glass tube of one mm. bore. Quinke first used an ungraduated tube, determining the height of the fluid with a tape measure ; others, among them being Sladen and Crohn, have used a graduated glass tube. Sladen employed pressure tubes made in two lengths of 400 mm. each, from glass tubing of six mm. diameter with one mm. bore. Crohn devised a similar apparatus, dishing used a mercury manometer, in his experiments on intra- cranial tension and blood-pressure. The main objection to mer- cury instruments lies in the difficulty of sterilizing them after use in infective diseases. The normal cerebrospinal fluid pressure is from 60, at times less, up to 130 mm. Kronig found that in adults the pressure was 125 mm. and in the sitting posture 410 mm. The cerebrospinal fluid pres- sure may be roughly estimated by noting the force of the fluid as it flows through the needle, one drop of fluid every three to five seconds corresponding to normal pressure. The pressure, of course, depends upon the amount of hydrocephalus. It is therefore highest in tuberculous meningitis where one regularly sees extreme hydrocephalus. In one case I found a pressure of 830 mm. The pressure in epidemic meningitis varies according to the amount of hydrocephalus. Sladen made a careful tabulation of the pressure in 75 lumbar punctures. His average pressure was 327 mm. ; his highest was 650 mm. The lowest pressure at first tap was 160 mm., the average being 350 mm. The average amount of fluid re- moved in the 75 instances was 30 c. c. This was withdrawn to reduce the cerebrospinal fluid pressure. His table shows that in the average, 30 c. c. of spinal fluid removed succeeded in reducing the intraspinal 106 EPIDEMIC CEREBROSPINAL MENINGITIS. fluid pressure 300 mm., thus in general 1 c. c. of spinal fluid being the equivalent of 10 mm. pressure. An increase in the quantity and pressure of the cerebrospinal fluid may occur in many cerebrospinal conditions — in inflammatory menin- gitis (exudate) due to any of the pyogenic bacteria, in tuberculous men- ingitis, syphilitic meningitis, infantile paralysis, parasyphilitic diseases. It may be increased as a result of toxic irritations producing menin- gismus, as in pneumonia, typhoid, convulsions in children, rabies, drug poisoning, in alcoholic wet brain, in general anasarca. The cerebrospinal fluid pressure, therefore, suggests the amount of hydrocephalus and is an indication as to the quantity of fluid to be re- moved. Color. — A turbid fluid indicates a purulent collection of fluid and is obtained, as a rule, in acute pyogenic inflammatory conditions, not- ably due to the meningococcus, streptococcus, Streptococcus mucosus capsulatus, pneumococcus, influenza, staphylococcus, etc., and occa- sionally to the tubercle bacillus. A normal, clear fluid is usually only small in quantity. Chemical Examination of the Cerebrospinal Fluid. — The normal cerebrospinal fluid has a very small quantity of protein content. In inflammatory conditions, there is an increase of protein content, which may be demonstrated by a number of tests — the acetic acid test, nitric acid test, Noguchi's globulin reaction, Braun and Husler's hydro- chloric acid test. The acetic acid test described by Moritz consists in the appearance of a white cloud or a precipitate when a few drops of 5% acetic acid are added to 2 c. c. of fluid. The nitric acid test described by Runeberg is performed by adding a few drops of chemically pure nitric acid to the cerebrospinal fluid, inflammatory fluids giving a heavy white cloud. A modification of this — the ring test — consists in layering the cerebrospinal fluid over the nitric acid. This is a very convenient method. Nonne divides the albumin test into two phases, the reaction of each test being estimated by the degree of cloudiness. The first phase of the reaction is obtained by adding heat-saturated ammonium sulphate solution to cerebrospinal fluid in equal parts. It is asserted that this semisaturation precipitates the globulins and should be permitted to stand three minutes, when an estimation is made of the degree of reac- tion. Nonne states that the reaction in this phase occurs in every cerebrospinal fluid including the normal. In the second phase, the mixture of cerebrospinal fluid and ammonium sulphate is filtered, and to the filtrate is added one drop of dilute acetic acid and the whole LABORATORY DIAGNOSIS OF MENINGITIS. 107 boiled. The appearance of a cloud is considered to be due to serum albumin and is called a positive reaction. The degree of clouding varies in different specimens of cerebrospinal fluid. Noguchi's globulin test is one of the most important and significant gross chemical tests, and indicates an increase in the protein content in the cerebrospinal fluid. The test is made by mixing one part of cere- brospinal fluid with five parts of 10% butyric acid in physiological salt solution, boiling, then quickly adding one part of a normal solution of NaOH and boiling again for a few seconds. A normal fluid produces a slight, white, diffuse cloud that does not precipitate. Exudate in inflammatory meningitis produces a heavy, white cloud that precipi- tates in the form of large floculli. It is important to let the fluid stand from one-half to one hour before making the reading. Purulent fluids produce an exceedingly heavy precipitate. The test is of especial value in differentiating transudates from the clear fluid seen in certain forms of meningitis, as in tuberculous meningitis and infantile paral- ysis. Braun and Husler, in June, 1912, described another method of pre- cipitation of the serum globulin. To one c. c. of cerebrospinal fluid add n/300 HC1 (one part n/1 HC1 plus 299 parts aqua destillata) slowly, shaking constantly. If clouding does not occur after five c. c. have been added, then the reaction is negative. In positive cases, re- action usually takes place after a few minutes, though in some instances one must allow the test to stand for one-half hour. They used this test in a series of 41 cases and could differentiate normal fluids and transudates from exudates. Various methods have been used for quantitative estimation of the albumin content. Bybee and Lorenz employed Brandenberg's method used for urine analysis. They constructed a two-armed tube, allowing the nitric acid in on one side, and the cerebrospinal fluid in on the acid through the other arm. The normal reading as estimated by different observers averages between .01% and .06%. Relun used Esbach's reagent, averaging the normal at .02%. The reduction of Fehling's solution by cerebrospinal fluid has been considered a means of differentiation between exudate and transudate. Very purulent fluids even in large quantities, as a rule, do not reduce Fehling's solution. Slightly purulent fluids — the cerebrospinal fluid of tuberculous meningitis and of infantile paralysis — -however, regularly reduce Fehling's. The reduction frequently does not occur imme- diately, but can usually be found after a number of hours. After examining a great many samples of cerebrospinal fluid in different diseases, I finally abandoned this test in routine examination. 108 EPIDEMIC CEREBROSPINAL MENINGITIS. Mayerhofer described the relative quantitative reduction of perman- ganate when added to cerebrospinal fluid in an acid solution on boiling. His conclusions were : In normal fluids the reduction index is low. In meningitis, the index is high, from two to eight. After the injection of meningitis serum with favorable reaction, the index drops. He considers that the test might thus be used as an index to prognosis, and that transudates could be differentiated from exudates. Fibrin Content. — The rough gross estimation of the fibrin con- tent is obtained by allowing the cerebrospinal fluid to> stand unshaken for several hours after withdrawal. Some advise keeping the fluid in the incubator ; others prefer a cool place. I have had most success with the former. Normal fluids and transudates do not show any appreciable formation of fibrin ; exudates, as in purulent meningitis, in tuberculous meningitis, and in infantile paralysis display varying quan- tities of the fibrin network after standing. This is a simple and signifi- cant observation and helps to differentiate normal fluids and trans- udates from exudates. Bacteriology. — The determination of the specific bacterial agent in a cerebrospinal fluid is the most important of all of the tests. The in- vestigation may be divided into the general examination for all of the pyogenic bacteria and the special ^examination for tubercle bacilli. Examination for general pyogenic bacteria is the same as for all inflammatory exudate. The fluid is centrifuged for several minutes, until a moderate amount of sediment is collected. A little sediment is stained by Gram's stain. If influenza be suspected, staining with fuchsin demonstrates the organism a little better. The rest of the sediment is inoculated on suitable culture media. As a rule, ascitic glucose agar and bouillon, and blood agar give best results. A little of the sediment may be poured directly over the surface of the slants and into the fluid medium. At the end of 24 hours, if growth has been obtained, further identification of the organism may be made by employing the usual bacteriological methods. The immediate exam- ination of the fresh-stained sediment is very important. It gives one an idea of the number of organisms and their relation to the cells. A culture will not infrequently be contaminated, so that one may have to rely, at least for the time being, on the morphology and staining of the organisms in the sediment. A bacteriological examination of the sediment in the case of acute suppurative meningitis, due to the menin- gococcus and the other pyogenic organisms, will ordinarily enable one at the first examination to find the infecting organism. Exceptions occur in epidemic meningitis at different periods of the disease, as will LABORATORY DIAGNOSIS OF MENINGITIS. 109 be described, or in the cases of localized pneumococcus meningitis when clear fluid, uninfected, is obtained by puncture. Cytology. — The study of the cytology of the cerebrospinal fluid is next in importance to the bacteriology. A very good review of this subject was made by Bybee and Lorenz in 1911. The object of the study is to determine the total number of cells present as compared to the normal, and to obtain a differential count of the different cells in a stained specimen. The simplest and the most commonly used method is the one de- veloped by Widal, Sicard, and Ravant. It consists in certrifuging the cerebrospinal fluid, pouring the sediment on a slide and staining. This obviously will not give one an accurate count of the total number of cells per cubic centimeter, since the cells exhibit a decided tendency to clump and to adhere to the bottom and sides of the centrifuge tube. The amount of the sediment also varies considerably with the shape of the centrifuge tube and with the rate and time of the centrifugation. While the actual count is inaccurate, one can still form an idea of the relative number of cells as compared to the normal. The great advan- tages of the method are its simplicity and practicability, together with the fact that one can study old fluids, while in the other methods used for cell count, the fluid must be counted immediately on withdrawal, and that the examination of the sediment gives one an idea not only of the cell count, but allows one to study the type of cells present. The second method used is the cell-chamber method, first employed by Laignel-Lavastine, who centrifuged the fluid, and then counted on the Thoma-Zeiss blood-counting slide. This method obviously has the same error as the simple centrifuge method. Fuchs and Rosenthal later devised an improved method, using the cell-counting chamber, but omitting to centrifuge. They used a staining fluid consisting of : Methyl violet .1 Glacial acetic acid 2.0 Distilled water enough to make 50.0 This they drew up in an ordinary white-blood-counting pipette to the .5 mark, and then drew the cerebrospinal fluid up into the diluting chamber as in a blood-count. They devised a special counting chamber, which contained a large quantity of fluid. The ruled space of this chamber is 4 mm. square, its depth 0.2 mm. ; thus it offers 3.2 c. mm. for counting. Cornell demonstrated that erythrocytes also took this stain. He suggested that polychrome methylene blue be used in the same manner, and employed the ordinary Turk blood-counting chamber, counting at least three specimens. Bybee and . Lorenz state, however, that Cornell's stain 110 EPIDEMIC CEREBROSPINAL MENINGITIS. gave results similar to the Fuchs-Rosenthal. They devised a special technic, differing from the Fuchs-Rosenthal in that they employed a red-cell pipette, drawing the original Fuchs-Rosenthal stain up to 0.7, then wiping away the excess from the point of the pipette. They explain the rest of their technic as follows : The stain is then drawn up into the diluting-chamber so that it evenly coats the inner wall. This is accomplished by holding the point downward and causing the incoming air to form bubbles that paint the sides evenly. The first three c. c. of fluid to escape are collected in a centrifuge tube and subsequently used for the film method. The second two or three c. c. of fluid removed are collected in a small test-tube. The tip of the red-cell pipette is then dipped in the fluid at once (since according to Kafka, fluid on standing shows a high number of degenerate cells), and the diluting-chamber filled rapidly. The pipette is then thoroughly shaken for five or more minutes. After twenty minutes, the pipette is again thoroughly shaken, and five Thoma-Zeiss counting- chambers are filled from this pipette and permitted to stand for one-half hour. At the end of this period the entire number of cells within the square millimeter of ruled surface, as well as an equal surface outside of the ruled space of each chamber, are counted. This can readily be accompanied by the use of an Ehrlich eyepiece. We then have the number of cells in an entire cubic millimeter of cerebrospinal fluid. In those fields showing a small cell content, two or more cubic millimeters of fluid have been counted to insure greater accuracy. The calculation of the number of cells in the cubic millimeter is simple, since the dilu- tion of the fluid is only slightly more than 1/200. The specimen taken in the centrifuge tube, to which is added 3 drops of a 40% formaldehyd solution, according to the suggestion of O. Fischer, is swung at the rate of 1,200 revolutions per minute for a period of one-half hour. The specimen of the supernatant liquid is then taken off by means of a newly drawn pipette, which is introduced into the column of fluid so that the fluid taken is from 1 a point at about the juncture of the middle and lower thirds. The droplet is blown out on a freshly prepared cover-slip, permitted to dry in the air, subsequently fixed and stained, and a careful search made for cells. After removing this specimen of supernatant liquid, the tube is in- verted and permitted to drain thoroughly. The residue is then drawn into a freshly prepared pipette. The suggestions of Nissl and E. Meyer are followed, and finally the contents of the capillary pipette are marked off into equal parts. Each part is spread over a square centi- meter Of surface on two freshly prepared cover-slips, in this respect following the technic of Kafka. After drying in the air the film is LABORATORY DIAGNOSIS OF MENINGITIS. Ill fixed by absolute methyl alcohol, washed in distilled water, and stained for ten minutes in a weak Delafield's hematoxylin (5 drops to a watch crystal of distilled water). It is then washed in distilled water and permitted to remain in tap water for a few minutes. The excess of stain is removed by immersing for a few seconds in acid alcohol (one drop of dilute hydrochloric acid in 50 drops of 70% alcohol). After thoroughly washing in distilled water the film is placed in a weak aqueous eosin solution (six drops of a 0.5% eosin to a watch crystal of distilled water) for four or five minutes. The film is washed in distilled water, dried between blotting papers, then high above a flame, and mounted in cedar oil. The film stained in this manner was used for the most part for field and differential count. A number of films were stained with Jenner's stain for this same purpose. The field counts were made for the pur- pose of comparison with the cell-chamber counts, the object being to determine the relative value of these methods in the quantitative estima- tion of the cells present. Their comparative values are well shown in the accompanying table from Bybee and Lorenz prepared from studies of cerebrospinal fluids in general paresis. It may be noted in passing that Jenner's stain was rendered useless for the films when formal- dehyd had been added to the fluid. The field counts were made, using a 1/12 oil-immersion lens (Zeiss) and a 22.5 mm. eyepiece (Zeiss). TABLE VII. Chamber Method Centrifuge Method Differential Cell Count in Percentages U , c h*c o £ o 3 O &3 Pi m O^ p. -d .a , ??fa .2 o a c2 Ufa o o cS c c 13 " s >> fa CO .—i v 6 u u s co CTJ id o u o ° a fa en 5 ° +j o ft © B u ' o O S3 S3 O O O S3 ■*-* be B CD CD «w PJ t— i 02 a 02 'S oS bfl o + + + + + + + w ° "'H 6C S3 ft 1 !>• 'P P. © . + + CD s a ° o ft CD ^> ^-s S3 ft ci o S3 w CD © CD CD + + 1 1 S3 O 3 cd m ft © B °* m a o " 2 3 P O ■3 5 Pi ^ O CC + 1.2 en 00 o c 02 S3 ft S3 cd 1 + + CD ^ a 2 o i ft 2 ►» ■ *-% Pl ^ 0) o O o o bfl + + + + + + »P S3 O 'P + +J o IC » o H .a 02 + + + ft © S33 '3 P u 02 B d CD O O +J CD CD 3 o en 6 58 rd ^ p o.2 a bo cd C£ 3 + S3 >> CD ^ s 2 »^ o S3 ° cd a & 05 o . 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'• • bX) # B ■\-' 02 CD o "S 02 'fH +J © >^ >4 "o d CD ^2 P u +j bJO • rH •i-i +■> tp •l-H f- c i S3 03 CO CO S3 O i—i o CD +J a a p X5 • l-H CD cd 02 02 O 1— ' P XJ o c i Eh S3 >» c£ I-H fn i-H C ) fc a O PQ <«J O o o fH «t-i cd CD fn ft 02 -P P P o «M o p CD U cd 3 02 1—1 Jsi '3 © CD « M © P CD £ fH CD 02 I CD ►^ p © CD P T3 LABORATORY DIAGNOSIS OF MENINGITIS. 127 OTHER LABORATORY AIDS IN DIAGNOSIS OF EPIDEMIC MENINGITIS. Blood Examination. a. Leucocyte Counts. — All observers agree that epidemic menin- gitis is regularly accompanied by a leucocytosis. Sladen in his tabulation of twenty-one cases of epidemic meningitis, in whom repeated blood-counts were done, found in all a leucocytosis with relative polynucleosis. The average count was about 30,000 leuco- cytes. Only four cases had counts less than 20,000. The rest had counts between 20,000 and 45,000. From his tables, he concludes that the degree of leucocytosis did not appear to have any relation to age, severity, day of the disease, or prognosis, except as an indi- cation of the relationship in this disease, as in others, between the severity of the disease and the resistance of the individual. Of the four cases with counts below 20,000, two were in mild cases and two were in men of very poor resistance. Dow made routine examinations in a large number of cases, and made the following deductions : 1. Cases of epidemic cerebrospinal meningitis are always accom- panied by a leucocytosis, whether the attack is acute, abortive, mild, or chronic. 2. The character of the leucocytosis is practically the same in all instances, both in adults and children, and is the result mainly of an increase in the polymorphonuclear leucocytes. 3. That, nevertheless, a lymphocytosis may be very occasionally observed in infants and young children. 4. There is a relative decrease of the large, mononuclear ele- ments, alike in fatal and non-fatal cases, though less marked in the chronic type. 5. That in the first three groups, there is sometimes an absolute decrease of the large mononuclear elements, and occasionally total absence of these cells; in the chronic type, absolute decrease like relative decrease is little marked. 6. That eosinophylic corpuscles in acute, fatal cases are always absent, although present in varying degrees in all other groups. b. Blood Cultures. — Gwyn, in 1899 (Bull. Johns Hopkins Hos- pital) first reported the isolation of the meningococcus from the blood in epidemic meningitis. Since then this has been frequently accomplished. Unfortunately, the meningococcus is even at its best difficult of initial cultivation, and especially so from blood cul- tures, so that the percentage of positive results has so far been 128 EPIDEMIC CEREBROSPINAL MENINGITIS. rather small. Elser isolated the meningococcus eleven times in forty-one cases examined — about 26.5%. With improved technic, the percentage of positive results will undoubtedly rise considerably higher. At the present time, however, the isolation of the menin- gococcus as an aid in the diagnosis of meningitis is of only slight value. c. Serological Examination of the Blood Serum of Meningitis Patients for Diagnosis. — 1. Agglutinins. — Agglutinins are com- monly present in the blood of meningitis patients, at times in con- siderable quantity. Von Lingelsheim, in 1900, reported reliable results with the serum of meningitis patients by using killed menin- gococcus cultures. Among 593 samples of serum from meningitis cases, this observer reported positive results in 218 instances. He considered dilutions of 1-25 as positive. MacGregor examined the blood of 75 cases of epidemic menin- gitis, making 400 observations at different periods of the disease. His conclusions were : 1. In very acute infections where toxemic symptoms are severe and death rapidly ensues (the chief epidemic type), there is an en- tire absence of agglutinin from the blood. 2. The degree of the agglutinating power that is developed in any case depends upon the initial features of the case, being propor- tional to the acuteness of onset, the duration of primary toxemia, and the degree of reaction. 3. Agglutinins are produced only in response to the early tox- emic phenomena; they appear to be independent of the subsequent course of the case. 4. In a number of acute cases examined (most of whom recov- ered), lasting from two to three days, agglutinins were absent or very feeble, hence they are of little value in diagnosis in such short cases. Davis, 1907, reporting the agglutination tests in eight cases, states that in all a positive result was obtained in dilutions of 1 :50, and in one case at the fourth week, up to 1 : 500. Two other cases gave a distinct reaction up to 1:100 dilution; the others agglutinated only up to 1 :50. Elser and Huntoon state that the diagnosis of epidemic menin- gitis by agglutination tests is surrounded by many difficulties. The values obtained with a given serum are in large part determined by the strain of meningoccoccus employed for the test. They refer to two sera of meningitis cases, which agglutinated one strain in dilu- tion of 1 :400, yet that agglutination with four other strains did not LABORATORY DIAGNOSIS OF MENINGITIS. 129 exceed 1 :50. While none of these strains were agglutinated by normal serum or serum from patients suffering from other diseases, tests undertaken one week later, with sera derived from two cases of typhoid, one of lobar pneumonia, and one of tuberculous menin- gitis, showed that the transplanted strains had become unusually sensitive to the action of non-specific agglutinins. The serum of one of the typhoid patients agglutinated the most agglutinable strain in dilution of 1 :100, and the four other strains to the same extent (1 :50) as the serum from the two meningitis patients. They state, however, that in certain cases coming under observation late in the disease, that the agglutination test may be the only labora- tory means of arriving at a diagnosis. They advise that every'test should be controlled by parallel tests with normal serum. Costa, 1912, described a simple method, a macroscopic agglu- tination test, which could be employed in a manner similar to the usual test. The culture is grown on agar 24 to 48 hours (preferably 24 hours). A little of the culture is emulsified in two drops of salt solution. Use a loop containing one twenty-fifth of a drop, for the serum. Take one loopful of the serum, mix with the culture. Mix for several minutes ; if no agglutination occurs macroscopically, add another loop of serum, making titre one-twenty-fifth. Mix, and if in two to three minutes no agglutination occurs, the serodiagnosis is negative. One can make dilutions of any titre in this way. He considers agglutinations at 1 :50 as positive. (Note. — Of course the same objections advanced by Elser and Huntoon hold for this method, as for the regular method of agglutinating.) 2. Opsonins. — MacGregor studied the opsonins in a series of 55 cases, making 175 observations in addition to studies on the agglutinins. He observed : a. The highest indices occur mostly in those cases with acute initial symptoms of not too short duration. These cases are also apt to have high agglutinins, and vice versa. b. The indices tend to be highest in the second and third week of the disease. c. A high opsonic index is a sign of forcible reaction to a fairly severe infection, and is of no prognostic value, as cases with low index may recover, and those with high may die. d. The degree of immunity after recovery as measured by the opsonic index is very variable. There may be no active opsonin in the blood for many weeks after resolution, or it may occasionally disappear relatively rapidly. 130 EPIDEMIC CEREBROSPINAL MENINGITIS. e. The opsonic index is of little diagnostic value, although it is very characteristic in a typical, severe case. Houston and Rankin, during the Belfast epidemic, studied over 370 samples of blood from suspected cases of epidemic meninigitis. They believe : a. A positive high opsonic index is present in most cases after the fifth or sixth day of the disease. b. Normal serum or the serum of other diseases than meningitis has little effect on the meningococcus, while in epidemic meningitis, it has a decided phagocytic effect. c. In all they obtained positive phagocytic reactions in 98% of the positive cases, examined after the sixth day. They believed the test could be used in diagnosis. Davis, 1909, in a number of observations on opsonins, found that, on the whole, there was somewhat greater phagocytosis of the men- ingococcus with meningitis serum than in normal serum. Some determinations did not show so great a difference between normal and meningitis serum, while others showed quite marked differ- ences. Some strains of meningococcus displayed a marked differ- ence of phagocytosis in favor of the meningitis serum, others very little or none at all. It is well to remember the considerable irregularities in readings that are at best obtained in opsonic studies. While in the Research Laboratories, I made a great many opsonic determinations with meningococcic sera and the meningococcus. Readings very often were extremely irregular and unreliable. Many strains of menin- gococcus show marked spontaneous phagocytosis, so that one can only use certain strains for the work. These strains also, will suddenly show spontaneous phagocytosis. Another important ele- ment to be remembered is the difference in strains in the meningo- coccus family, which has been described in a previous chapter. Thus if one used for diagnosis, an organism which belonged to a different strain than that which had produced the disease, one ob- tained widely varying readings. In view of the technical objections to the opsonic test in general, the special objections in this group of organisms, the irregularity in the opsonic content in the blood of meningitis patients as shown by MacGregor and Davis, the opsonic test, for diagnosis of meningitis, must be accepted with a great deal of reserve. 3. Precipitin Test. — Vincent and Bellofs test has been applied with blood of the patient against his own cerebrospinal fluid. A vary- ing degree of precipitin reaction is obtained in many instances, but LABORATORY DIAGNOSIS OF MENINGITIS. 131 the test, as already described in the diagnosis of the cerebrospinal fluid, is not absolutely reliable. 4. Complement-Fixation. — Meakens, 1907, reported that he ob- tained positive complement-fixation, using the serum of meningitis pa- tients in dilution of 1 :80, against the meningococcus antigen. He studied three cases, obtaining the serum for tests on the fifth, eighth, and thirteenth days of the disease respectively. Subsequently Dopter and others also showed the presence of immune bodies in the blood of meningitis patients by complement-fixation. I have demonstrated, however, in a previous chapter that there is considerable cross-fixation between the meningococcus and gonococcus and their respective sera, if non-specific bacterial antigens are used. Since patients suffering from gonococcus infection also, in the majority of cases, show immune bodies by complement-fixation, it would be absolutely necessary, for diagnosis, to use specific bacterial antigens, which do not give cross-fixation with other sera. If McNeil's specific antigen be proved by further studies to be specific, complement-fixation may then be of considerable diag- nostic value. 5. Bactericidal Substances. — Davis observed that the serum of meningitis patients, especially late in the disease, acquires definite bac- tericidal properties against the meningococcus. In the blood of several meningitis patients tested at varying times, from the tenth day of the disease to the seventh week, the meningococci, without exception, were rapidly killed, the plates usually being sterile at the end of three hours. It was also found that normal serum excited the same influence, but that the meningococcidal effect of the serum of meningitis patients was much greater than the normal. Dopter, likewise, later calls attention to the bactericidal properties of serum of meningitis cases. 6. Clinical proof of immune bodies in the blood of meningitis pa- tients, was demonstrated by McKenzie and Martin in the Glasgow epi- demic. They introduced the serum of recovered meningitis patients intraspinally in other acute cases as specific treatment, with fair results. They injected two acute cases in the sixth and seventh days of their illness with serum from their own blood ; both recovered. Summary of Blood Examinations in Epidemic Meningitis. — 1. There is constant leucocytosis with relative polynucleosis in epidemic meningitis. 2. Blood-culture in a small percentage of the cases shows the meningococcus. A greater percentage of positive blood cultures will probably be obtained with improved technic. 3. Immune bodies have been demonstrated in the blood of menin- gitis patients by agglutination, opsonin, precipitin, complement-fixation, 132 EPIDEMIC CEREBROSPINAL MENINGITIS. bactericidal and clinical tests. For establishing positive diagnosis, how- ever, examination must be made of the cerebrospinal fluid, which in the great majority of instances, will enable one to make an absolute diagnosis. The demonstration of specific immune bodies in the blood of meningitis cases has too many possible sources of error to be considered as one of the regular methods for diagnosis of meningitis. The tests should rather be reserved for the small percentage of cases, in which positive bacteriological examination of the cerebrospinal fluid cannot be made, especially in old chronic cases, with few organisms in the cerebrospinal fluid. PRESENCE OF MENINGOCOCCI IN OTHER SECRETIONS —ITS DIAGNOSTIC SIGNIFICANCE. a. Conjunctivitis. — The purulent discharge in conjunctivitis complicating meningitis, which is so common, usually shows intra- and extracellular meningococci in considerable numbers. b. Herpes, especially when purulent, readily shows the menin- gococcus in many instances. c. Urine. — During the stage of invasion, accumulative stage, of general bacteremia, meningococci may be present in the urine in con- siderable numbers, even before the active symptoms of meningitis have set in. (See case description, page 60.) During the acute stage of meningitis, meningococci can be readily demonstrated in the urine of many cases. As the disease progresses, either to recovery or to the subacute or chronic stage, the meningococci disappear. In the com- plication of meningococcic pyelitis, the meningococci are present in very large numbers. McKenzie and Martin isolated the meningococ- cus from the urine of a patient who recovered from meningitis. It is possible that that patient may also have had a slight pyelitis. d. Meningococci in Other Suppurative Foci in Meningitis. — 1. Otitis media, purulent. 2. Joint effusions as described under complications. ■ 3. Pericardium — especially in cases with suppurative pericar- ditis. 4. Pleura and spleen, quoted by McKenzie and Martin. 5. Sputum, in cases with meningococcic pneumonia, which oc- curs as a complication, or occasionally preceding the attack of meningitis. LABORATORY DIAGNOSIS OF MENINGITIS. 133 URINE EXAMINATION IN MENINGITIS. 1. Bacteriological findings as described. 2. Regular chemical examination is, in most cases, negative, except for the usual febrile reaction. Temporary albuminuria is seen in a moderate number of cases. True nephritis is uncommon. I met one instance of temporary glycosura during the acute illness. 3. Solbeit and Shubert have found that the condition of the urine in meningitis differs from that in other febrile disorders. During the acute stage, urea and phosphates are much in excess of the normal, while the chlorides are greatly diminished. The total amount of urine passed is much increased. If the urea remains high, when the temper- ature falls, and the symptoms have improved, the amelioration is only apparent and serum injection should be continued. These findings are very interesting, and should be confirmed by study of many cases. CHAPTER IV. COMPLICATIONS. Before the introduction of the specific serum treatment for menin- gitis, all complications were very common and resulted in many severe permanent disorders, if the patient ultimately recovered. Most com- plications are apt to occur during the subacute and chronic stages of the disease, though I have seen practically every complication during the first few days of the acute stage. Fortunately, specific serum treatment is now introduced early in most cases, so that complications, especially the graver ones, of the central nervous system are much less frequent. Complications may be classified into : 1. Those due to general meningococcus sepsis. 2. Those due to local lesions in the central nervous system. * GENERAL MENINGOCOCCUS SEPSIS. General septic phenomena occur in epidemic meningitis as a result of the general sepsis, as they do in other general bacteremias, due to other organisms, as from streptococcus, pneumococcus, and staphylo- coccus bacteremia. Thus, we meet with meningococcus pneumonia, pleurisy, endocarditis, pericarditis, joint inflammation, suppurative lesions in the eyes and ears, pyelitis, phlebitis, neuritis, adenitis, and even chronic general bacteremia, similar to chronic streptococcus bac- teremia, encountered in ulcerative endocarditis. These complications may persist long after the meningitis has subsided and may retard con- valescence for months. All complications are most apt to arise in the cases having evidence of severe general sepsis, especially in the petechial cases. Joint Complications. — These are very frequent, in some epidem- ics averaging between 10% and 15%. The inflammation in many cases occurs during the very acute illness, though it may be temporarily overlooked. A number of cases develop polyarthritis during their con- valescence; some at least may be explained as the result of general toxemia, such as seen in other acute infections. The lesion appears to be essentially a synovitis rather than true arthritis. Even where 134 COMPLICATIONS. 135 there has been extensive purulent inflammation, there appears to be little destruction of joint tissue. The infection apparently is a very benign one. In a few cases, where I had the occasion to examine the joint fluid, I found a thin, purulent fluid containing many meningococci. The involvement is usually polyarticular, both the larger joints, shoul- der, elbow, wrist, hip, knee, ankle, and the smaller joints of the fingers and toes being involved. As a rule, subjective pain is not marked, es- pecially when the joint is at rest, so that the patient may not call atten- tion to the joint involvement. The joints show varying degrees of accumulation of fluid, some becoming very tense. The shape of the swelling conforms to the collection of fluid within the joint. At times, however, one sees the fusiform swelling that occurs in the gonococcus joint. There is local heat, but redness of the skin is usually absent. There is tenderness, which is sometimes very ex- quisite on touch or manipulation. The joint involvement may, for description, be divided into: a. The usual acute form, which occurs at the very outset of the ill- ness, shortly after the onset, or at the beginning of the convalescence. As a rule the involvement is not very severe, though many joints may be affected. The collection of fluid is only moderate and causes little dis- comfort, the resulting disability lasting only for a few days, then clear- ing up completely, within a few days to a week or a little longer. b. This is really a subdivision of type a, differing from it only in the extent of the involvement. The joints become very tense and are accompanied by much local discomfort and by high fever. These cases sometimes require radical treatment. c. Subacute and Chronic Joints. — It is not uncommon for the in- flammations to persist for weeks or months. In the last Texas epi- demic, I saw a number of cases where symptoms were active four months later. In two instances, that of a father and son, there was a distinct synovitis, with a moderate accumulation of fluid in the knees and interphalangeal joints for four months after the acute attack of meningitis. The principal symptoms at this time were the tense feel- ing about the joints, some slight disability, and pain after using. Dur- ing the first two months the joints had been painful and had to be held immobile. Another case, a physician's wife, developed a polyarthritis twenty-four hours after her attack of meningitis. Three and a half months later, some of the joints were still painful and swollen ; the fingers were flexed and appeared to be ankylosed as if there had been an arthritis. Careful examination, however, showed that there was still some movement in the joints and that they were probably fixed from disuse. The previous two cases described showed that this 136 EPIDEMIC CEREBROSPINAL MENINGITIS. apparent ankylosis can be prevented even if chronic effusion persist, if passive and active movement be begun early. Prognosis in all joint inflammations is very good. Septic Pneumonia. — Septic pneumonia during the course of men- ingitis is very frequent. It was the most common complicating infec- tion that caused death during the period that I studied the Dallas epi- demic. It occurred not infrequently while the patient was in good general condition, so that one could not consider it merely as a terminal infection. It appeared chiefly among the negro patients. A number of them were very robust ; some had only a mild attack of meningitis ; others were recovering under serum treatment when they suddenly developed pneumonia. Fully 90% died. The complication was less prevalent among the whites, but among them also the mortality was very high. The lesion is most often a disseminated bronchopneu- monia, beginning at the base and running a rapid course, killing fre- quently in 48 hours. Undoubtedly the hypostasis at the base of the lungs, which can develop very easily in delirious unconscious patients who lie in one position for hours, if not changed, is an important pre- disposing factor. I believe that pneumonia can be avoided in a fair percentage of cases if sufficient care be employed to prevent hypos- tasis. Pyelitis. — Little or nothing has been written in the literature on this important complication. I was astonished, especially in studying many cases daily in the wards during the Texas epidemic, to' see how often this complication appears. Theoretically one would expect pyelitis as a frequent complication, meningitis being accompanied by a severe general bacteremia in many cases. The urine, as I will show later, excretes many of the meningococci. In describing this condition, I refer to a true inflammation of the kidney, not merely to the excretion of the bacteria in the urine. I should estimate that the complication occurs in about 5% of the cases, being most frequent in the severely septic cases. It occurs during the height of the infection or in the subacute stage or in convalescence. Subjective symptoms are fre- quently absent ; at times there may be complaint of pain in the lumbar region. Fever is usually moderate and irregular and chills are absent. Physical examination usually elicits distinct tenderness over the kidney and the ureter; enlargement of the kidney can occasionally be deter- mined. The urine is purulent and shows many extra- and intracellular meningococci. This form of pyelitis is benign and ordinarily subsides very promptly under general measures. I have never seen it develop into a true surgi- cal kidney. The condition is very important to remember especially COMPLICATIONS. 137 for diagnostic reasons. A patient may be recovering or be convalescent from meningitis. He, however, continues to run an irregular temper- ature and is not gaining ground. A careful examination will not in- frequently show this condition as the source of the trouble. Case. — Boy, aged six, had a severe form of epidemic meningitis, but re- sponded promptly to serum treatment; the meningitis had apparently sub- sided on the seventh day. He, however, continued to run a daily temperature of between 101° and 103°. Careful examination showed that his left kidney was palpable, slightly enlarged, and very tender. There was also some ten- derness over the course of the ureter. His urine was lightly purulent and contained many meningococci. Under general treatment and urotropin the condition subsided, the urine cleared up and the temperature dropped to normal. Chronic General Septicemia — Probably Accompanying Ulcera- tive Meningococci Endocarditis. — This condition is very rare. The general pathology of meningitis, however, can easily explain its occur- rence. Westenhoffer, in his pathological study of twenty-nine cases of epidemic meningitis, reported two instances of acute verrucous endo- carditis associated with this disease. One patient, a child, one year old, had been ill three weeks with epidemic meningitis. Autopsy showed a suppurative meningitis, bronchopneumonia, and vegetations on one of the mitral leaflets. The second case was a patient 21 years old, who died after a five days' illness. Autopsy showed suppurative meningitis and fresh gray vegetations over both mitral leaflets. The following case is a complete picture of chronic septicemia with infarctions, such as is seen in other forms of sepsis, especially in strepto- coccus or pneumococcus sepsis with verrucous endocarditis. Case. — Woman, aged 45, had acute onset, with chill, high fever, vomiting, severe headache. Several hours later, she was covered with a profuse pete- chial and purpuric eruption. Meningitic symptoms, however, did not appear for another 12 hours. Her urine at this time contained many meningococci. She responded very well to serum treatment; and her meningitis cleared up in about ten days. Her convalescence, however, was retarded. She con- tinued to fail; looked septic, and ran a persistently irregular temperature. During the acute attack of meningitis, the patient developed a polyarthritis, affecting most of the smaller and larger joints. Fourteen weeks later, some of these joints were still painful and swollen. In about the third week of her convalescence there appeared an extensive phlebitis of the external jugu- lar vein and the deep thoracic veins, as shown later by many superficial col- lateral veins over the chest. She recovered from this, then about a week later developed a dry pericarditis, which was accompanied by a blowing systolic mitral murmur. This condition subsided, the cardiac murmurs dis- appearing. Temperature, however, continued irregular, and she still looked septic. Several weeks later, she suddenly developed a large patch of pneu- monia with pleurisy. This, in turn, cleared up only to recur several weeks later. Again it resolved. A blood-culture at this time was negative. At 138 EPIDEMIC CEREBROSPINAL MENINGITIS. about the fourth month of her illness I again saw her. Physical examination was as follows: Patient looks emaciated and septic. She is irrational at times, but there is no evidence of meningitis. Her skin is pasty and yellow; she is very anemic. A few petechial spots are present over one shoulder and chest. There are a number of large superficial dilated veins, over the right chest anteriorly. Heart is slightly enlarged; there is a soft systolic murmur over the right auricle. Lungs negative. Spleen is enlarged, firm, three fingers below the free border of the ribs. Several of the interphalangeal joints of both hands, one elbow and one knee are swollen and very tender to pressure. Summary of physical examination: Anemia. Petechia. Enlarged spleen. Cardiac murmur. Another blood-culture was taken but was negative. The urine, un- fortunately, was not obtained. Fever up to the present time had been irregu- lar, being normal for a few days, then fluctuating between 100° and 103°. Discussion. — In spite of the negative blood-culture, the negative result of which may be explained by the technical difficulty to isolate the meningo- coccus from the blood and by the probability that bacteria were being dis- charged into the blood only periodically, the whole picture corresponds to a chronic sepsis with periodic infarctions, which occurred twice in the lung, by pericarditis and probably splenic infarcts. The most likely diagnosis was a chronic ulcerative endocarditis, due to the meningococcus. Phlebitis. — Phlebitis is an uncommon complication. I have seen it affecting the jugular veins, the deep thoracic veins, but most often the veins of the lower extremity. Neuritis. — Neuritis is also an uncommon complication. In a few instances it affected the posterior tibial nerves. Pericarditis. — Pericarditis is one of the rarer complications. Suppurative pericarditis has been described. I have in few instances seen pericarditis siccus which cleared up promptly, but never the former condition. COMPLICATION OF LOCAL INVOLVEMENT OF CENTRAL NERVOUS SYSTEM. Hydrocephalus. — Many cases of meningitis recover, with a per- sisting moderately sterile hydrocephalus. In some, symptoms may be absent or very mild, occurring especially after active exertion. The patient will complain of occasional headache, of vertigo, of apparently unexplainable irritability at times, of weakness of vision after pro- tracted use of the eyes, and he may suddenly vomit. These symptoms may last for several weeks or months, but gradually disappear and do not require very active measures. COMPLICATIONS. 139 In another group of cases, there is a greater accumulation of fluid, which increases in quantity during convalescence. These cases cause definite symptoms and are very annoying. The symptoms are usually very irregular. The patient will feel perfectly well for several days or a week or longer, then he will suddenly develop a group of pressure signs. Vomiting is repeated; headache is very severe; vertigo very pronounced on sudden turning of the head. The patient becomes very irritable and restless, and may complain of some pain in the back of his neck, though there is no rigidity or limitation of movement. Diplopia also is quite frequent. Examination shows a rational, but irritable patient. Macewen is marked. The pupils are dilated, respond- ing poorly to light. Slight strabismus may be present. Pulse is rapid, frequently of high tension and may be intermittent. The reflexes are often exaggerated. A high temperature up to 104° or 105° may be present. Simple rest in bed will usually cause these symptoms to sub- side in a few days, but they are very apt to recur. If lumbar puncture be done, one obtains large quantities (sometimes over 100 c. c.) of clear fluid, which shows no' bacteria and normal cytology. There is prompt improvement in all symptoms after the puncture and cure may result. (Case description, see under "Treatment.") A very curious picture results from the hydrocephalus in some cases. There may be no subjective symptoms at all, only a persisting, high, intermitting, irregular fever, occurring daily or every few days. The patient appears to be very comfortable, except for some irritability, even with the high fever, and may gain in weight and improve in other ways. Temperature, however, may persist for weeks unless the condi- tion is relieved. Physical examination usually gives evidence of hydro- cephalus at least by Macewen's sign or bulging fontanel or some pupil- lary change. Two brothers, one 5 years of age, the other 2, developed this curious picture. They recovered promptly from a mild attack of meningitis and continued well for about ten days. Then they both developed a high intermitting daily temperature. Physical examination gave marked Macewen's sign in both, distention of the veins over the scalp, wide sluggishly responding pupils, and very exaggerated reflexes. Otherwise they appeared normal. Clinical and laboratory examinations were made for other complicating diseases. Lumbar puncture in both showed a marked hydrocephalus. The fever did not recur for a few days, then again ran the same curve for a few more days, when the patients were again punctured. In all each was punctured three times when the fever dropped to normal and stayed there. The cerebrospinal fluid was clear and showed no meningococci by smear or culture. In a medical student who was three weeks convalescent from menin- 140 EPIDEMIC CEREBROSPINAL MENINGITIS. gitis, the condition of hydrocephalus caused a queer complaint. He noticed that his pupils had remained very widely dilated ever since his recovery. In addition he had occasional headache and vertigo. Exam- ination showed very widely dilated pupils, which responded very slug- gishly to light. The fundi showed some engorgement of his vessels. Macewen's sign was distinct. Deep reflexes were very much exagger- ated. There was gradual, steady improvement with complete recovery in two months. It is well to remember that severe hydrocephalus, whether it be present during the active stage of meningitis or in convalescence must be carefully handled. During the acute disease, sudden sitting up of the patient has caused death, while in convalescents, death has similarly been reported as occurring very suddenly after some quick, active physical exertion. Mentality. — During the active stage of meningitis, mental symp- toms frequently occur. Periods of perfectly clear sensorium are inter- rupted by intervals of delirium, delusions, irrationality. At other times a state of childish weakness is present throughout the entire illness. Occasionally one sees the condition similar to insanity occurring in typhoid convalescents, a rambling, irrational, at times, violent inco- herence. Change in disposition is very striking in many cases. During convalescence all mental symptoms ordinarily disappear, and the patient returns to the normal in full mental power. In about 2% of the serum- treated cases, complicating mental imperfections occur and persist dur- ing convalescence. They may be classified into : a. Change of Disposition. — In some cases this lasts a long time. As a rule, however, there is gradual improvement after a period of weeks or months. A notable illustration is the following: A child of six, before the attack of meningitis, was amiable, sweet-tempered and obedient. During convalescence a striking change in disposition was first noticed. Three months later, there was still no improvement. The child had become very wilful, destructive, disobedient, impossible to control, and a source of constant annoyance and terror to her mother. b. Persisting Imbecility. — In one instance, a boy of 18, who had been very bright and active before his attack of meningitis, was left weak-minded and idiotic for weeks after his recovery from the disease. After two months a slight improvement, as evidenced by restoration of memory, was observed. c. Evidence of Sclerotic Patches in the Brain and Cord, from a Diffuse, Severe Menin go -my elo encephalitis. — Such cases are exceed- ingly rare. The following is a very complete clinical picture of what may be seen. Man, aged 55. Previous history and health perfectly COMPLICATIONS. 141 good. He developed acute, active symptoms of meningitis, which cor- responded in every way to*those typical of epidemic meningitis. Lumbar puncture was not done by the attending physician, owing to objections by the family. The patient responded slowly, many of his meningeal symptoms cleared up and fever dropped to normal in about three weeks. It was noticed then that the patient was not convalescing. His mind was obscured and there was gradual development of other severe symptoms of derangement of the central nervous system. Two months after the onset of his meningitis he presented the following picture : Mentality was very much obscured. At times, the patient appeared to realize his environment, but for the most part, he lay with a staring, vacant expression — paying no attention to his surroundings. The eyes showed a divergent strabismus ; his pupils were dilated and irregular, but responded well to light. Fundus was negative ; slight lateral nys- tagmus ; slight left facial palsy. When the patient spoke, which was only occasionally, his words were thick, uttered slowly in syllables, and incoherent. There was a constant, marked coarse tremor of both hands, which was aggravated on voluntary motion. Both lower extremities were stiff and spastic; there appeared more relative weakness of the left limb. Knee-jerks were exaggerated. Ankle-clonus and Babinski present on both sides. There was incontinence of bladder and rectum. It was difficult to> determine the sensory disturbance and ataxia with any degree of accuracy, owing to his mental condition. Swallowing was very difficult so that the patient had to be fed by nasal gavage. During the previous week, a few general epileptiform attacks had oc- curred, at which times the patient was unconscious and had severe clonic convulsions ; the attack lasting a few minutes. Unfortunately, no lumbar puncture was allowed. Resume. — Types a and b of mental disturbance are the usual forms seen, and have a tendency to complete recovery. In many cases a con- siderable hydrocephalus is present and probably accounts, at least to a certain extent, for the symptoms. Type c is fortunately very uncom- mon and consists of widespread disseminated destruction through the brain and cord. Paralysis. — Any palsy or combination of paralyses may occur in epidemic meningitis. Some caused by nuclear lesions often occur during the acute stage. Thus, we commonly see the ocular palsies, principally divergent strabismus, and ptosis. Facial paralysis, also often occurs early. The more extensive paralyses, such as hemi- plegias or monoplegias, are not very common in meningitis. They are most apt to appear late in the disease, at the height of the active process. The following case illustrates: Girl, aged 14, developed 142 EPIDEMIC CEREBROSPINAL MENINGITIS. a very severe form of epidemic meningitis. Specific treatment was not begun by her physician, until the sixth day of her illness, when the patient was very acutely ill. On the eighth day, at a very crit- ical period of the disease, a complete left hemiplegia suddenly ap- peared. No convulsions occurred with the paralysis nor did there seem to be any aggravation of her meningitis. She ultimately recovered. Six months later, the hemiplegia was still present but showed a little improvement. At this time there was a spastic paralysis of the left upper and lower extremities. Most of the paralyses that occur in meningitis are due to cere- bral lesions but paralyses due to lesion of the cord are also present, and one of them, causing paralysis of the bladder, is extremely common and distressing. It frequently occurs at the onset of the disease, and persists throughout the entire course, gradually clear- ing up in convalescence. More extensive lesions of the cord are not frequent in menin- gitis. In a small percentage of the cases, very severe paralyses occur. In most instances the lower extremities are affected with a resulting paralysis usually complete and flaccid of one or both limbs. The limbs are flaccid, the reflexes are lost, and reaction of degeneration and trophic changes quickly set in. Loss of sensa- tion is usually associated with this condition. One patient, a girl of 10, had a complete flaccid paralysis of both lower extremities with lost reflexes, loss of sensation, and deep bedsores ; she also had paralysis of the bladder. This patient was admitted to the hospital on about the tenth day of the disease when the paralysis was two days old. No lumbar punctures had been done at the home of the patient, so that injury to the cord by puncture could be excluded. Another patient, a child of four, developed a flaccid paralysis of the whole right lower limb on the fifth day of the disease. Two lumbar punctures had been done, the last 24 hours before the paralysis appeared, and one would here have to consider the possi- bility of injury to the cord by the puncture. Another group of paralyses has interested me very much. I have seen about twelve cases, and in all, the lesions were first noticed during convalescence, when the patient attempted to walk. The symptoms were identical in each case, there being inability to use the lower extremities and considerable ataxia. Examination showed patients who had spastic paraplegia, affecting both lower extremities with very much exaggerated reflexes, clonus, and Babinski. Sensation was normal. Bladder was unaffected. In practically every instance pupils were very widely dilated and re- COMPLICATIONS. 143 sponded poorly to light. Romberg was pronounced in most. Two of the cases were lumbar punctured and gave a dry tap. A third yielded only a small quantity, about six c. c, of a clear fluid. I had occasion to observe two cases two months later. Both had im- proved considerably but were far from entirely recovered. The prognosis for the paralysis occurring in meningitis is a little better than for the similar lesions due to the usual other causes. The cranial nerve palsies, especially the ocular palsies, frequently the facial, clear up quite promptly. The more extensive paralyses, the mono- and hemiplegia, the severe paralysis of cord origin, do not have a very favorable outlook for complete recovery, though considerable improvement usually occurs. Eye Complications. — The great frequency of eye complications in meningitis may possibly, to a very great extent, be explained by the structure of the optic nerve and its intimate association with the brain. It is frequently described by anatomists as a prolongation of the brain substance rather than as an ordinary cerebrospinal nerve. As it passes from the brain, it receives sheaths from the cerebral membrane, a perineural sheath from the pia mater, an in- termediate sheath from the arachnoid, and an outer sheath from the dura mater, which is also connected with the periostium as it passes through the optic foramen. These sheaths are separated from each other by spaces that communicate with the subdural and sub- arachnoid spaces respectively. The innermost or perineural sheath sends a process around the arteria centralis retinae into the interior of the nerve, and enters immediately into its structure. Thus, in- flammatory affections of the meninges or of the brain may readily extend themselves along these spaces or along the interstitial con- nective tissue in the nerve. The intimate association between the infected meninges and the ocular nerve may thus readily explain the frequent eye suppurations in epidemic meningitis. Another possible mode of infection in meningitis, may be due to the severe general bacteremia (sepsis) which is frequently present in the acute stages of the disease. The suppuration of the eye in meningitis may affect any of the eye structures. The most common infection is conjunctivitis, which may be one of the earliest lesions, and be present in the first general bacteremic stage, even before the occurrence of the active meningitis. The infection is benign and subsides quickly and spontaneously. The conjunctival purulent secretions show the men- ingococci, extra- and intracellular, in abundance. 144 EPIDEMIC CEREBROSPINAL MENINGITIS. The next most frequent infection is suppurative choroiditis. There is often complaint of little pain, attention being called to the condition, by the pronounced congestion of the conjunctiva, with chemosis and swelling of the lids. The cornea becomes clouded, and pus appears in the aqueus and vitreus. Sight is rapidly lost. Panophthalmitis sometimes results. There are two probable great causes for the blindness which may result without external evidence of suppuration : 1. From hydrocephalus (pressure). 2. Nuclear lesions. 1. Bundness from Hydrocephalus. — The most severe general pressure symptoms from hydrocephalus occur in posterior basic menin- gitis, in which there is an encapsulation of fluid within the ventricles of the brain. One of the earliest symptoms noticed is a peculiar staring expression, with considerable dimming of vision, which later is followed by total blindness. Dr. Taber of Dallas examined the fundi of a number of these cases for me. In some, no appreci- able changed was noted in the fundus ; in other cases, however, he observed a marked blanching of the vessels, which was immediately relieved on release of the hydrocephalus by direct ventricular punc- ture. Likewise there was an apparent return of vision in cases treated by ventricular puncture, with regular relief of the hydro- cephalus. These cases of blindness, therefore, may be readily explained on the basis of hydrocephalus. 2. Bundness from Nuclear Lesions. — The diagnosis of blindness as a result of nuclear lesions is made principally by exclusion. Pathologic examinations have been very incomplete in this group of cases. These cases show upon examination a normal eye and normal fundus, thereby excluding any local etiology. No evidence of hydrocephalus can be found, either by physical signs or by lum- bar puncture. Thus, by exclusion, the blindness must be explained by either retrobulbar neuritis or nuclear lesion. The prognosis of such cases following meningitis, is bad. Ear Complications. — Ear complications and sequelae, formerly so dreaded, are fortunately now very much less common. The lesion consists of: 1. Local middle ear suppuration. 2. Deafness. 1. Middle ear infection here is clinically the same as any middle ear infection, but does not appear to be as virulent as other infec- tions. Rarely does it sufficiently affect the mastoid, to necessitate operation. -COMPLICATIONS. 145 2. Deafness. — This unfortunate condition occurs most often as a late complication, though it is by no means uncommon, within the first few days of the disease. It has appeared in a number of cases in my experience, on the third and fourth days of the illness, and in one case was noted on the second day. The cases of deafness may be separated for prognostic purposes into: a. Those that recover, b. Permanent deafness. a. Cases of Deafness That Recover. — Quite a large number of cases of deafness, following meningitis, show gradual steady im- provement beginning with convalescence from meningitis, with complete return of hearing after several weeks or months. I be- lieve that these cases of deafness are, to a very great extent, the result of hydrocephalus. They show other distinct clinical and physical signs of hydrocephalus as the following case illustrates: Mr. D., aged 56, developed chronic meningitis. He had afebrile normal periods for intervals of a week to ten days, then suddenly developed fever, with cerebral symptoms. He became irritable and somewhat stuporous, vomited, complained of intense headache, and became very deaf. Sudden turning of the head from side to side caused severe vomiting and marked nystagmus. Lumbar puncture regularly showed a large collection of clear fluid under pressure. Following the operation all the symptoms cleared up, the hearing immediately began to improve and became normal in a few days. With a return of the hydrocephalus there was an immediate recurrence of the deafness and of all the other symptoms mentioned. The patient experi- enced a number of such attacks, each relieved by puncture. He finally re- fused to have any more punctures performed. All of his symptoms, especially his deafness, grew very much worse for one week, then gradually began to improve. He made a complete recovery in six weeks. Cases like the above are commonly seen, especially among chil- dren, who often develop extreme hydrocephalus. These cases of hydrocephalic deafness begin to show improvement within a short period of days or a few weeks at the most, after the attack of men- ingitis, unless the hydrocephalus is unusually persistent. 2. Permanent Deafness. — Permanent deafness, as a distinct and separate complication, is probably due to nuclear lesion. It may occur very early in the disease, and ' is entirely independent of hydrocephalus. It shows no improvement from the time of its occurrence, and is permanent and unamenable to treatment. Boy, aged six, had a severe attack of meningitis. On the fourth day he was found to be totally deaf. His meningitis cleared up promptly under treatment ; but the deafness persisted. Six months later there was still no improvement in his hearing. 146 EPIDEMIC CEREBROSPINAL MENINGITIS. Labyrinthian Involvement. — In the 1912 epidemic in Texas, Dr. Taber examined many cases for evidence of labyrinthian disorder. In most of the acute cases, he failed to elicit evidence of labyrinth- ian involvement. In a number of cases of deafness, which he examined after the recovery from the active meningitis, he found evidence of consider- able involvement of the labyrinth in the affected side. During the acute stage of meningitis, one should expect a certain degree of labyrinthian involvement accompanying the increase of cerebrospinal exudate. In the case of Mr. D. the very severe symp- toms of vertigo, vomiting, and nystagmus, appeared to be due to such involvement. RESUME OF SYMPTOMS OCCURRING DURING CONVALESCENCE. The various complications that may occur in meningitis, have been described. It has been seen that some of the complications may be manifested by fever with few other general or local symp- toms. It is thus important to bear the possible complications in mind, when one is confronted by irregular fever, which occurs dur- ing apparent convalescence, and which seems to have no effect on the general health of the patient, so that even older children will not complain. To summarize, the most common conditions which may compli- cate convalescence, and the principal symptom of which may be only fever, are: 1. Simple hydrocephalus. 2. Polyarthritis — without much effusion. 3. Pyelitis. 4. Relapse — mild. COURSE OF EPIDEMIC MENINGITIS. The acute cases have a tendency to run a rapid course. Before the introduction of serum therapy, this course was a fatal issue in 80 to 90% per cent of the cases, and death occurred frequently in a few days. Since the introduction of serum therapy, figures have been re- versed, and most cases recover in as many days as the disease required to kill formerly. COMPLICATIONS. 147 A certain number of acute cases, without serum treatment or with imperfect serum treatment, a small number in spite of serum treatment, lapse into the chronic stage. The outlook here is un- favorable. These cases run a course lasting from a few weeks to two or three months, in most cases, ultimately terminating fatally. The further course of meningitis depends, to a very great extent, on the complications. CHAPTER V. STUDIES ON BLOOD-PRESSURE IN MENINGITIS. My studies on the subject of blood-pressure in meningitis were undertaken to determine primarily the change in blood-pressure induced on injecting serum into the subarachnoid space in the course of treatment; whether this change was a constant one and whether it could be utilized to control the administration of serum. I was concerned essentially with relative changes in blood-pressure rather than the initial blood-pressure before the operation. I have taken over one thousand readings since undertaking this work; patienis were studied at all stages of the disease. Cushing, in 1901, showed by a number of experiments on dogs that when the intracranial tension was raised by means of salt solu- tion forced into the subdural space of the cranium and vertebral column, the blood-pressure rose. He noted also that the rise of blood-pressure tends to find a level, slightly above that of the pres- sure exerted against the medulla. Robinson, in 1910, made a series of clinical observations on the variations in blood-pressure in different stages of meningitis and the relationship between the degree of intracranial pressure and the blood-pressure curve, especially upon removing fluid by lumbar puncture. He noted that heightened blood-pressure was present in many of his cases of meningitis. The highest blood-pressure ap- peared early in the disease with the severe symptoms and late in the disease with the preterminal symptoms, before the final failure of the circulation. There seemed to be a relationship between the severity of the symptoms and the blood-pressure in a number of instances, the pressure rising as symptoms became worse. He likewise noticed that in five cases of apparent relapse, there was an accompanying rise in blood-pressure. He also made observations on the change in blood-pressure after withdrawing cerebrospinal fluid by lumbar puncture, and found that the change in blood- pressure was not constant. In 23 instances there was an average reduction of 10 mm. of mercury on removing 23 c. c. of fluid; in 11 cases there was an average rise of 7 mm. of mercury on removing 37 c. c. of fluid; 5 cases showed no change in blood-pressure on removing about 30 c. c. of fluid. 148 STUDIES ON BLOOD-PRESSURE IN MENINGITIS. 149 There was no apparent relationship between the day the lumbar puncture was done and the effect on the blood-pressure nor did the initial blood-pressure nor the cerebrospinal fluid pressure indicate whether the withdrawal of fluid would cause a rise or fall. He concluded that there was no constant relationship between the heightened intracranial tension and the heightened blood-pressure seen in meningitis. He mentions as other possible causes for the high blood-pressure in meningitis the following: 1. Active muscular movements associated with the delirium. 2. Fever. 3. Reflex stimulation of the blood-pressure-raising mechanism, by irritation of the central nervous system or less directly through pain. 4. Irritative phenomena, analogous to the slow, vagus pulse, photophobia and delirium, seen in meningitis. (Suggested by Janeway.) 5. Reflex peripheral sensory stimulation, especially on the pos- terior spinal nerve-roots. In order to simplify my tables, I have selected only 110 histories containing my records of about 300 lumbar punctures for analysis. The studies will be classified into : I. Blood-pressure in epidemic meningitis. II. Effect on blood-pressure of withdrawing fluid by lum- bar puncture. III. Effect on blood-pressure of injecting serum. I. BLOOD-PRESSURE IN EPIDEMIC MENINGITIS. A study of the following tables will enable us to consider the following data : 1. Usual Blood-Pressure in Cases of Epidemic Meningitis. — In the majority of cases of epidemic meningitis, blood-pressure is raised above the normal. This appears to be especially marked in children up to 10, whose blood-pressure not infrequently is as high as that of adults. In many cases of meningitis, however, particu- larly in adults, the blood-pressure is considerably below the normal, this being seen among patients who are only moderately sick, ulti- mately recovering. It is quite commonly low also, in the severe septic, toxic patient. 2. Variations in Blood-Pressure at Different Periods of the Disease. — It has been stated by Robinson that the blood-pressure is frequently highest early and late in the disease. The blood-pres- 150 EPIDEMIC CEREBROSPINAL MENINGITIS. 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In those who recover with clearing-up of the hydrocephalus, one would theoretically expect a lower blood-pressure at the end of the disease. In many cases, however, the blood-pressure shows little change. Some cases show a high blood-pressure on recovery, while a somewhat larger number show a moderate fall in blood-pressure. There is similarly a very irregular change in those in whom the disease grows progressively worse, ultimately causing death. The end readings noted in Table XI were taken before failure in circula- tion, in most cases 24 hours before exitus. While a number of cases showed the rise in blood-pressure that Robinson describes as occurring with aggravation of symptoms, a great many showed the opposite change at all periods of the disease, so that it would be im- possible to predict aggravation of symptoms by this measure. This was especially well illustrated in treating a number of cases of chronic meningitis and in relapse cases in whom symptoms, prin- cipally hydrocephalic, appeared very irregularly at intervals of days or a week or longer. These cases showed very irregular curves, frequently a lower pressure, at other times a rise. I tabu- lated many records where there was considerable intracranial ten- sion, proved by removing large quantities of cerebrospinal fluid. Both high and low blood-pressures were encountered. In practically every case of meningitis, there was increased intracranial tension at some time during the disease. Observations of the cerebrospinal fluid pressure were made in a number of cases, the pressure readings usually obtained being between 150 and 400 mm., other times higher. In the cases with marked hydrocephalus, readings at times as high as 800 mm. water pressure were obtained. The blood-pressure had apparently no relation to the degree of intracranial tension. Summary. — 1. Heightened blood-pressure occurs in many cases of epidemic meningitis. The rise is frequently especially marked in children up to 15 years of age. In children of one year, a blood- pressure of 90 to 100 mm. is not uncommon. 2. Heightened blood-pressure, however, is not a constant fea- ture. Many cases, especially septic adults have a low blood- pressure. 152 EPIDEMIC CEREBROSPINAL MENINGITIS. 3. During the course of the disease, there is frequently very wide, irregular fluctuation in blood-pressure, apparently regardless of the course of the disease. Cases with very high blood-pressure early in the disease showed an appreciable drop later where im- provement was evident ; others manifested the very opposite change while many displayed no change. While aggravation in symptoms was occasionally accompanied by a rise in blood-pressure, this was by no means a constant feature and showed the same irregularity as the cases that recovered. Heightened blood-pressure may be of some diagnostic signifi- cance in suspected meningitis in children under 15 years. II. EFFECT ON BLOOD-PRESSURE OF WITHDRAWAL OF FLUID BY LUMBAR PUNCTURE. Table XII is a compilation of 264 lumbar punctures. The table is divided into three parts, according to the initial blood-pressure, whether it be high, normal or low. The quantity of fluid with- drawn is noted, and its effect on the blood-pressure. A study of Table XII indicates that the initial blood-pressure before the lumbar puncture does not show how it will be influenced by the removal of fluid. Cases with initial low or normal blood- pressure are apparently similarly affected by the removal of fluid, in most instances there being a drop of from 3 to 10 mm. of mercury, very occasionally more. In a small number of cases there is no change in blood-pressure, and in others there is a rise. The rise in blood-pressure is usually small, being commonly between 2 to 10 mm. of mercury. Occasionally the rise is considerable, up to 20 mm. Cases with initial low pressure, more than others, appear to respond to the withdrawal of fluid by a rise. Effect of Quantity of Fluid Withdrawn and Rapidity of With- drawal on the Reaction in Blood-Pressure. — In most instances the drop in blood-pressure occurs only when the larger quantities of fluid are withdrawn. Very frequently, however, as is seen by the table, very large quantities can be removed without causing any change, or in some cases even causing a rise. The rapidity of withdrawal of the cerebrospinal fluid is an im- portant factor, especially in cases with very high cerebrospinal fluid pressure. If one allow the fluid to flow as rapidly as it can through the usual lumbar puncture needle of about 19 mm. bore, a drop in blood-pressure will not infrequently result. This is particularly STUDIES ON BLOOD-PRESSURE IN MENINGITIS. 153 true where the cerebrospinal fluid pressure is high and the quantity of exudate large. TABLE XII. Changes in Blood-Peessure on Withdrawing Cerebrospinal Fluid. Total No. of Cases No. with No. with Drop in B. P. no Change No. with Rise A. Initial High 129 85 29 5 Pressure Amount of Fluid 7-72 c. c. 10-50 c. c. 12-65 c. c. Removed Average Change (— ) 3-10 ( + ) 2-12 in B. P. B. Initial Normal 90 77 11 2 Pressure. Amount of Fluid 10-80 c. c. 15-50 c. c. 35-60 c. c. Removed Average Change (— ) 3-10 ( + ) 5-10 in B. P. C. Initial Low 44 38 3 3 Pressure Amount of Fluid 5-96 c. c. 10-55 c. c. 10-40 c. c. Removed Average Change (— ) 3-10 ( + ) 3-20 in B. P. Gross Tabulation of A. B. and C. in Above Table. Amount of Fluid Removed Average Change in B. P. 263 210 7-96 c. c. (— ) 3-10 43 10-55 c. c. 10 10-65 c. c. ( + ) 2-20 The Change in Blood-Pressure After Lumbar Puncture in Later Punctures. — This is an important point to determine — whether the changes are less marked in later punctures than in the first opera- tion. A study of many records fails to establish any regularity in this respect. Some cases will show less response in later punctures with less drop on removal of fluid, while other cases, especially very severe cases with considerable hydrocephalus, later show a larger 154 EPIDEMIC CEREBROSPINAL MENINGITIS. drop in blood-pressure on removing relatively smaller quantities of fluid III. EFFECT OF INJECTING SERUM ON THE BLOOD-PRESSURE. We have seen that the removal of cerebrospinal fluid causes a moderate drop in blood-pressure in most cases. The next impor- tant step is to determine whether replacing the fluid withdrawn, by injecting serum, causes a rise in blood-pressure and theoretically re-establishment of conditions as they were before the lumbar punc- ture. Upon this point hinges, to a very great extent, the establish- ment of a dose of serum that can be safely injected. In over 95% of cases, injecting a moderate quantity of serum, e. g., in children over 4 c. c, in adults over 8 c. c, causes a decided drop in blood- pressure with steady and increasing drop as the larger quantities of fluid are introduced. Thus, the first important fact has been established — that there is a drop in blood-pressure on injecting serum, irrespective of the previous change in blood-pressure on simple removal of cerebrospinal fluid whether it causes a fall or rise. TABLE XIII. Change in Blood-Pressure on Injecting Serum. Cases Being Divided According to Initial High, Normal or Low Pressure. Initial Blood-Pressure No. of Cases Average Dose of Serum Drop in Blood-Pressure A. High B. Normal C. Low Average of A. B. & C. 105 85 45 235 14 c. c. 24 c. c. 18 c. c. 15 c. c. 11 mm. of mercury 15 mm. of mercury 16 mm. of mercury 11 mm. of mercury Table XIII is a compilation of about 235 treatments recording the quantity of serum injected in each case, with the total change in blood-pressure. The record is divided into three groups — 1st, where the initial blood-pressure was higher than normal; 2nd, where the blood-pressure was normal, and the 3rd, where it was below normal. The quantity of fluid withdrawn apparently is no guide as to the quantity of serum that can be injected without causing a further drop in blood-pressure. Thus, the removal of even very large quantities of cerebrospinal fluid may be accompanied by only STUDIES ON BLOOD-PRESSURE IN MENINGITIS. 155 slight change in blood-pressure, while in injecting relatively a very small quantity of serum, there may be a considerable drop in blood-pressure. In very many cases, however, the preliminary removal of large quantities of cerebrospinal fluid that has not caused much change in blood-pressure, will enable one to inject somewhat larger quantities of serum with only moderate drop in blood-pressure. In cases where there is less marked hydrocephalus, the removal of the smaller quantities of cerebrospinal fluid will fre- quently be followed by a larger drop in blood-pressure on injecting smaller quantities of fluid. Thus, for example, on removing the large quantities of fluid, as 40 c. c. or more, one can frequently inject 20 c. c, at times even more, with only moderate drop in blood-pressure ; while in cases where one can remove only small quantities of fluid, such as 5 to 10 or 15 c. c, one can usually inject only a few c. c. of serum without causing much drop in blood- pressure. The exceptions to these results are so very frequent, that it must be strongly emphasized that one cannot in any one case predict the change in blood-pressure that will result on injecting any quantity of serum. In some patients one can inject even larger quantities of serum than fluid withdrawn without causing much change in blood-pressure; while in others injecting much smaller quantities of serum than cerebrospinal fluid withdrawn will cause much greater drop in blood-pressure. The only absolute guide is by taking blood-pressure observations in every case. Patients who have initial high or normal blood-pressure will very often bear the injection of large quantities of serum with less change in blood- pressure than those with initial low blood-pressure, though this also has many exceptions. Those with initial high blood-pressure can, of course, bear a larger drop in blood-pressure with less discomfort and danger than can patients with initial low pressure, relatively a much smaller drop. As a rule, injecting larger quantities of serum than the amount of cerebrospinal fluid withdrawn, causes a very large fall in blood- pressure. The rapidity of injecting serum and the pressure used in inject- ing, are two very important elements that affect the change in blood-pressure. Injecting only very small quantities of fluid, very rapidly under considerable pressure, will usually cause a much greater fall in blood-pressure than injecting larger quantities of fluid slower under low pressure. The rate of injecting serum in any particular case can only be determined by observing the effect on the blood-pressure, so that, in some, one can inject much more 156 EPIDEMIC CEREBROSPINAL MENINGITIS. rapidly than in others. As a rule it requires about 20 minutes to inject 20 to 30 c. c. of serum, though I have frequently taken longer to inject smaller quantities. Rise in Blood-Pressure After Injecting Serum. — The total per- centage of cases that had a persistent rise after injecting moderate doses of serum is very small in my series — about 2%. A number of cases have a temporary rise on injecting only a few c. c. of serum, followed by the usual fall in blood-pressure. The total rise in blood-pressure is usually only very small, though occasionally, as in one chronic case, there was a rise of 20 mm. after injecting 10 c. c. of serum. It is most apt to occur in those patients who have an initial high blood-pressure. Change in Blood-Pressure After Operation. — In most cases where there has been only a moderate drop in blood-pressure after lumbar puncture with removal of fluid and injection of serum, there is a tendency for the blood-pressure to rise and regain most of the drop, a few minutes after the operation. Most important, however, is the fact that where there has been a large drop in blood-pressure with the severe symptoms of shock occurring later, the tendency of the blood-pressure is to continue dropping even after the operation. It is important to guard against this. • Changes at Later Puncture. — The same holds true here as in the simple removal of fluid. There is no regularity in the way the patient bears the injection of serum at later punctures as compared to the early injection. In many cases there is a tendency toward a greater fall in blood-pressure after injecting serum in later treat- ments. This, however, cannot be predicted as the opposite occurs very commonly. Average Quantity of Serum That Can Be Safely Injected. — This depends on three factors : the initial blood-pressure ; the quantity of cerebrospinal fluid withdrawn, and the immediate effect of the injection on the blood-pressure. In cases with initial normal pressure, an average dose (based on the observation of many cases, considering the usual amount of hydrocephalus) is as follows : Under 1 year 3 to 9 c. c. 1 to 5 years 3 to 12 c. c. 5 to 10 years 5 to 15 c. c. 10 to 15 years * 10 to 20 c. c. 15 to 20 years 15 to 25 c. c. 20 years and over 20 to 30 c. c. Very High 12 c. c. 15 c. c. 20 c. c. 25 c. c. 30 c. c. 40 c. c. STUDIES ON BLOOD-PRESSURE IN MENINGITIS. 157 In those with initial low blood-pressure, the quantity of serum may be very small, at times less than the smaller quantities men- tioned in the above list. Blood-Pressure Observations in Cases of Posterior Basic Menin- gitis. — The same general readings and results were obtained in these cases as in the usual form of meningitis. The tapping of the ventricles by direct brain puncture frequently caused little or no change in blood-pressure. The injection of serum was usually accompanied by a fall in pressure, though the direct introduction of serum into the ventricles appeared to cause less change than in injecting a similar quantity of fluid by the spinal route. INTERPRETATION OF OBSERVATION ON BLOOD- PRESSURE IN MENINGITIS. I believe that all of the changes described, theoretically at least, can best be explained by Cushing's description of a vasomotor reg- ulatory center that raises blood-pressure in increased intracranial tension. According to his explanation, the rise in blood-pressure is due to the stimulation of the regulatory center. In meningitis, there are two important agents which must be considered : first, hydrocephalus frequently increasing and of long-standing; and second, general sepsis and toxemia. With hydrocephalus alone, at first one would expect an increase in blood-pressure; such appar- ently occurs very often. With long-standing, and frequently rap- idly increasing hydrocephalus, the center may be unable to produce a sufficient regulatory rise in blood-pressure, due to its exhaustion from long overstimulation, accounting for some of the low blood- pressures that one sees in patients — especially in some of the chronic cases suffering principally from hydrocephalus. In other cases the marked general sepsis probably plays an important role in depressing the center, and accounts for irregular readings during the disease. In cases with high blood-pressure, one would expect, according' to this explanation, a large drop in blood-pressure on removing fluid. In many cases there is a moderate drop, while in others there is no change or even a rise in blood-pressure. I believe that these irregular results, in view of the changes occurring on inject- ing serum, can be best explained by vasomotor depression, result- ing from the rapid removal of a large quantity of fluid that took a relatively long time to accumulate. The rise in some of the cases is 158 EPIDEMIC CEREBROSPINAL MENINGITIS. difficult to explain, but the considerable rise in some cases that have initial low blood-pressure — such as a rise of 20 mm. in an adult with initial pressure of 60 — would seem to indicate the stim- ulating effect of the release of pressure in cases where the vaso- motor center was very much depressed, failing to show any response to the accumulation of fluid. The increase of intracranial tension by the injection of serum differs from the usual pathological increase of intracranial tension that occurs much slower, and requires at least from several hours to days to accumulate. This would allow a gradual accommoda- tion in blood-pressure. In injecting serum there is a very rapid increase in intracranial tension produced in a number of minutes. This would be expected to act and apparently does act as a depress- ant, causing a rapid fall in blood-pressure, which increases with the quantity of fluid injected. This depression is probably all the more marked, since the centers have already been overtaxed by a continuous pathological hydrocephalus. This explanation would account for the fall in blood-pressure on injecting serum as being due to the immediate mechanical effect. The coincident change in blood-pressure during the injection of serum and the tendency to regain the loss and return to the reading before the puncture, which frequently takes place a few minutes after the operation in those who had only a moderate fall, together with the tendency to further fall in those who have had a very large drop, would point to the mechanical explanation. It has been demonstrated by different observers that, on inject- ing sera into the general circulation of animals, there is a marked depression in the blood-pressure. This chemical factor in the serum would therefore have to be considered as a possible explana- tion for the fall in pressure, following intraspinal injection of serum. A possible anaphylactic phenomenon would also have to be con- sidered All data point to the mechanical explanation. It would be desirable, for the sake of accuracy, to definitely establish this point. OBSERVATIONS ON PULSE-RATE DURING LUMBAR PUNCTURE. It is difficult to make true observations, since the excitement during the operation, and especially following struggling, causes an immediate rise in many. As near as could be determined, the pulse rate in most cases of meningitis is accelerated; in some, a smaller. STUDIES ON BLOOD-PRESSURE IN MENINGITIS. 159 number, the pulse is very much slower. The immediate withdrawal of fluid does not appear to cause very much change in most patients. In some who have an initial rapid rate, there appears to be a mod- erate slowing in the rate. In most cases there is a rise of from 10 to 30 beats per minute after the injection of serum. A smaller percentage manifest a little slowing in the rate. Toward the end of the Texas epidemic, Dr. Carter undertook some experimental work on dogs to learn the cause of the severe shock that sometimes follows the injection of serum into the sub- arachnoid space of the spinal cord. Some of his conclusions were as follows : "No definite limit can be fixed to which the intraspinal pressure may be increased with safety. In some animals, serious symptoms developed when it was increased to 10 mm. of mercury, while in others this only occurred with a pressure of 50 or 60 mm. of mercury. The normal intraspinal pressure in dogs varies from 3 to 10 mm. of mercury, or 40 to 135 mm. of water. A sudden increase of pres- sure, even though a small amount be given, is more dangerous than a larger amount given gradually by gravity. The first mechanical effect of increasing the intraspinal pressure from injections made by lumbar puncture is the cessation of respira- tion quickly following it, or coincidently with it ; there is profound cardiac inhibition, which causes a tremendous and sudden fall of blood-pressure. The fall of pressure is often so abrupt that it frequently drops from normal to zero within a half minute. Atropin removes the cardiac inhibition and restores blood-pres- sure by its paralyzing effect upon the cardio-inhibitory nerve center. Atropin fails to stimulate the respiratory center, while cocain is the most valuable respiratory stimulant for such an emergency. The fall of pressure is not due to vasomotor disturbance. There is, therefore, no indication for the administration of adrenalin. On the contrary it is positively contraindicated on account of its well- known action in producing cardiac inhibition. Lowering the intraspinal pressure, by allowing fluid to escape from the needle after the characteristic symptoms develop, fails to relieve the condition." It may be noted here that the last observation does not hold true in the human being. The symptoms of shock, fall in blood-pres- sure, respiratory embarrassment are immediately relieved in the 160 EPIDEMIC CEREBROSPINAL MENINGITIS. great majority of cases on removing fluid from the canal, after the symptoms have developed. The explanation of these experimental data, as related to clinical cases in treatment, are discussed in^detail under "Treatment" (see page 211. CHAPTER VI. TREATMENT. i THE ANATOMY OF THE CEREBROSPINAL MENINGES AND OF LUMBAR PUNCTURE. The Meningeal Spaces — (Howell). — The general arrangement of the meningeal membranes, and particularly of the meningeal spaces, is important in connection with the mechanics of the brain circulation. In the skull the dura mater adheres to the bone, the pia mater invests closely the surface of the brain, while between lies the arachnoid. The capillary space between the arachnoid and the dura, the so-called sub- dural space, may be neglected. Between the arachnoid and the pia mater, however, lies the subarachnoidal space more or less intersected by septa of connective tissue, but in free communication throughout the brain and cord. This subarachnoidal space is filled with a liquid, the cerebrospinal liquid, which forms a pad inclosing the brain and cord on all sides. The liquid surrounding the cord is in free commu- nication with that in the brain, as is indicated in the accompanying Fig. VIII. Within the brain itself there are certain points at the angles and hollows of the different parts of the brain, at which the subarach- noidal space is much enlarged, forming the so-called cisternal, which are in communication one with another by means of the less conspicu- ous canals. The whole system is also in direct communication with the ventricles of the brain, on the one hand, through the foramen of Magendie, the foramina of Luschka, and perhaps at other places, and on the other hand, along the cranial and spinal nerves it is continued outward in the tissue spaces of the sheaths of these nerves. The Pac- chionian bodies constitute also a peculiar feature of the subarachnoidal space. These bodies occur in numbers that vary with the individual and with age, and are found along the sinuses, especially the superior longitudinal sinus. Every body is a minute pear-shaped protrusion of the arachnoidal membrane into the interior of a sinus, as represented schematically in Fig. IX. Through these bodies the cerebrospinal liquid is brought into close contact with the venous blood, the two being sep- arated only by a thin layer of dura and the very thin arachnoid. The 161 162 EPIDEMIC CEREBROSPINAL MENINGITIS. number of Pacchionian bodies is hardly sufficient to lead us to sup- pose that they have a spinal physiological importance. Intracranial Pressure. — By intracranial pressure is meant, the pressure in the space between the skull and the brain — therefore the pressure in the subarachnoidal liquid and presumably also the pressure in the ventricles of the brain, since the spaces are in communication. This pressure may be measured by boring a hole through the skull, dividing the dura, and connecting the underlying space with a ma- nometer. Observers who have measured this pressure state that it is always the same as the venous pressure within the sinuses. This we skull rain dura-mater cerebrospinal liquid Subarachnoidal space spinal column dura- mater cerebrospinal liquid spinal cord. Fig. VIII. Diagram to show the connection of the subarachnoidal space in the brain and the cord. (From Howell's Physiology.) can understand when we remember the close relations between the subarachnoidal liquid and the large veins and sinuses. We may con- sider that the large veins are surrounded by the cerebrospinal liquid, and consequently an equilibrium of pressure must be established be- tween them; any rise in the intracranial pressure raises venous pres- sure by compression of the veins. This statement holds true at least so far as the intracranial pressure is due to the circulation. Variations of pressure from the pathological causes — tumors, clots, abscesses, etc. — may exercise apparently a local effect. The intracranial pressure is caused and controlled normally by the pressure within the arteries and TREATMENT. 163 capillaries. This pressure, by enlarging these vessels, tends to expand the brain against the skull, and exercises a pressure, therefore, upon the intervening cerebrospinal liquid. This pressure, however, cannot exceed that in the veins, since, as said, an excess will be equalized by a corresponding compression of the veins. The venous pressure in the end determines, therefore, the actual amount of intracranial pressure. Conditions that alter the pressure in the cerebral veins affect the intra- cranial pressure correspondingly. Thus, compression of the veins of the neck raises the pressure in the cerebral veins and also intracranial pressure, and a higher general arterial pressure also results finally in a higher pressure in the cerebral veins and therefore in the subarach- noidal space. The recorded measurements of the intracranial pressure show that it may vary from 50 to> 60 mm. of mercury, obtained during the great Fig. IX. Scheme to show the relations of the Pacchionian bodies to the sinuses. d, d, folds of the dura mater enclosing a sinus between them ; v, b, the blood in the sinus ; a, the arachnoidal membrane ; p, the pia mater ; Pa, the Pacchionian body as a projection of the arachnoid into the blood sinus. (From Howell's Physiology.) rise of pressure following strychnin poisoning, to zero or less, as ob- tained by Hill (Bayliss and Hill, Journal of Physiology, 18, 356, 1895) from a man while in the erect posture. In this position the negative influence of gravity is at its maximum. The Effect of Variations in Arterial Pressure Upon the Blood- Flow Through the Brain. — Quite a number of observers have proved experimentally that a rise of general arterial pressure is followed, not only by an increase in the intracranial tension, but also by an increased blood-flow through the brain. There has been much discussion as to whether a rise of the arterial pressure in the basilar arteries can cause any actual increase in the amount of blood in the brain, or whether it expresses itself solely or mainly as an increased amount of flow. In the other organs of the body, except perhaps the bones, a general rise of pressure, not accompanied by a constriction of the 164 EPIDEMIC CEREBROSPINAL MENINGITIS. organ's own arteries, causes a dilatation or congestion of the organ together with an increased blood-flow. Physiologically the congestion — that is, the increased capacity of the vessels — is of no value; the important thing is the increase in the quantity of the blood flowing through. In the brain, owing to the peculiarities of its position, it has been suggested that perhaps no actual increase in size is possible. It is evident, however, that the existence of the liquid in the subarach- noidal space makes possible some actual expansion of the organ. For as the pressure upon this liquid increases it may be driven into the dural sac of the cord and along the sheaths of the cranial and spinal nerves. To what extent this is actually possible in man we do not know, nor do we know how much cerebrospinal liquid is contained in the skull and brain of man. In the dog, Hill finds experimentally that the brain can expand only by an amount equal to 2 or 3 c. c. without causing a rise of intracranial tension; so that probably these figures represent the amount of expansion possible in this animal by simple squeezing out the cerebrospinal liquid. If the rise of arterial pressure is such as to expand the brain beyond this point, then it may not only force out cerebrospinal liquid, if any remains, but as explained in the last paragraph, it will compress the veins and raise intracranial pressure. To the extent that the veins are compressed as the arteries expand, no actual increase in the size and blood-capacity of the brain takes place. That an expansion of the brain arteries compresses the veins is in- dicated very clearly by the normal occurrence of a venous pulse in this organ. The blood flows out of the veins of the brain in pulses syn- chronous with the arterial pulses, and this venous pulse may be recorded easily. In this case the sudden expansion of the arteries compresses the cerebral veins, giving a synchronous rise of pressure in the interior of the sinuses. Some authors, on purely theoretical grounds, have held that this compression of the veins may result in a diminished blood- flow through the organ — a sort of self -strangulation of its own circu- lation. Actual experiment shows that this is not the case. Any ordi- nary rise of general arterial pressure is accompanied by a greater blood-flow through the brain, and Howell has shown that sudden vari- ations of arterial pressure far beyond possible normal limits cause no blocking of the venous outflow. Whether the brain increases in vol- ume as a result of a rise of arterial pressure is, on the physiological side, unimportant; the main point is that the amount of blood flowing through it is increased under such circumstances as would cause a like result in other organs. That the compression of the veins does not produce any sensible obstruction to the blood-flow may be understood easily. In the first place, this compression does not take place at the TREATMENT. 165 narrow exit from the skull, since at that point the sinuses are pro- tected from the action of intracranial pressure. The compression takes place doubtless upon the cerebral veins emptying into the sinuses, and at this point the venous bed, taken as a whole, is so large that the expansion due to an ordinary rise of arterial pressure is distributed and has but little effect on the volume of the flow. Secondly, very great increases in arterial pressure, up to the point of rupture of the walls, have less and less effect in actually expanding the arteries ; a point is reached eventually at which these tubes become practically rigid, so that farther expansion is impossible. This, of course, is true of every organ. ANATOMY OF THE SUBARACHNOIDAL SPACE. The study of the anatomy of the subarachnoidal space was done extensively by Key and Retzius in 1828. They made the following important observations : That the anterior subarachnoidal space of the cord is entirely free and open, but that the posterior part of the subarachnoidal space in the dorsal region is divided up by interrupting membranes attached in the lines of the nerve-roots. They also state that the posterior arachnoidal mid-membrane and trabeculae is usually very richly developed, and contains a number of larger and smaller subarachnoidal spaces, at times breaking up into a thick trabecular network, which occupies a large portion of the space between the cord and nerve-roots. They describe a constant valve-like flap in the upper part of the anterior subarachnoidal space between the levels of the second attachment of the ligamentum denticulatum and the fourth cer- vical nerve, convex upward, which permits a free flow of the cerebro- spinal fluid from brain to cord in front of the ligamentum denticu- latum, but obstructs the free passage of cerebrospinal fluid from cord to brain within this area. Quincke called attention to the close contact of the spinal subarachnoid membrane with the dura, and to the fact that the conus medullaris in very young children lies lower than in adults. In several young children below one year of age he found the end of the conus at the level of the third lumbar vertebra; in children three years old, at the level of the second lumbar vertebra; and once in a four year-old child at the level of the fourth lumbar vertebra. The position of the nerve-roots of the cauda equina in the sub- arachnoidal space is important. Gerstenberg and Hein state that the position is variable, sometimes the roots lying close to the posterior and lateral walls, other times nearer the anterior wall ; and that the usual condition is one in which the nerve-roots divide into halves, 166 EPIDEMIC CEREBROSPINAL MENINGITIS. leaving the anterior wall of the space free. They describe the sub- arachnoidal space of the spinal region above the cauda equina as di- vided by the garland-shaped ligamentum denticulatum, into an anterior portion and a posterior portion, the two portions communicating with each other through the spaces between the concavities of the ligamen- tum denticulatum and the arachnoid sac. They also note the pres- ence of a posterior median septum, in which are holes affording com- munication between the two sides. Lusk made a series of eleven dissections of the arachnoid membrane, to determine the anatomical relationship between the membrane and the cord in order to locate the site at which puncture could be done Fig. X. Diagram of a cross section through the dorsal spine, showing how the arach- noid membrane may be adherent to the posterior surface of the cord, which was the pre- dominating anatomical arrangement in this and the lower cervical regions in six out of ten dissections. The close contact between the arachnoid and dura is here illustrated. (From Lusk.) most safely. Of the eleven dissections above the conus, in but three was there a complete posterior arachnoid space present all the way up into the cervical region. In all of these three, there were, at intervals, interrupting transverse septa, so that the channel posteriorly was not continuous. However, the lateral communications with the anterior portion of the subarachnoid space allowed free circulation of the cere- brospinal fluid. In the other eight dissections there were adhesions between the posterior arachnoid space and cord in some sites above the conus ; in one the posterior arachnoid space was present throughout ex- cept for an adhesion of the arachnoid membrane to the cord for an inter- val of about half an inch opposite the first dorsal vertebra ; in three dis- TREATMENT. 167 sections the arachnoid membrane was adherent to the posterior surface of the cord, all the way from the conus up into the cervical region. In one dissection, the arachnoid membrane was completely adherent to the posterior surface of the cord above the level of two inches above the conus ; in another above the level of three inches above the conus ; and in two others, above the level of the fifth and seventh dorsal vertebrae respectively. His conclusion therefore was that if cerebrospinal fluid could be constantly drawn by mesial puncture, the substance of the cord must be traversed by the needle, and the fluid taken from the anterior sub- arachnoid space. Fig. XI. Diagram of a cross section through the dorsal spine, showing how the sub- arachnoid space may completely surround the cord. An anatomical arrangement of the posterior part of the arachnoid sac, like that here pictured, was found to exist throughout both dorsal and cervical regions in but three out of eleven dissections, and in these the con- tinuity of this posterior part of the channel was interrupted at intervals by transversely lying septa. There is free communication between the anterior and posterior portions of the subarachnoid space through the openings between the concavities of the ligamentum denticulatum and the arachnoid sac. ANT.R., POST.R., nerve-roots. (From Lusk.) Puncture Below the Level of the Conus Medullaris. — While the distribution of the nerve-roots of the cauda equina within the arach- noid sac was found to vary considerably, their general order of arrange- ment with relation to one another was found to be uniform. The nerve-roots arise serially from the conus medullaris and pass downward in regular order to their fixed foramina of exit, arranged in a vertical row on each side of the spinal canal. Thus the first lumbar root has the most lateral and highest origin from the conus medullaris. The root passing through the second lumbar foramen of exit takes its origin from the conus medullaris next below the first root, and so on down the 168 EPIDEMIC CEREBROSPINAL MENINGITIS. whole series, until from the apex of the conus, the lowest sacral nerve- roots arise, which in natural order occupy the most mesial position of all the nerve-roots, either lying in close relationship with, or in cases where there is a cleft, diverging a little from the median sagittal plane. The mesial position of the lowest sacral nerve-roots would render them the most liable of any to injury in median lumbar puncture — trauma- tism that could be offered in explanation of those cases of paralysis of the bladder and' sphincters that have followed lumbar puncture. Where the nerve-roots of the cauda equina lay together in masses, they did not individually float free in the cerebrospinal fluid, but were bound closely together by delicate adhesions, which though they could Fig. XII. Diagram of cross section of dissection opposite the fourth lumbar inter- space. Below the lower border of the fifth lumbar vertebra all the nerve-roots were adher- ent to the arachnoid. Above this level the arachnoid was firmly adherent over the posterior surfaces of the laterally situated nerve-roots of the cauda equina, while mesially it lay loosely over the posterior surface of the nerve structures, to which it was connected by delicate trabeculae from about one-eighth to one-quarter inch in length, the shorter tra- becule occupying the more lateral position. Fluid tests were not made, but it would seem likely that in the presence of a fluid content within the arachnoid sac, with the nerves relaxed by posture, there would have been mesially in the posterior part of the sac a depth of about one-quarter of an inch of fluid which could be traversed by the puncturing needle before nerve structure would be touched. (From Lusk.) be broken apart with the use of almost no force at all, were neverthe- less strong enough to hold the roots together as one solid impermeable structure. Occasionally the nerve-roots were found to float free, but only in the lower part of the subarachnoid space, below where the main mass had been distributed. Lusk notes that the picking up in the line of puncture of a nerve- root attached to the arachnoid membrane, on the end of a needle with a sharp, pricking point, might help explain those cases in which, on subarachnoid puncture, the flow of cerebrospinal fluid through the needle comes slowly in drops from evident partial obstruction of its caliber. TREATMENT. 169 He states that the site at which lumbar puncture of the subarach- noid space could have been made without liability of injuring the nerve-roots in all the fifteen dissections, using a needle not too sharply pointed and relaxing the mesially lying nerve-roots by sacral extension, was mesially in the interval between the fourth and fifth lumbar ver- tebrae. A puncture mesially in the lumbosacral space could probably have been done with equal safety in all the dissections, but it must be regarded as second in order of desirability, since at this level there was a greater tendency for the nerve-roots to become adherent to the pos- terior wall of the arachnoid sac, as well as for the subarachnoid space Fig. XIII. Diagram of cross section of dissection at level of fourth lumbar interspace. It indicates the result of an effort made to injure these nerve-roots with a short hat pin which had not a sharply pricking point, directed against them from without the dura, sub- sequent to opening the spinal theca. When the dural flap, held by forceps, was allowed to yield a little before the pressure of the puncturing agent, repeatedly the latter would drive before it a wedge of dura, cleaving therewith a path between the nerve-roots, which would recede on either side of the wedge to places of safety before the membrane gave way. Only when the dural flap was drawn very taut by the holding forceps did it seem possible for the hat pin to prick the underlying nerve, which it would then carry inward on its point. (From Lusk.) to become shallower. In one dissection the subarachnoid space termi- nated at the upper border of the first sacral vertebra. Hemorrhage. — Hemorrhage arising from spinal puncture may be either epidural or subdural. If pure blood flows out through the needle, the source of the hemorrhage is epidural. If blood-tinged cerebrospinal fluid is drawn, the source is subdural (Quincke). Since the posterior epidural venous arcades underlie the bony arches of the lumbar spine and since the mesially lying anterior epidural venous plexuses occupy only the transverse hollows of the posterior surfaces of the lumbar vertebrae, there are therefore normally no sizable epidural veins in the line of a straight, forward puncture, which is directed 170 EPIDEMIC CEREBROSPINAL MENINGITIS. toward an intervertebral disc, and the liability of hemorrhage occur- ring from this source is very slight. LUMBAR PUNCTURE. Paralytic Sequelae of Lumbar Puncture, Especially with Refer- ence to the Lumbar Injection of a Spinal Anesthetic. — Owing to an almost general obedience to Quincke's early injunction to enter the puncturing needle below the conus medullaris, which could then only encounter individual nerve-roots, the cases of paraplegia following lumbar anesthesia attributable to the needle puncture have been few. On the other hand, isolated paralyses of the lower half of the body following lumbar anesthesia, which might be due to injury of individual nerve-roots of the cauda equina, are more frequent. The latter sequelae seem to affect exclusively the bladder and anus and the area of distribu- tion of the peroneal nerve. That the nerve-roots of supply to the bladder and anus, which are the third and fourth sacral, should be ones of selection for injury by the needle it is easy to understand, since they occupy the most mesial position of all the nerve-roots of the cauda equina, and consequently, excepting where a mesial cleft exists, lie in line with a median puncture. The comparative infrequency with which paralysis has followed lumbar puncture, in the face of the indisputable anatomical evidence here presented that nerve-roots may so frequently be in relation with the posterior arachnoid wall opposite the second and third lumbar inter- spaces, would seem to be an evidence that the trauma of a needle pene- trating nerve-roots of the cauda equina is generally well borne. This observation, however, should not be construed as furnishing a reason why the utmost punctiliousness should not be observed to avoid the nerve-roots in practicing lumbar puncture. It is of importance in this connection to consider the work of Rehn, who injected physiological doses of tropacocain, novocain, and stovain into the spinal cords of animals, causing immediate death with typical medullary symptoms. This result occurred regularly, even with dimin- ishing of the doses of the drugs to very small amounts. To test whether the effect of these injections was mechanical or toxic, physio- logical salt solution alone was injected into the spinal cords of animals without any recognizable effects. Apparatus. — The selection of a good needle is important. It should be about 10 to 11 cm. long and about 1.5 to 2 mm. in diameter. An ordinary heavy steel needle is good, though of course irido-plati- num needles are better. A needle with a trochar is preferable. It is TREATMENT. 171 best to use a fairly sharp needle, with a short beveled edge. This has the advantage of readily penetrating the tissues, and still not being sharp enough to easily injure any nerve-roots that may. be met. Bier pointed out, that if the point of a long beveled needle be arrested when but partially passed within the spinal theca, it might both tap the sub- arachnoid space and at the same time be the cause of a peridural spill- ing of the fluid. Posture of Patient for Puncture. — It may be given as a safe rule, never to puncture a meningitis patient in an erect posture. The Fig. XIV. This picture illustrates the operation of lumbar puncture and the technique in injecting the antimeningitis serum. The patient is lying on his left side over the right side of the bed. His back is bowed by the physician in the middle of the photograph by flexing the hips on his abdomen and bending his head forward. The skin at the site of the operation has been painted with tincture of iodine. The site of the operation is draped off with sterile towels. The needle has been inserted at the level of the crest of the ileum, which is marked with tincture of iodine. The assistant at the head of the patient is taking blood pressure observations. The serum is being injected by gravity. clinical condition of these patients, the danger of sudden collapse due to hydrocephalus, fully explain this necessary precaution. Lumbar puncture for conditions other than meningitis, as for spinal anesthesia, may be conveniently performed in the sitting posture. In the erect posture of the body the pelvis is tilted sufficiently back- ward to relax the sacral nerve-roots, and also the amount of space between the spinous processes, though less than with acute lumbar flexion is sufficient for the performance of median lumbar puncture. 172 EPIDEMIC CEREBROSPINAL MENINGITIS. In forced lumbar extension, the spinous processes crowd slowly to- gether, which movement when suddenly made by the patient during median lumbar puncture may cause breaking of the needle. A convenient posture for right-handed operators is to have the pa- tient lie on his left side. The back should be well bowed. This may be readily accomplished by an assistant, who places one arm under both knees of the patient and flexes the thighs on the abdomen. His other arm is placed under the neck of the patient, flexing the head well for- ward. By clasping both hands after he has placed the patient in this position, one assistant can usually hold the patient easily and prevent sudden change in posture from struggling. Preparation of Site of Operation. — The skin is sterilized very carefully as for surgical operation. Painting the skin with iodin is a very efficient and simple method. It is well to drape off the surround- ing parts with sterile sublimate towels. Route of Puncture. — There are two routes of puncture of the subarachnoid space : 1. The lateral. 2. The median. The lateral route, theoretically at least, has undoubtedly a number of advantages, among them being principally the ability to avoid the thick interspinous ligament and of using a blunt needle that affords a more delicate sense of touch. Lusk also mentions the advantage of being able to perform the operation if desired in the position of extreme lumbar extension. The puncture is made by selecting a point just lateral to the finger tip on the interspinous interval in the median line of the back, and is directed slightly upward and inward. The needle can be felt to pene- trate two resistances : 1. The ligamentum subflavum. 2. The dura mater. By this method the needle may easily get outside of the limits of the interarcuol space. The point could thus pierce the interspinous liga- ment and impinge on the lamia of the opposite side, or it could strike the under margin of the spinous process. Median Puncture. — Admitting some of the advantages claimed for the lateral route, the median route has the great advantage of sim- plicity. It can be easily performed even by the inexperienced and will save the patient usually the annoyance of repeated punctures. I have done many punctures, employing both the lateral and the median routes. In using the lateral route, I found the main objection to be that one had to point the needle just so in a certain direction, or one would usually TREATMENT. 173 impinge on one of the spinous processes and would frequently necessi- tate manipulating the needle around and changing direction. The median route is simple. Select the interspinous space. Place the thumb of the left hand in the space, pressed well between the spines, and hold it there, using it as a guide to the needle. Direct the needle perpendicularly in the median line between the spines, or better still at an angle of about 45° upward and inward. If one feel the spines dis- tinctly and insert the needle directly in the median line between the spines, one will find the operation a very simple one. A tubercle projects downward from the lower margin of a lumbar spinous process close to its posterior extremity, so that in performing median puncture the needle should be made to follow as closely as pos- sible the upper border of the lower spinous process of the interspace through which it is passed to avoid encountering the tubercle. Level to Be Chosen. — The level of puncture usually chosen is the fourth lumbar space which is at the level of the crest of the ilium, or in the lumbosacral space. As has been indicated by anatomical sections this site is preferable : first, because it is below the conus ; and second, by mesial puncture there is least liability of injuring the nerve- roots. In practical experience in over a thousand lumbar punctures, I have usually chosen the level described for a puncture. Occasionally, however, even when one is apparently in the subarachnoid space, possi- bly due to impaling of some nerve-fibers at the end of the needle, one is unable to obtain fluid at this level. In repeated punctures also, ad- hesions are very apt to form and shut off the subarachnoid space. It is also desirable, even if perfect technic be employed, not to perform too many punctures at the same level, on account of the added danger of infection from the irritated and inflamed skin over the punctures. I have encountered all of these conditions, and accordingly have fre- quently been compelled to puncture at higher levels, many times at the third and second lumbar spaces and sometimes, though seldom, at the first space. I have never met with any unpleasant complications from the punctures at the higher levels. Occasionally I have observed some temporary paresis of the bladder, which cleared up with convalescence, and which I am 1 inclined to believe was probably due to the meningitis proper, at least in some of the cases. I have met none of the extensive paralyses described. It is important to note that the cases of paraly- sis- following lumbar puncture have most often occurred in cases who have had spinal anesthesia. In puncture for spinal anesthesia where there is little space between the nerve-roots in the subarachnoid space there is probably very frequent injury to the nerve- roots, with no appar- ent unpleasant symptoms in the great majority of cases. In meningitis 174 EPIDEMIC CEREBROSPINAL MENINGITIS. where there is a marked distension of the subarachnoid space, with separation of the enclosed tissues, the danger is relatively much less. I would therefore consider that the site of choice for lumbar punc- ture in meningitis should be the fourth lumbar space, but on meeting any of the conditions I mentioned, interfering with the flow of fluid or with the free injection of serum, I should not hesitate to go to the higher levels even with the slightly increased danger. Practical clinical experience certainly bears out this course of procedure. Depth of Puncture. — Quinke estimated the depth of lumbar puncture to be usually from 4 to 6 cm. in adults ; in large muscular men from 7 to' 8 cm. ; and in fat people even to 10 cm. Henry Heiman devised a little metal clip that could be attached to the needle, at a place corresponding to the estimated depth of the subarachnoid space. In lumbar punctures one meets first the marked resistance of the ligament, then the fine, grating resistance of the dura. If the puncture be done slowly and deliberately, one can often feel the end of the needle "give" as one strikes the distended subarachnoid space. I do not believe that marking the needle by estimating the probable distance helps mate- rially. The sense of touch and the feeling of "giving" of the needle are in my estimation more reliable. Occasionally the fluid will fail to run or run very slowly. This is due probably, as described, to possible impalement of a nerve filament or to adhesions arising from previous puncture. A gentle twisting of the needle will frequently start the flow. Accidental Breakage of Needle. — This accident should really never happen, if a proper needle be selected for the puncture. This needle should be large and powerful. Several private firms have placed on the market some very well-built needles, which were, however, en- tirely of too small a caliber and too delicate. I have seen a number of instances where the needle snapped off in its middle during an operation after the canal had been reached, caused by a sudden contraction of the muscles of the back. Several such cases came under my care subse- quently. In almost every instance the physician had dissected exten- sively for the needle, but failed to find it. In none of these cases did I attempt to locate the needle. Several patients recovered completely and complained of no symptoms that could be explained by the pres- ence of the needle. I believe it is best to do nothing but wait to see how much damage is actually done before radical measures be insti- tuted. In many cases there should really be no subsequent symptoms. The dissection of the membrane is an extensive and difficult operation and should not be attempted unless absolutely indicated. TREATMENT. 175 Anesthesia. — While local skin anesthesia will help control the pain of the initial skin puncture, I believe it is usually unnecessary. The pain caused by the quick skin puncture during lumbar puncture is ordinarily not severe enough to indicate local skin anesthesia. I usually dispense with it. General anesthesia for lumbar puncture of meningitis cases adds a considerable element of danger, especially in the effect on the heart, respiration, and blood-pressure. I believe that anesthesia should only be resorted to when absolutely necessary, as in very violent, robust pa- tients, or in very nervous individuals. I have ordinarily employed chloroform for the purpose. A rather valuable aid of which I have availed myself extensively is the "water anesthesia." I have found that if water be administered through a straw during lumbar puncture, patients will frequently drink large quantities of it during the operation and stay very quiet and apparently very comfortable. A number have asked for the water and straw in subsequent punctures. I have humor- ously called this "water anesthesia." It has saved me many a general anesthesia and many a struggle with a restless patient. HISTORY OF THE INTRODUCTION OF THE SPECIFIC ANTIMENINGITIS SERUM. In May, 1905, Jochmann was pursuing experimental studies on a specific immune serum against epidemic meningitis in the Medizinische Klinik of Breslau. After studies in smaller animals, he induced the Merck Company to prepare the serum on a large scale by immunizing horses. In April, 1906, he reported before the Kongress fiir Inncre Medizin the results in 38 cases of epidemic meningitis, which had been treated by his serum. At first he employed the subcutaneous method in treatment. Later the intraspinal method was used. He found the latter apparently safe in doses of 10 to 20 c. c, and obtained prompt beneficial response. During the course of the year, the serum was used in 30 more cases, with a mortality of 27% as against a mortality of 53% in untreated cases. Jochmann tested the potency of his serum by the opsonic test as recommended by Neufeld, by the bactericidal test, by protecting small animals (guinea-pigs, white mice) against fatal doses of live and dead culture, and by agglutination tests. At about the same time as Jochmann's report appeared, Kolle and Wassermann, Institut fur Ansteckende Krankeiten of KgL, reported that they had also prepared an immune antimeningitis serum, which, however, up to that time had not been used in man. In 1907, they 176 EPIDEMIC CEREBROSPINAL MENINGITIS. published the results in 57 cases of meningitis treated with their serum. Their results were as follows : 57 cases— 27 died 47.3% 14 cases — 1st and 2d day of disease 21. % 7 cases — 3d day of disease 28. % 7 cases — 5th day of disease 28. % 4 cases — 6th and 7th day of disease .75. % 14th day and later 80. % and over The serum was administered by the subcutaneous and intraspinal routes. They called attention to the importance of instituting early treatment. In 1908, Levy reported 23 cases of meningitis treated by the Kolle-Wassermann serum, with a mortality of 21.7% and at the end of 1908, the further results in 43 cases of meningitis, with a mor- tality of 16.2%. Flexner's studies on the meningitis serum have been most import- ant in definitely establishing the value of the antimeningitis serum and the method of administration. Exhaustive studies were carried on for a long time, not only in the laboratory in producing and studying the properties of the serum, but also in the use and in the clinical results following the administration of the serum. Flexner's work on the antimeningitis serum began a little after Jochmann's in 1905. On August 25, 1906, he reported in the Journal of the American Medical Association on his production of a specific immune antimeningitis serum, which protected small animals against fatal doses of culture and which protected monkeys that were first injected with serum and later experimentally infected by the Diplo- coccus intracellulars. He produced a disease in monkeys similar to epidemic meningitis in the human being by inoculating large doses of virulent culture by spinal puncture into the subarachnoid space. This produced a virulent form of meningitis, which in all important clinical and pathological findings resembled the disease in the human being. The infection so produced ran a very short, fatal course. Flexner first prepared the immune serum by immunizing rabbits, goats, and large monkeys. Rabbits were injected with single strains; the goats with many strains of cocci. The monkeys were injected with a number of strains of meningococci and with exudates (aggressin), from the peritoneal cavity of guinea-pigs which had been injected intra- peritoneally with the meningococcus. He rioted that rabbits proved poor animals for the work, as they developed hypersensibility to the injections, from which many died. The first tests of the protective power of the goat serum were made with serum obtained on November 18, 1905. Guinea-pigs injected TREATMENT. 177 intraperitoneally with live culture of the meningococcus and the serum lived; controls without serum died. Subcutaneous injection of serum also protected. Rabbits' serum was toxic for guinea-pigs ; too little serum failed to protect ; and too much serum prejudiced the results by reason of its toxicity. After several months of additional injection of the goat, its serum was again tested, on March 14, 1906, and was again found to be potent. The first tests with the goat-serum on monkeys were made December 2, 1905, and proved inefficient, failing to save an infected animal. Two large monkeys (Macacus nemstrinus) were immunized for the production of an homologous serum. Injections of diplococci and of exudate (aggressin) from guinea-pigs were made during a period of nine months. The animals were bled June 15, 1906, and the serum was tested. Five monkeys were infected by injections of live culture intraspinally and were treated with serum by intraspinal injection. A control animal, without serum, was used in each instance. The con- trols all died. The other five monkeys were saved. Another monkey, so treated, died. As a result of this work, Flexner proved that a specific immune antimeningitis serum could be produced, which would save monkeys, if injected intraspinally. He stated, in conclusion, that he did not be- lieve, however, that the intraspinal injection into man of an alien serum should be undertaken until its physiologic action had been studied. Flexner continued his experimental studies of the antimeningitis serum, and later immunized horses, for its production. The first oppor- tunity to use this serum in the United States came in May, 1907, in an epidemic in Akron, Ohio. Here the serum produced striking results. As against a previous mortality rate of 90%, there was a recovery rate of 75% after using the serum. Eleven cases were treated with the serum by Dr. Tadd of Cleveland ; 8 recovered, 3 died. Very soon the serum was extensively used in this country at the beginning of a fresh epidemic in New York, Philadelphia, Castalia. In Edinburgh, it was used by Dr. Claude Ker, and in Belfast, by Dr. Gardner Robb. The report of the early cases appeared by Flexner and Jobling in the Journal of Experimental Medicine, November 9, 1907. An exten- sive report of an analysis of 400 cases of epidemic meningitis, treated with the antimeningitis serum, appeared by Flexner and Jobling in September, 1908, in the Journal of Experimental Medicine. Of 393 cases tabulated, 295, or 75%, recovered and 98, or 25%, died. In October, 1909, they reported 712 cases treated with the serum; there was a total mortality of 31.4%. A subsequent report was based on 1300 histories; 893 recovered, 402 died — a mortality rate of 30%, this 178 EPIDEMIC CEREBROSPINAL MENINGITIS. including patients of all ages. Of 125 infants under one year of age, in whom the disease is highly fatal, there was only a 50% mortality with serum. As a result of these exhaustive studies in a great many cases, the status of the antimeningitis serum, as a curative agent of high efficiency, in epidemic meningitis, was definitely established. The report of the 400 cases was based upon the reports of Dr. L. W. Ladd of Lakeside Hospital, Cleveland; Dr. A. Gardner Robb of Belfast, Ireland; Dr. C B. Ker of Edinburgh, Scotland; Dr. W. T. Longcope and Dr. Morris J. Lewis of the Pennsylvania Hospital, and Dr. Franklin Rbyer of the Municipal Hospital, Philadelphia ; Dr. Charles H. Dunn, Dr. John Lovett Morse, Dr. J. L. Ames, and Dr. Frederick Shattuck, Boston; Dr. Frank Fulton of the Rhode Island Hospital, Providence; Dr. L. F. Barker, Dr. Frank J. Sladen, and Dr. Harvey Cushing of the Johns Hopkins Hospital, Baltimore; Dr. James D. Morgan and Dr. W. W. Wilkinson, of the Garfield Hospital, and Dr. S. S. Adams, Washington; Drs. Henry Koplik, Henry Heiman, Morris Manges, and Alfred Meyer of the Mt. Sinai Hospital, Dr. L. Emmett Holt of the Babies' Hospital, Dr. C. H. Lewis of St. Vincent's Hospital, Dr. G. M. Swift of St. Mary's Hospital, Dr. George L. Peabody of the New York Hos- pital, Drs. Walter James, John A. Thacher, and W. F. Northrup of the Presbyterian Hospital, New York ; Dr. Charles W. Duval of the Mon- treal General Hospital, Montreal; Drs. Frank S. Churchill and Maxi- millian Herzog of Chicago; Dr. Alfred I. Cole of the City Hospital, Cincinnati ; Dr. Philip King Brown of San Francisco, and Drs. Austin Miller and L. A. Barber of Portersville. Good results with Jochmann's serum have been reported by Kovari- zek, Stetze, Arnold Lenzmann, and O. Mayer. With the Kolle-Wassermann serum good results have been reported by Levi, Tobben, Beckmann, Krohne, Quennstadt, Luck. The serum has also been prepared by Ruppel in Hochst, 1907, by Poltauf in Austria, by Dopter in France. PREPARATION OF THE ANTIMENINGITIS SERUM. Merck's serum, prepared for Jochmann, was obtained by injecting horses intravenously with increasing doses of killed meningococci, later with live culture. Jochmann called attention to probable advantage in using freshly isolated strains of meningococci. The Kolle-Wasserman serum was prepared in much the same way as the Jochmann serum. They used, however, in addition, water ex- tracts of the meningococcus, in order to obtain the soluble products of TREATMENT. 179 the meningococcus. They believed that this increased the antitoxic properties of the serum. Ruppel immunized his animals with a strain of meningococcus, that he said had been made highly virulent, killing guinea-pigs, mice, and rabbits in 1/1 millionth of a dose. No other worker has had such experience in increasing the virulence. Flexner's Serum. — The serum prepared at the Rockefeller Insti- tute was obtained by immunizing horses with increasing doses of the soluble products (autolysate), of the meningococcus, injected subcu- taneously, later using live culture. This method was subsequently employed by me while in charge of the Meningitis Department in the Research Laboratories of New York City. The detailed de- scription of the method follows : 1. Many strains of meningococci were used. Strains were used that had been isolated in different epidemics, in this country and abroad. Fresh strains from new epidemics, also from 1 sporadic cases were con- stantly added. At first immunization was begun with 21 strains, later the number increased to 40. 2. Preparation of Soluble Products or Autolysate. — The stock cultures were kept alive on slants of ascitic, glucose-agar neutral to phenolpthalein. The cultures were frequently transplanted, usually every four days. For preparing the autolysate, the cultures are sub- inoculated first on glucose-agar slants, without serum. After 24 hours' growth, about 3 c. c. of salt solution are added to each slant, and the culture emulsified. It is then poured over the surface of glucose-agar slants in large 500 c. c. Blake bottles. For a 500 c. c. Blake bottle use 35 c. c. agar ; place bottle on one side and allow the agar to solidify. Grow in the incubator for 18 to 24 hours. The agar is usually covered with a heavy, uniform, diffuse growth. Add 10 c. c. of normal salt solution to each bottle. The culture is usually easily washed off by gently moving from side to side ; if neces- sary a long heavy loop may be used. Each bottle is tested for con- tamination by staining a loopful of the emulsion with Gram's stain. Each bottle is emptied into a common vessel, preferably a large liter graduate. This emulsion corresponds to the live culture and may be used as such. The autolysate is prepared by adding 2% toluol to the emulsion, mixing well, and incubating from 18 to 24 hours. The toluol is then allowed to evaporate, or it may be immediately filtered off through sterile gauze soaked in salt solution. This preparation may keep for 180 EPIDEMIC CEREBROSPINAL MENINGITIS. 1 £ 2 S s- S a 2 a s 5 r 03 MH IfV s > / jjji « »»IC f ■ ( s \ e ) \ < - -- a s ?t 9 5 CJ M 1 \ 5 .lip "11 Jijn < < 5 > t ; s ™«n '/ « :c '09 - m "J. > _: = 7TI . X W IPS |l >0C - < » 1 ! 5 — s s ii-Ti *1«»" ■" < J 5 5 a oq *tV < --* t i ») q-TO "4 »*- V "H 4"J V a ^ • *j^ «« «ll II « *> G IS* >> <( » ) ■ , . J> - \ a t ^3 3l "JT l\ I E ; * n" hpalH ■or ■ ' 3 F" «1 « 3 e }J<\ (fnj Mif *»l i » »i« -yo Of *~~- c-" "T s « ». J "•- • Vim Ml| « 1 « aj 4ii3 3AI/ OS 1 s * V 5 *jni "3 3 M| J > *^ -^ 31 -=: «jn. [Hi 111 -i* s 1 3 ■mi n? i Al| -3T a s 2: £ ») 9f..|< .TO men S 1 ^ •3 nfc "i ■r- »J W«*l|< "V «, >• a »- •o i> ™M< <*> i * •4 M-H,< "» «■». s • tm. «>1 m < » »a •cli|l n-z <^ V U} c/: o A O c O ^ o C u n rd rt o N s 03 N U OJ Ih 5 o o * n ( J U) is CJ o o3 TREATMENT. 181 about two months, if placed in the refrigerator. It is desirable, how- ever, to prepare the extract fresh every month. Doses. — Begin with 2 c. c. gradually increasing, depending on how the animal reacts, till 10 c. c. per dose are reached; then begin injecting with 2 c. c. of live culture, increasing the doses the same as with the autolysate. The animals usually are less disturbed by the live culture than by the autolysate, so that the doses can be more rapidly increased. After 10 c. c. of live culture are reached, begin injecting with autolysate and live culture alternately, gradually increasing the dose, till a maxi- mum of from 30 to 35 c. c. per dose is reached. The latter is then used as the regular dose. Injections are given from every 5 to 7 days till the large doses are reached, when they are given every ten days or two weeks. The cul- ture is injected into the subcutaneous tissue about the neck and abdo- men. Before injecting, the culture should be diluted with two parts salt solution. The animals show quite marked reaction, especially after the large doses of autolysate. They are depressed, have fever, and look sick. There is considerable induration and tenderness at the site of inocula- tion. Abscesses commonly develop after the larger doses. Horses are favorable subjects for immunization. It is unusual to find an animal that does not respond to a high degree of immunity after immunization. Horses retain their immunity for a long time. One animal, one of the original Rockefeller Institute horses, six years later, was still yielding a highly potent serum. If properly cared for, few horses are lost during the immunization. Horses so dying usually show extensive hemorrhage in the liver. Bleedings can usually be begun, being guided by suitable tests, about the fourth month after immunization has been instituted. The horse can be bled every two weeks, oftener if necessary, 6 to 8 liters of blood being removed each time. The bleeding should be timed between the periods of injection; a good time is a day or two before an injection. STANDARDIZATION OF THE ANTIMENINGITIS SERUM. An accurate method of standardizing the antimeningitis serum has not yet been found. An antimeningitis serum, of high immune body content, and properly prepared, has bacteriotropic, antitoxic, and bac- tericidal properties. Krauss and 'Dorr believed that the chief action of the serum depended upon its antitoxic properties. Jochmann, Flex- ner, Wassermann, and Neufeld believed the antitoxic properties to be an important constituent of the immune serum, but claimed that the 182 EPIDEMIC CEREBROSPINAL MENINGITIS. principal action of the serum depended upon its bacteriotropic prop- erties. Various tests have been employed for determining the efficiency of the antimeningitis serum. Thus, the opsonic index, the complement deviation, and neutralizing the fatal doses of live culture and autolysate for animals, have all been used and advocated by different observers. While the antimeningitis serum was being prepared at the Rocke- feller Institute, Jobling used the opsonic test, as the method of choice. He found the other tests unreliable and inaccurate and states : "The part taken by specific opsonins in promoting recovery from infection with Diplococcus intracelhdaris suggests their employment as a measure of the therapeutic activity of the antiserum. Methods of quantitative estimation of opsonic content of the antimeningitis serum being avail- able, it would seem advantageous to adopt for the present as a standard of value a definite and suitable strength in opsonins of the antimenin- gitis serum. "As a definite and suitable standard of strength, a minimum dilution activity of a 1-5000 dilution of the antiserum is proposed." He used Neufeld's method in his tests. Neufeld's Method. — Selection oe Culture. — Great care must be employed in selecting a suitable culture for the tests. Most cultures are too readily digested by the leucocytes, showing "spontaneous phago- cytosis," while others are not readily subject to phagocytic inclusion. Thus, for a long period, culture number 21 was used for the test ; sud- denly, however, it showed marked spontaneous phagocytosis, and an- other culture was selected. Culture. — The culture is grown 18 to 24 hours on a glucose-agar slant. If possible, obtain a uniform growth, always using a slant of the same size. Add^4 c. c. each of' bouillon and of salt solution, and emul- sify the growth. Serum. — Dilution made in salt solution. If the serum is fresh, less than 15 days old, inactive 30 mm. at 56° C. Leucocytes. — These are obtained by injecting aleuronat solution or saturated solution of peptone intraperitoneally into guinea-pigs. Twelve to eighteen hours later, the animal is killed, the peritoneal cav- ity opened, and the exudate collected. The cells are thoroughly washed about four times in normal salt solution, then are suspended in sufficient quantity of normal salt solution to equal in opacity .3% lecithin emul- sion in normal saline. Technic. — Small test-tubes are desirable. To each test-tube, add two drops of diluted antiserum, and one drop of the emulsion of the culture. TREATMENT. 183 Incubate for one hour at 37° C. Then add two drops of the suspension of leucocytes. Incubate again one-half hour. At the end of the second incubation, the leucocytes will have settled to the bottom of the tubes. Pour off the supernatant fluid in each tube. Mix the sediment well with a loop, then make smear on slides. Make normal salt controls. Dry smear in the air. Fix about one minute in methyl alcohol. Stain in 1-10 dilution, Manson's methylene-blue solution. The readings are based on the gross relative appearance of the spreads, without counting the phagocyted diplococci. The relative amount of phagocytosis was noted as compared against the normal controls. Modified Leishman Method. — This test differs principally from the previous one described in the fact that it is done in capillary tubes, and the readings are made by counting the included cocci. The great- est dilution yielding a higher count than the saline control was taken as representing the ultimate strength of the serum. While associated with the Meningitis Department of the Research Laboratories of New York City, I made many tests of the meningitis serum, using the various methods mentioned. We paid special atten- tion to the opsonic test, on account of its index as to the therapeutic value of the serum. There are a number of serious objections to the opsonic test. 1. The great irregularity and inaccuracy in the readings in all op- sonic work. Even if great care be employed in selecting a suitable meningococcus strain, which is sufficiently subject to phagocytic inclu- sion, but does not show too much spontaneous phagocytosis, there is great irregularity in repeated tests. 2. The meningococcus family is made up of a number of different strains, as differentiated by immune serum tests, the various strains reacting differently with their autogenous sera and with the sera of the other members of the group. In testing a polyvalent serum, therefore, it would be advisable to use an antigen made up of all of the organisms used in the immunization. This is impossible in opsonic tests, as many of the meningococci show marked spontaneous phagocytosis ; and a single strain which does not show this property must be used. Complement-Fixation Tests. — Comparative complement-fixation tests were done in the Research Laboratories for a number of months. Tkchnic. — Technic is essentially the same, and the materials pre- 184 EPIDEMIC CEREBROSPINAL MENINGITIS. pared in a manner similar to that described in the chapter on "Etiology Under Strain Differentiation." 1. Sheep hemolytic system. a. Guinea-pig complement. b. Sheep corpuscles. c. Antisheep amboceptor. 2. Bacterial meningocoecic antigen. On repeated tests we found our results were uniform, allowing, of course, for the usual errors in such work, which are controlled in every series of tests. Control experiments were made with normal horse serum, and showed some fixation at low dilutions. Controls with other immune sera, antitetanic, diphtheritic, and streptococcic, were also made, and they showed no> fixation or only at low dilution. A gonococcus serum of high immunity gave fixation with meningococcus antigen as high as that with the antimeningitis serum. This would show only that the test was not absolutely specific and would interdict its use as a means of diagnosis, but would not invalidate readings, when working with known ingredients, as meningococcus antigen and meningococcus serum. (McNeil specific antigen had not be elaborated at the time of these studies.) A series of comparisons were made with opsonic and complement- deviation tests, using identical materials. In every instance, they cor- responded, a high opsonic reading being accompanied by a high comple- ment-fixation reading. This, of course, does not mean that the devel- opment of the opsonins and other immunue bodies go hand in hand, or are dependent upon each other. It has been proved by different workers that such is not the case, e. g., Torrey, in his determination of the agglutinations and bactericidal strength of gonococcus sera, showed that one can be high and the other low. The uniformity of our tests, however, would seem to show that in a high and prolonged immunity both of the antibodies are developed to a great extent. The complement-deviation readings were always clean- cut and definite, while those with the opsonic tests were irregular and indefinite. A large number of experiments were made with guinea-pigs to test the protective power of the serum. In most of the tests guinea-pigs of about 250 grams were employed. As found by Jobling, the patho- genicity of the organism varies considerably from day to day. The resistance of the different animals varies considerably, e. g., one animal will live when given twice the dose that proves fatal to another animal of approximate size and age. By preparing a large quantity of bac- TREATMENT. 185 terial emulsion and a few controls in each series of tests, to determine the fatal dose, and by using a standard quantity of serum mixed with varying quantities of the bacterial emulsion, inoculated intraperitoneally, some idea of the protective property of the serum could be obtained. The results, however, were irregular, and unless repeated several times, each time with -controls, little dependence could be placed upon them. The method is impracticable for general use. From our experience, we concluded that the therapeutic activity of the meningitis serum depended, probably to a very great extent, upon the opsonins. It is wise to use the opsonic test as one of the means of standardization. On account of the irregularity in the reading, however, and the inability to use the mixed strains of meningococci in the test, the limits of immunity, as determined by this method, are left in doubt. The complement- deviation tests have given uniform results and have corresponded as to degree of immunity with the opsonic reading. The readings have been uniformly sharp and have given us a more definite standard. Another advantage is that a mixed antigen made up of all of the organisms used in immunization is used in this test. It seemed to me, therefore, that it would be desirable in standardiz- ing the antimeningitis serum to use both methods, the opsonic as a control, the complement-fixation for more accurate recording of read- ings. I. PROPHYLACTIC MEASURES AGAINST EPIDEMIC MENINGITIS. Most writers agree that it is necessary to treat contacts in epi- demics of meningitis. Stewart in his review of the subject in the Medical Annual for 1910, mentions Setler's case where a man who had been infected three months before, returned to his regiment with the meningococcus still present in his nasopharynx. Seven days after his arrival, ten men out of thirty in his part of the bar- racks, were found to have become carriers. Systematic prophylaxis against epidemic meningitis, therefore, must consist of active measures against all known carriers, both healthy and sick; and during an epidemic must include measures that can be employed by everybody in an infected community. The treatment may be classified into : 1. Quarantine. 2. Medicinal treatment — local and internal. 186 EPIDEMIC CEREBROSPINAL MENINGITIS. 3. Specific treatment. (1) Serum prophylaxis. (2) Active vaccination. 1. Quarantine. — Quarantine is the most important step in the control of an epidemic ; quarantine of the sick and of as many known carriers as possible. A number of cities have established arbitrary periods of quarantine lasting from ten days to several weeks. The fallacy of such arbitrary time limit lies in the fact that a carrier may remain positive for a long time. If measures of quarantine be em- ployed, they ought to be controlled in an accurate way. This can best be done by the cultural examination of the secretions, both of the sick and of contacts. By this means, carriers can be positively iden- tified, and quarantine instituted. Likewise, quarantine can be raised only when the culture becomes negative. Several thousand people were so examined in the last Dallas epidemic. Many carriers were dis- covered and were prevented from infecting other healthy people. In addition they learned that they harbored a dangerous bacterium, and were advised to employ active prophylactic measures. At first glance, it would appear to be very difficult to cover a large city during an epidemic. Experience has proved, however, that this work can be done efficiently, if systematically planned. In Dallas, the work was carried on from a central station. Several assistants were sent out daily to the quarantined homes ; each assistant carry- ing enough swabs and cultural material for ten to twenty families. A simple method is to use ordinary throat-culture swabs and Loffier's blood-serum slants, as suggested by Hatchel and Haywood. After eighteen hours' incubation at 37° C, slides are stained from the growth with Gram stain. If Gram-negative cocci are found, a loop of the growth is subinoculated on several other slants, after first carrying through several water blanks. Typical discrete men- ingococcus colonies can usually be easily separated in this way. Another method, which I frequently employ, is to make streak plates on glucose-ascitic agar, direct with the swab. Typical plate colonies usually develop after eighteen hours' incubation. On morphology alone, these colonies can usually be quite definitely dif- ferentiated from the other Gram-negative cocci. Cultures were taken of the sick during their convalescence ; if negative, the patient was discharged when well ; if positive, cultures were repeated at three- to four-day intervals. Cultures were similarly taken from all contacts, especially the members of the family or neighbors who had been exposed. If the cultures were positive, they were repeated TREATMENT. 187 at regular three- to four-day intervals until negative, when the quar- antine was lifted. Even if the original culture of an immediate member of an infected family was negative, an arbitrary period of quarantine of a week to ten days was enforced, since we know that cultures may be negative one day and positive the next. Circulars were sent to all quarantined homes and to the public at large, explaining the contagious character of the disease, the portal of entry of the organism, and its mode of transmission. Especial attention was called to the importance of preventing attacks of common cold and of strictly preserving the principles of hygiene. They were advised to keep the mouth clean, to keep the homes properly ventilated and cleanly. They were cautioned against promiscuous spitting and against congregating in crowded places. The schools were closed temporarily. Fumigation. — On release from quarantine, the home of meningitis patients should be carefully fumigated in the regular way. 2. Medicinal Treatment. — (1) Local. — The object of local ap- plications, such as sprays and inhalations to the nose and throat, is to disinfect and free these parts of the meningococcus. Bethege, treating sixty carriers in an institution, divided them into six groups. The first was treated with pyocyanase; the second, with hydrogen peroxid; the third with serum used as a spray; the fourth, with protargol ; the fifth, with one per cent salt solution ; and the sixth, received no treatment at all. He concluded that hydrogen peroxid preceded by salt solution gave the quickest results. Hatchel and Haywood controlled an institutional outbreak among two hundred children by isolating all the carriers, as proved by cul- ture, then treating them with sprays, releasing them from quaran- tine as their cultures became negative. Before this treatment was begun, a number of cases of meningitis developed among the chil- drn. After it had been instituted, no further cases developed, the healthy carriers were promptly rid of the organisms, and the disease was stamped out of the institution. In the few carriers treated, they obtained quickest results with the antimeningitis serum used as a spray. Stewart mentions that chlorin water and menthol were used for disinfecting purposes. The following are the detailed instructions for the disinfection of the nasopharynx as issued by the French Army, 1910: 1. All carriers must have the nasopharynx, mouth, and tonsils carefully disinfected by antiseptic inhalations and swabbing. 188 EPIDEMIC CEREBROSPINAL MENINGITIS. 2. For inhalation, the following mixture, first suggested by Vin- cent and Bellot, is recommended: Iodin 12 gms. Guiacol 2 gms. Thymol 35 centigrammes. Alcohol 60% (200 gms.). (Note. — In order to dissolve the iodin, 6 gms. of iodid of potash should be added to the above.) This mixture is put in a porcelain dish, which is floated in a basin of boiling water. The patient is directed to sit with his head bent over this at a distance of a few inches and inhale the fumes, breathing slowly through each nostril. The sitting should last two or three minutes and should be repeated five times in twenty-four hours. Disinfection of the pharynx is carried out by swabbing with gly- cerin containing 3% of iodin; the swabbing to be done most care- fully morning and night. For disinfection of the mouth, they recommend a gargle contain- ing 20 parts of peroxid to 180 parts distilled water; the mixture being supplied in a separate corked bottle to each man. Doctor DuBois and Miss Warren, who were associated with me in the Research Laboratories, tested a number of antiseptics against the meningococcus and found that hydrogen peroxid in "ft to 1% strength, and argyrol 9% destroyed the meningococcus quicker than any other measures that could be used as a spray. During the Dallas epidemic, the most generally used antiseptic was peroxid ft% as nose spray and gargle, preceded by a cleansing douche of salt solution. This treatment, in most instances, rendered the parts antiseptic within a few days; and in persistent cases, rarely longer than ten days. Internal Medication. — Urotropin is split up after ingestion into formaldehyd and ammonia, for the most part in the urine. The products, however, are secreted through other mucous membrane, thus its use in cholecystitis. Recently it has been described as being secreted through the nasal and nasopharyngeal mucosa. Its secretion into the cerebrospinal fluid was first described by Cushing and Crowe. This remedy, therefore, would tend to disinfect, at least to a certain exent, the portal of entry (e. g., nose and throat) of the meningococcus, and would also be secreted into the cerebro- spinal fluid. Flexner found that the preliminary administration of the drug in the monkey afforded some protection to the animal TREATMENT. 189 against poliomyelitis virus which was later inoculated to produce experimental poliomyelitis. I advised the use of this drug in the 1912 epidemic in the South- west as a prophylactic, in doses of 20 to 30 grains a day. It was employed extensively. In most instances where the drug was used, local sprays and gargles were also employed so that the effect of the drug alone in clearing up carriers could not be studied. It would be instructive in subsequent epidemics to make such observations. 3. Specific Treatment. — By specific treatment, I mean the pro- duction of a specific immunity. This may be produced by injecting serum, causing a passive immunity; or by injecting vaccine, causing an active immunity. Jochmann in his original publication on the antimeningitis serum mentioned the feasibility of using the serum prophylactically. Sim- ilarly, Ruppel, in 1907, advised its use, recommending 20 c. c. as a dose. The use of this serum to produce prophylactic passive immu- nity is analogous to the use of other immune sera, such as diph- theria and tetanus antitoxins and plague serum, for this purpose. The dose of the antimeningitis serum, as a prophylactic, must nec- essarily be arbitrary, depending on the standard of immunity of the serum. An average dose is about 10 c. c. The serum should be injected subcutaneously as one injects diphtheria antitoxin. This measure has not been generally or systematically employed except in isolated instances by different observers. During the 1912 Texas epidemic, I advised the more extensive use of serum as a prophylactic, especially for those who were very intimately ex- posed to the disease. Many physicians and nurses were injected, and a considerable number of contacts. In no instance did the dis- ease develop within a month after the injection (this being the limit of time during which one would expect protection). One case, a porter in the meningitis hospital, developed meningitis six weeks after serum vaccination. It is interesting to note that he had no anaphylactic symptoms on the spinal injection of serum for thera- peutic purposes. There are a number of serious objections to the use of serum prophylactically : First, the fact that the immunity produced is only temporary as in all passive serum therapy, lasting only several weeks. Second, the frequent occurrence of serum sickness, due to the injection of a large quantity of unrefined serum. Third, the danger of producing anaphylactic shock if the subject 190 EPIDEMIC CEREBROSPINAL MENINGITIS. subsequently develops meningitis necessitating the therapeutic use of the serum. A resume of the various remedies so far described shows that while a number are of very considerable value, none are absolutely certain in their protection. The local measures described disinfect, but do not otherwise protect against the disease. The serum pro- tects only temporarily and has a number of other objections to its use. The desirable prophylactic would be a measure free from danger, that could be used widely with little inconvenience, which would afford a high degree of immunity against the disease, at least for several months, such as typhoid vaccine against typhoid. The utilization of active immunity as a mean of preventing men- ingitis has not, I believe, been previously advocated. The work of a number of observers has demonstrated the fact that a considerable degree of immunity develops during the course of the active infection in epidemic meningitis. Meakens demonstrated the third order of immune body in the blood, by complement-fixation, and employed this test for diagnosis. Many observers have demonstrated agglutinins in the blood of meningitis patients. Some, as von Lingelsheim, 1906, Kutscher, 1906, Krumbein and Schatiloff, have described uniform results in testing immune serum plus the meningococcus. Von Lingelsheim used killed culture for his experiments and declared that the test could be used for diagnosis. Most observers, however, as Traut- mann and Fromme, Eberle, Ditthorn and Gildermeister, Lieber- knecht, 1908, Elser and Huntoon, Arkwright, have had irregular results in the test, the main objections being the want of uniform reaction of an immune meningococcus serum with different strains of meningococci, and the fact that there is cross agglutination be- tween the meningococcus and other Gram-negative cocci. Also cer- tain strains of meningococci are inagglutinable, and the agglutinat- ing properties of any strain may change during cultivation. Thus Elser and Huntoon obtained agglutination with one strain of men- ingococcus in dilution of 1 :400 with serum of a meningitis case, while four other strains of meningococci agglutinated only up to 1 :50. One week later, the most agglutinable strain became unusu- ally sensitive to non-specific agglutinins, and was agglutinated in a 1 :100 dilution by serum of a typhoid patient. Davis studied eight cases of meningitis and obtained positive reactions in dilutions of 1:50 in all, in one case 1:500 dilution. The increase of opsonins has similarly been demonstrated by many observers. Houston and Rankin made opsonic determina- TREATMENT. 191 tions on sixty-three cases of meningitis and found high opsonic readings after the sixth day of the disease, all exhibiting an opsonic index over four, and some still higher. Davis demonstrated a de- cided increase in the opsonic index in some cases examined but not in others. He vaccinated himself with a very large dose of dead culture, injecting the full growth of several small blood-serum slants, and discovered a marked immediate increase in opsonins. He found no evidence of a negative phase. Von Eberts and Hill, Birnie and Smith vaccinated a few epidemic meningitis patients with meningococcus bacterin, and found a considerable increase in opsonins following inoculation. McKenzie and Martin in the Glasgow epidemic used and recom- mended the use of the blood-serum of meningitis patients, especially of those recovering from the disease, to be used therapeutically by intraspinal injection. Some improvement was obtained by the method. This might be considered as the clinical demonstration of immune bodies in the blood-serum. Immune bodies have been demonstrated in the cerebrospinal fluid of epidemic meningitis patients. Thus precipitins have been demonstrated by Vincent's method, and the other immune bodies in smaller quantities. Thus immune bodies have been demonstrated in those ill with meningitis, both in the blood and cerebrospinal fluid. There was a marked response in opsonins in the meningitis cases treated with vaccine. In smaller animals, especially rabbits, and in larger animals, such as sheep and horses, there is prompt response in the production of immune bodies after repeated vaccination. These facts, plus the apparent analogy of this disease (which probably begins in most, if not all instances, as a primary bacteremia) to other bacterial dis- eases, as typhoid, and the wonderful results obtained by extensive prophylactic typhoid vaccination led me to employ and advocate this measure in the recent Texas epidemic. The absolute demonstration of the efficacy of this measure must be determined by experimental evidence, by the demonstration of a large immune body content following the administration of the vac- cine, and by clinical evidence of protection against the disease, as observed during epidemics, especially among those who have been exposed to the disease. 192 EPIDEMIC CEREBROSPINAL MENINGITIS. EXPERIMENTAL EVIDENCE. I undertook this work with the assistance of Dr. Black, at the end of the Texas epidemic, in the Southwestern Medical College. Eleven medical students volunteered to be vaccinated for the purpose. Preparation of Vaccine. — All glassware was neutralized. An organism, about five generations old, isolated from the cerebrospinal fluid of one of the patients in Dallas, was used. It was grown on 2 per cent glucose-agar. After eighteen hours' incubation it was washed off in distilled water, shaken for twenty minutes in the usual way, then heated at 50° C. for one hour and tested for sterility. It was counted by the Wright method, and standardized. Vaccination. — Eleven students were vaccinated. They were in- oculated subcutaneously just below the deltoid; five were injected with 500,000 bacteria as the first dose, and five were injected with 1,000 million. Seven days later, they were vaccinated again, with the same vaccine, in doses of 1,000 million and 2,000 million, respec- tively. Again, a week later, they were vaccinated a third time, with 2,000 million with a freshly prepared vaccine. Observations were made on the blood-count and the general and local symptoms. Their serums were examined every four days for agglutination and complement-fixation. Blood Analyses. — The examination of the blood showed, in prac- tically all instances, a slight leucocytosis twenty-four hours after the injection, with return to the normal on the fourth day. There was very little change noted in the total differential blood count. The leucocytosis was greater after the second and third injection. Agglutination Studies. — Tschnic. — Macroscopic agglutination tests were done. The blood was collected from the finger in small glass capsules ; the serum was separated and dilutions were made. Culture. — The Elser-Huntoon organism (which these authors have found especially good for the purpose), which gave no spon- taneous agglutination and was readily agglutinable by immune serums, was used. Uniform emulsions of culture were used. After mixing, the culture and the immune serum were incubated for two hours, then placed on ice for twelve to twenty-four hours before reading. DISCUSSION OF TABLE XIV. 1. The highest agglutination was obtained in those patients who had been given three injections of vaccine; the larger doses used, ap- TREATMENT. 193 to .5 nS 0) C o rt J3 *M he < c t- +■ c c i ! 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Treatment was begun in this case during the accumulative stage, the disease being promptly aborted. Fever did not rise over 100.6 degrees. ewen's sign was distinct. Lumbar puncture gave 35 c. c. almost clear fluid. Serum — only 12 c. c. could be injected. A few free organisms were found in the fluid ; a few polynuclear leucocytes. Eighteen hours later. — Meningeal signs more distinct, but general condition much better. Lumbar puncture gave a more turbid fluid, showed a moderate number of intra- and extracellular organisms. This patient recovered very nicely under the intraspinal administration of serum. TREATMENT. 203 Discussion. — When first seen, this patient was apparently suffering from a violent sepsis. There were practically no signs of meningitis at this time, the intraspinal injection of serum would have been futile, the subcutaneous injection of the serum reaching the site of infection (the general circulation). CLASSIFICATION OF ACTIVE TREATMENT. 1. Acute cases. a. Treatment of first stage of general bacteremia. b. Treatment of active stage of meningitis and general bac- teremia. 2. Subacute and Chronic cases. a. Serum treatment. b. Vaccine treatment. c. Relief of hydrocephalus. d. General measures. 3. Complications. 4. Treatment of Active Meningitis. In dealing with an active case of meningitis, it is important to re- member that the following conditions must be treated : 1. Local suppurative meningitic inflammation. 2. General sepsis. 3. Hydrocephalus. 4. General constitutional symptoms. Each measure is equally important and influences the ultimate out- come. SERUM TREATMENT OF MENINGITIS. • The wonderful results with serum treatment of epidemic meningitis are due to two causes : 1. The proper production of a highly potent polyvalent immune serum. 2. The recognition of the fact that in active meningitis the serum must be introduced subdurally, directly into the meninges. Subcu- taneous administration alone is practically worthless during the active meningitis. Sera that are injected into the general circulation are secreted into the cerebrospinal fluid only in small quantities and very slowly. Thus, in local infections of the central nervous system, when it is desired to introduce large doses of the remedial serum, it is necessary to inject 204 EPIDEMIC CEREBROSPINAL MENINGITIS. the serum directly into the subarachnoid space. This is especially im- portant in using the antimeningitis serum, which benefits to a very great extent by its local opsonic action. The subarachnoid injection of serum can be employed in all pyo- genic infections of the central nervous system, such as those caused by the meningococcus, bacillus influenza, streptococcus, pneumococcus and tubercle bacillus. The best results have been obtained clinically and ex- perimentally in epidemic meningitis, and experimentally at least, in in- fluenza meningitis, the reason being that these two infections are local, even though primarily they may be of hematogenous origin. The focus of infection is thus directly reached. The opposite, however, is the case with the pyogenic infections, produced by the streptococcus, pneu- mococcus, tubercle bacillus and other organisms. These are almost always secondary to the primary foci, and tuberculous meningitis is fre- quently accompanied by a general miliary tuberculosis. METHOD OF INJECTING THE ANTIMENINGITIS SERUM. 1. Syringe Method. Most men have injected the antimeningitis serum, by using a syringe, which is attached to the needle, after the cerebrospinal fluid has been withdrawn, and the serum slowly injected. 2. Gravity Method. This method consists in allowing the serum to run in by gravity, using a funnel and tube arrangement. I believe the first one to employ this method was Henry Heiman in Mt. Sinai Hospital in 1908. A simple apparatus may be made by using the barrel of a 15 to 25 c. c. syringe as a funnel, attached to a twelve-inch rubber tube, at the end of which is a small metal end piece. After a lumbar puncture has been done, and the cerebrospinal fluid withdrawn, the metal end piece is attached to the needle, and the serum is allowed to run in by gravity. The operation of lumbar puncture is only moderately painful. Most pain is felt when the membranes are reached, then lightning, sharp, shooting pain occurs, referred to the back, or commonly to the epi- gastrium, to one of the hips or shooting down the back of one leg. A somewhat unusual symptom is sharp pain in one ear. These symptoms are usually only momentary in simple puncture. The injection of serum is usually accompanied by severe, at times, agonizing pain, referred to any or all of the regions mentioned. It occurs as soon as the introduction of serum is begun, and usually sub- sides to a very great extent, at the end of the operation. Sometimes, however, it continues severe and unabated for hours after. TREATMENT. 205 Dunn suggested that the pain was due to the injection of cold serum, and that preliminary warming of the serum to body temperature would prevent it. While cold serum appears to aggravate the pain, it is certainly not the chief cause, since similar symptoms are evident regu- larly on injecting warm serum. The symptoms are most likely due to stretching and local irritation of the nerve-roots at the site of puncture. I have found that the very simple expedient, "water anesthesia," previously described, will help to soothe. Even delirious patients will reflexly suck on the straw and quickly become quiet. Patients will sometimes drink as many as nine glasses of water during the operation. It acts especially well in children. For persistent pain after the operation, local application of heat gives relief. Morphine or other sedatives are sometimes necessary. Method of Administering Serum Subdurally. — (Description of author's new method.) — The object of the intraspinal treatment is to remove a quantity of the infected cerebrospinal fluid, thereby relieving pressure symptoms, and eliminating a certain quantity of infectious ma- terial, then to inject a suitable dose of specific serum, in order that it may bathe the infected membranes in the brain and cord, and act locally. The present method of standardizing the antimeningitis serum, as generally accepted, is by determining the opsonic index and by similar immune-serum tests. There is, however, no measure of efficiency placed on the serum such as we have in the case of diphtheria or tetanus antitoxin. The dose is therefore measured entirely by volume. Since the serum acts principally by its local action, the idea was, and still is, to introduce as much serum as possible without injury. It was believed that, after the removal of a quantity of cerebrospinal fluid by lumbar puncture, one could, to a certain extent, re-establish conditions in the central nervous system by injecting an equal or slightly smaller volume of serum. Thus, in an ordinary, moderately severe case in an adult, if one withdrew 45 c. c. of cerebrospinal fluid, an injection of 30 c. c. of serum would be safe and ample, while in a severe case one would be 'justified in injecting 45 c. c. or more of serum. It is seen by analyzing this method that one hopes and believes that conditions are established, but one has no proof. On this assumption many severe symptoms occurring either during or a few hours after an injection had been attributed to the disease proper. Undoubtedly tox- emia, in some cases, accounts for the symptoms. An analysis, however of many cases would make one suspicious that possibly the symptoms, in some, were the direct result of the injection, especially when they oc- curred during or immediately after the operation. 206 EPIDEMIC CEREBROSPINAL MENINGITIS. I had been dissatisfied with the old method for a long time. There was no reliable guide indicating the quantity of serum one could safely inject. It occurred to me that if one could made determination of the cerebrospinal fluid pressure during the operation, one might so have a definite guide, the idea being to inject serum only in sufficient quan- tity to bring the cerebrospinal fluid pressure to the original reading be- fore the removal of fluid. In that way one would cause least disturb- ance or shock. To obtain such result was evidently the reason for instituting the old arbitrary method. I therefore began to take cerebro- spinal fluid pressure readings during the puncture. After withdrawing a quantity of fluid, which reduced the pressure to normal, I attempted to inject serum in sufficient quantity to raise the pressure to the original reading before the removal of fluid. Thus, if the initial cerebrospinal fluid pressure reading was 400 mm. (water pressure), I removed the fluid until the pressure dropped to normal, or below, usually to between 20 to 100 mm. I then attempted to inject serum: in sufficient quantity to raise the pressure to about 400 mm. I shall not cite cases here. The results by this method, however, were misleading and unreliable as indicating the true intracranial pressure. Theoretically one would expect a return to the original pressure on injecting a volume of serum equal to the cerebrospinal fluid withdrawn. This was not the case. One could inject even larger quantities of serum than fluid withdrawn, but the pressure readings were frequently lower than the initial reading before the removal of fluid. Even with readings showing a lower intracranial tension after the injection of serum, one would meet severe, even very dangerous, symptoms. I learned very quickly that this method was misleading and even dangerous. I believe that the error was very probably mechanical and that the later readings were not a true index of the intracranial tension. It is very probable that injecting serum, even with little pressure, would produce a local distention of the subarachnoid space at the site of injection and give readings which did not present a true picture of the uniform intracranial pressure. I then began to study blood-pressure during lumbar puncture, espe- cially with reference to the effect of injection of serum. I have now made blood-pressure readings in about 500 cases of meningitis, making 1500 lumbar punctures. I have found almost uniform results in blood- pressure-change on injecting serum, and have applied those changes as a guide to the quantity of serum that could safely be injected. The blood-pressure-change was also frequently a guide, indicating the quan- tity of fluid that could be withdrawn safely. The effect on the blood-pressure is constant on withdrawing fluid by lumbar puncture in meningitis. Most often there is a drop in blood- TREATMENT. 207 pressure, occasionally quite large, especially on withdrawal of large quantities of fluid. My ordinary procedure in an adult case, beginning with an average blood-pressure of 110 mm. of mercury, is to stop the further withdrawal of fluid if there is a moderate drop in blood-pres- sure, for example of 10 mm. of mercury; in children of 5 mm. Occa- sionally the blood-pressure begins to drop very quickly as soon as the removal of the fluid is begun. The blood-pressure then is a guide indi- cating how rapidly or slowly the fluid may be withdrawn. In other cases there is no change in blood-pressure, or there may even be a rise, on re- moving fluid. In such cases one can withdraw as much fluid as pos- sible, usually until the cerebrospinal fluid pressure is normal, this being roughly estimated by counting the drops of fluid as they flow from the needle. One drop of fluid every three to five seconds corresponds to a normal pressure. After a withdrawal of a suitable quantity of cerebrospinal fluid, the serum is ready to be injected. As usual, the serum is warmed to body temperature and then injected slowly, by the gravity method preferably or by syringe. I much prefer the gravity method of injecting the serum. It has many advantages and few of the disadvantages of the syringe method. As a rule, as soon as the injection of the serum is begun, the blood-pressure drops and continues to drop steadily. Rea- soning by the old method of injecting serum, one would expect a rise in blood-pressure; this, however, is rarely the case. As stated, in the great majority of cases when the injection of serum into the subarach- noid space is begun, the blood-pressure drops and continues dropping steadily as the larger quantity of serum is injected. After there has been a material drop, for example of 20 to 30 mm. of mercury, the blood-pressure begins to drop relatively much faster if more serum is injected. Thus, if an injection of 15 c. c. of serum causes a drop of 20 mm. of mercury in blood-pressure, injecting only a few more cubic centimeters of serum may cause a sudden drop of 40 more mm. of mercury, making a total drop of 60 mm. or more. In one robust adult whom I treated, there was a drop of 30 mm. cf mercury after inject- ing only 12 c. c. of serum. His was a very severe case and I wished to introduce as much serum as possible. I injected 3 c. c. more, making a total of 15 c. c. of serum. His blood-pressure, at one bound, dropped 30 mm. more, making a total drop of 60 mm. His clinical signs at this time did not indicate shock ; the pulse was fair but rapid, the color was good, the breathing was shallow and a little irregular. I decided, however, to watch him for a time. A few minutes later he suddenly stopped breathing, then his heart stopped. Immediate active treat- ment, which I shall indicate later, gave instant response. It is easy 208 EPIDEMIC CEREBROSPINAL MENINGITIS. to see how these patients who have had a large drop in blood-pressure, with not much other evidence of shock, may thus suddenly succumb either during or after the injection. My usual technic in the operation of administering serum is to have one assistant take blood-pressure readings throughout the whole oper- ation. If the blood-pressure drops during the removal of the cerebro- spinal fluid, I use it as a guide indicating when to stop withdrawing fluid. I accept, as a rule, the arbitrary drop of 10 mm. of mercury. I use the blood-pressure as an absolute guide, indicating the quantity of serum I can safely inject; here it is also a guide as to how quickly the serum may be injected. As a rule, very rapid injection under con- siderable force will cause a greater drop in blood-pressure. By the gravity method the serum is allowed to run in slowly by gravity, the funnel being raised or lowered to regulate the flow. Ten minutes is a good average time to allow for the fluid to run in, though I have fre- quently taken 20 minutes or longer, especially in cases beginning with a low blood-pressure, or when the blood-pressure dropped very quickly. It is much harder to control the rate of injection by the syringe method and one may accidentally use too much force in injecting. I have found that a total drop of 20 mm. of mercury in an adult with average blood-pressure of 110 to 120 mm. of mercury is a safe indication to stop the further injection of serum. Occasionally there is an initial rise in blood-pressure after the injection of a few cubic centimeters of serum, followed by a subsequent drop as larger quantities of serum are injected. Very rarely the blood-pressure shows a material rise after the injection of serum. It occasionally happens that the injection of serum even in fairly large doses, at the first treatment causes relatively much less drop in blood-pressure, than is caused by injecting only small quantities in later punctures. I have not infrequently seen the reverse, however, and after analyzing several hundred cases with 1500 lum- bar punctures, I have come to the conclusion that the reaction of the blood-pressure to injection of serum is very irregular during dif- ferent lumbar punctures in the same patient; at times a small dose of serum causing a large drop in blood-pressure, other times a much larger dose of serum causing relatively much less drop in blood- pressure ; the importance of blood-pressure in controlling the ad- ministration and dose of serum is that it indicates the quantity of serum that can be safely injected at that particular time, but is absolutely no guide as to the quantity that one might be able to safely inject without blood-pressure control at any other time. Since I began using this method, the average dose of serum that I have used has been considerably smaller, frequently not more than TREATMENT. 209 15 c. c, averaging 20 to 25 c. c. in adults and in proportion in children. When the blood-pressure has allowed, I have injected larger quantities also, 30 to 40 c. c, very rarely more. Judging by the good results with the smaller doses of serum, I believe that it is very rarely necessary or beneficial to inject more than the maximum of 40 c. c. of serum. The method is of great benefit not only in the average case, but also in the atypical and difficult ones. Thus in cases with thick plastic exudate, when the fluid will not run through the needle, it is a beautiful guide, absolutely indicating how much serum one can inject safely under pressure ; similarly, in cases with little exudate, in which one introduces a larger quantity of serum than the cerebrospinal fluid withdrawn. If the fluid be injected into the subarachnoid space, under wrong diag- nosis, in cases with posterior basic meningitis, the drop in blood-pres- sure will be very large after injecting only a few cubic centimeters. The blood-pressure is also a guide in injecting serum directly into the ventricles, in cases of posterior basic meningitis. If uncontrolled by blood-pressure observations during the opera- tion, the quantity of serum injected should not be larger- than the amount of cerebrospinal fluid withdrawn so as to avoid symptoms. The average doses are as follows : 1 to 5 years 3 to 12 c. c 12 c. c. 5 to 10 years 5 to 15 c. c 15 c. c. 10 to 15 years 10 to 20 c. c 20 c. c. 15 to 20 years 15 to 25 c. c 30 c. c. 20 years and over 20 to 30 c. c 40 c. c. Occasionally more. Shock during the injection accompanied by the fall in blood-pres- sure is due principally to the following causes : 1. Undue pressure excited in the injection of serum. 2. Too rapid injection. 3. Injection of too large a quantity of serum. The great advantage of the gravity method of injecting serum is, that all of the above causes can be more easily controlled and danger to a very great extent eliminated. The rate of flow can be regu- lated by raising or lowering the serum container. If untoward symp- toms occur, lowering of the container will permit the serum to run back into it. Frequently the serum can be reinjected, even in larger dose, without causing symptoms, after a few minutes have elapsed, if the serum be introduced very slowly and carefully controlled by blood- pressure change. If symptoms occur during an injection by syringe, the barrel of the syringe must be quickly disconnected from the needle 210 EPIDEMIC CEREBROSPINAL MENINGITIS. APPARATUS FOR INJECTING ANTI-MENINGITIS SERUM. This special gravity container has been devised by Mr. E. R. Alexander, formerly of the Research Laboratory of New York, and the Author, with the purpose of supplying the serum in a condition ready for use in a sealed aseptic container with sterile apparatus easy to assemble with little manipulation. It is especially adapted for the superior and safer gravity method for administering the antimeningitis serum. DIRECTIONS FOR USE. Fig. XV. 1. After making lumbar puncture remove the trocar "B" from needle "A" and allow the cerebrospinal fluid to escape. NEEDLC 'a" TROCAR. "B" Fig. XVI. 2. Plunge stylet "C" attached to rubber tubing through the hole in rubber stopper of container at end "D" until the bead in the stopper is dislodged. CONTAINER STYLET EN6Y Fig. XVII. 3. Remove capping skin from end "E" and similarly plunge stylet already attached until bead is dislodged and the flow will be started. 4. When serum appears at the end "F" of rubber tube attach the latter to the needle. 5. Control the rate of flow by raising or lowering the serum container. RUBBER BULB Fig. XIX. Fig. XVIII. 6 If the serum does not flow well, the bulb may be attached to the upper stylet at end "E" and the necessary pressure slowly exerted. This procedure is not advised, how- ever, since under normal conditions the flow runs well by gravity alone. N B See that the beads, which are in the holes in rubber stopper at each end of the container are dislodged. If they adhere to ends of stylets a gentle shaking will quickly dislodge them. TREATMENT. 211 to allow the fluid to run off from the canal. The serum which so flows off is wasted. What conical symptoms are associated with the drop in blood- pressure ? In the order of their appearance these are : Stupor, which deepens more and more as the blood-pressure falls. Respiration be- comes superficial and irregular, at times deep, stertorous, slow and irregular. With a large drop in blood-pressure breathing may stop suddenly. Pulse will often continue good, even with a large drop in blood-pressure, and with marked change in the breathing. At times the pulse becomes slow and irregular. The pulse, therefore, is very often misleading. The pupils dilate, increasing in size with the greater drop. Incontinence of feces and urine occurring during lumbar punc- ture usually accompanies a drop in blood-pressure and is a warning. What is the immediate treatment for severe symptoms during or after the injection of serum? As already indicated, with a material drop in blood-pressure, further injection of serum should be stopped. If, however, there is sudden, extreme fall in blood-pressure, possibly accompanied by the above-mentioned symptoms, the indication is im- mediately to remove fluid from the canal. If one uses the gravity method of injecting, this is easily done by lowering the funnel. In bad cases in which the breathing stops, as much fluid as possible should be removed and active artificial respiration begun. Atropin and cocain should be administered hypodermically in large doses. In his experi- mental studies, increasing the intraspinal pressure in dogs, Dr. Carter found that the first mechanical effect of the increased intraspinal pres- sure was respiratory depression and marked cardiac inhibition. Atro- pin removes the cardiac inhibition, while he found that cocain as a respiratory stimulant gives prompt response. Discussion of Blood-Pressure Change During Serum Injection. — Dr. Carter, in his experimental work on dogs, found as I did in the human, that the blood-pressure changes occurring during the intra- spinal injection of fluid apparently were entirely or for the greater part mechanical, and that they were influenced especially by the quantity of fluid injected, by the pressure used and by the rate of the injection. In my observation of about 1500 punctures, where the blood-pressure was used as a guide for the injection of serum, there was not a single instance of death occurring during or shortly after the operation, re- sulting from the injection of serum. In all cases, there was a pre- liminary warning of fall in blood-pressure, followed by clinical symp- toms of respiratory irregularity and embarrassment, and the other symptoms mentioned, if more serum were injected. 212 EPIDEMIC CEREBROSPINAL MENINGITIS. As a result of the observations in about 1500 treatments, the follow- ing deductions are warranted : 1st. That untoward symptoms of collapse and shock and respiratory embarrassment can be prevented in almost every instance by blood- pressure control during the injection; a moderate drop, as I have ex- plained, indicating that further injection of serum be stopped. 2nd. That the dose of serum is smaller than formerly as controlled by this method ; but that the results in many cases so treated prove that the large dose of serum is not necessary, and that the average dose of serum that one is able to inject as controlled by this method is suffi- cient and gives better results than formerly. 3rd. That the average number of injections as judged by my 150 tabulated cases is 3 to 4 ; which is not only not more, but somewhat less than the average number of injections previously given where individual larger doses of serum were introduced in each treatment. 4th. If one gave a preliminary injection of atropin and cocain before a treatment, one ought even then have a blood-pressure control, to see how large a dose could be safely injected. 5th. The valuable experimental evidence found by Dr. Carter showed that severe symptoms when they occur, producing death, are due to respiratory center depression and that they can be immediately relieved by cocain given preferably intravenously or intramuscularly. It would be wise, therefore, to have this drug plus atropin on hand always, to be used in emergency, if symptoms occur. My evidence proves, however, that in almost every instance symptoms can be pre- vented by the preliminary warning drop in blood-pressure which occurs before the severe symptoms. Most of the cases in which blood-pressure observations were made were studied in the Texas epidemic. The results were extremely good. The general reaction following the injections was usually not as severe as formerly. Temperature did not rise as much. The patient was usually more comfortable and the general condition better. The dose of serum, as stated, was much smaller. Very young children about or under one year especially, at times could not bear more than 2 to 3 or 4 c. c. of serum, and in a number of cases responded wonderfully well. Conclusions. — 1. The old method of administering serum is inac- curate and sometimes, dangerous. 2. Blood-pressure change is a very accurate guide to the quantity of serum that can be safely injected, frequently also indicating the amount of cerebrospinal fluid that can be withdrawn. 3. The average dose of serum as controlled by blood pressure is smaller than by the old method. TREATMENT. . 213 4. Following an injection of serum, controlled by blood-pressure, the after-effects are usually much less severe. Mortality figures which will be accurately tabulated later show unusually good results. It is evident that the important indication is to inject as much serum as possible without depressing the patient. It is equally important, however, not to depress the patient even by the remedial agent, since that may be the turning point in allowing the infection to overcome the patient. It is desirable, therefore, to rather inject an inadequate dose of serum without depressing the patient than inject a large dose with considerable depression, allowing the infection to overcome the patient before the serum can act. Case 1. Mrs. S. — 111 24 hours with a violent septic form of meningitis. All the severe active signs of meningitis present. Blood-pressure at begin- ning of operation — 88. Lumbar puncture — 40 c. c. very turbid fluid under very high pressure. Serum injected very slowly by gravity method — 15 c. c. of serum caused a drop in blood-pressure to 60. Pupils were becoming widely dilated. Respirations were becoming irregular. Further injection of serum was stopped. Twenty-four hours later, patient was much improved. Blood- pressure was 110. This time 30 c. c. of serum could be injected. Discussion. — If the arbitrary volume method of determining the dose of serum had been used here, serious consequences would have resulted; either the patient might have succumbed on the table, or she would have been left in a very much depressed condition for a number of hours later, very likely causing the disease to become aggravated. Case 2. Child — 14 months old — ill 48 hours with meningitis. Admitted to the hospital unconscious, in very precarious condition. The initial blood-pressure was 50 — 20 c. c. of very turbid fluid were re- moved. Serum was injected very slowly by gravity. 4 c. c. caused a drop of 5 in blood-pressure, 7 c. c. of serum caused a drop to 20. Breathing became very shallow, then convulsions developed; child's condition became very poor. I quickly withdrew all the serum (about 7 c. c.) from the canal, raised the head of the child and gave atropin and other stimulants. The child re- sponded. After trying for about 20 minutes, I could inject but 3 to 4 c. c. of serum safely. The following day the child was much improved — 6 c. c. of serum could now be injected. The child recovered after three more treatments; the later doses being between 6 and 8 c. c. Case 3. Man, aged 25. Moderately severe case. Jan. 20 — Blood-pressure 115. Pulse 80 — 30 c. c. of fluid removed. Cere- brospinal fluid pressure dropped to normal. Blood-pressure dropped 3. Serum injected, 30 c. c. Total drop in blood-pressure, 15. Pulse, 110. Jan. 21 — Blood-pressure 120. Pulse 116 — 30 c. c. of fluid removed. Blood- pressure dropped 8. Serum injected, 20 c. c. Drop of 7 more in blood- pressure, making a total drop of 15. Pulse 130. Jan. 22 — Blood-pressure 110. Pulse 116 — 18 c. c. of fluid removed. Drop 214 EPIDEMIC CEREBROSPINAL MENINGITIS. of 3 in blood-pressure. Serum injected 22 c. c, with further drop of 7 in blood-pressure : . making a total drop of 10. Note in this case, which reacted favorably, that the patient was not pushed to the limit; that after injecting a moderate, suitable dose of serum, no further serum was injected, even though blood-pressure might have allowed a little more. Case 4. Woman, aged 40. Severe septic case of meningitis. Jan. 10 — Blood-pressure 105. Pulse 98 — 25 c. c. of fluid removed. Drop of 5 in blood-pressure. Serum injected 12 c. c. Total drop of 25 in blood- pressure down to 80. Jan. 11 — Blood-pressure 130 — 40 c. c. of fluid removed. Drop of 3 in blood-pressure. Serum injected 25 c. c. Blood-pressure dropped to 120. Jan. 12 — General condition much better — fluid much clearer. Blood- pressure 135. Pulse 130 — 35 c. c. of fluid removed. No change in blood- pressure. Serum injected 30 c. c. Drop of 5 in blood-pressure. Jan. 13 — Blood-pressure 130 — 55 c. c. of fluid removed. Drop of 8 in blood-pressure. Serum injected 15 c. c. Total drop of 15 mm. in blood- pressure. Jan. 15 — Blood-pressure 120. Pulse 120 — 20 c. c. of fluid removed. Drop of 5 mm. in blood-pressure. Serum injected 12 c. c. Total drop of 15 in blood-pressure. Patient convalesced, requiring two subsequent punctures for relief ot simple hydrocephalus. Case 5. Child, aged 9. Extremely bad case on admission. Jan. 15 — Blood-pressure 90 — 50 c. c. of fluid removed. Blood-pressure dropped 5. Serum injected 25 c. c. Total drop of 13 mm. in blood-pressure. Jan. 16 — Blood-pressure 90 — 10 c. c. of fluid removed under low pressure. Drop of 5 in blood-pressure. Serum injected 14 c. c. Total drop of 19 in blood-pressure. Jan. 17 — Blood-pressure 100 — 40 c. c. of fluid withdrawn. No drop in blood-pressure. Serum injected 15 c. c, with drop of 15 mm. in blood- pressure. Jan. 18 — Blood-pressure 100 — 35 c. c. of fluid removed. Drop of 10 in blood-pressure. Serum injected 6 c. c, with total drop of 18 mm. in blood- pressure. Rapid convalescence. Note how irregularly blood-pressure responds to injection of serum. Cases Illustrating Treatment of Drop in Blood-Pressure and Shock on the Table. — Case 1. Negro, aged 30. Typical clinical course of meningitis; had had two previous injections of serum, average dose being 15 c. c. He stood the injections very badly; his blood-pressure dropped very consider- ably; he became stuporous and his general condition was poor. 3rd puncture — General condition better. Blood-pressure 110 — 35 c. c. of fluid removed. Blood-pressure dropped to 100. Serum slowly injected by gravity, 10 c. c. caused a drop of 15 mm. more, making a total drop of 25 mm. in blood-pressure. The injection of serum was continued slowly in spite of the drop in blood-pressure. When 15 c. c. of serum were reached, the patient had incontinence, and stopped breathing suddenly without other clinical TREATMENT. 215 warning. Pulse, however, continued, weak and intermitting. The head of the patient was raised. Artificial respiration was immediately begun. As much fluid as possible was withdrawn from the canal. Adrenalin 40 m. by hypodermic. Camphor 10 grains. Patient responded in a few minutes and became conscious. At end about 8 c. c. of serum was safely injected. Case 2. Negress, aged 35. Admitted in delirious condition. Ill several days. Blood-pressure 80 mm. Very turbid fluid (35 c. c.) removed under high pressure. Blood-pressure dropped to 68. Serum slowly injected. From ■s-» o 5 H3 o no • - Q r O y * » Wcc. Sec lOcc. IX Cl Ib'cc. IScc. lOcc. IZc.c. 4a 105 to 100 95 S 90 -5 S5 SO 70 60 Chart VII. the very beginning blood-pressure dropped steadily. When 8 c. c. of serum had been injected, the blood-pressure was 60. It was thought desirable to try to inject more serum. Her pupils at this time were dilated and she was more stuporous. Breathing was superficial and irregular. Upon injecting 3 c. c. more of serum the blood-pressure suddenly dropped to 40. Then breath ing stopped. A few moments later her pulse could not be felt. Active measures, such as illustrated in the last case, were immediately instituted. The patient responded after about 10 minutes. Chart VII illustrates a very large fall in blood-pressure, accompanied by symptoms of severe shock, respiratory embarrassment, incontinence of blad- 216 EPIDEMIC CEREBROSPINAL MENINGITIS. der and rectum, all of which occurred with the injection of larger doses of serum in spite of a warning large drop in blood-pressure. Note the immediate response in blood-pressure and general improvement on withdrawal of fluid from the canal. Chart VIII. This record indicates a very extreme fall in blood-pressure with severe symptoms following the injection of only a small dose of serum. Symptoms were relieved and pressure immediately rose on removing all of B.P 100 95 90 85 go 75 70 65 60 55 50 I- o 3 o no V) — o '3 «+- VJ V 60c.c 5 ex. lOcc I2.cc Wcc lOcc \5c.c I7cc 5cc lOcc tf.ee Chart VIII. the serum injected. 10 c. c. of serum were injected very slowly, causing an immediate moderate drop in blood-pressure. Case Illustrating Frequent Effect of Anaesthesia.— Man, aged 23. Ex- tremely violent case of meningitis. Anaesthesia absolutely necessary. Chlo- roform given. Blood-pressure 120 — 70 c. c. of fluid removed. Blood-pressure rose to 160. Serum injected 40 c. c. Blood-pressure 150. As the effects of the anaesthesia TREATMENT. 217 began to wear off, the blood-pressure dropped 40 at one bound, fortunately no further. Cases Illustrating Rise in Blood-Pressure on Injecting Serum. — Case 1. Initial rise. Man, aged 19. Blood-pressure 130 — 40 c. c. of fluid removed. Blood pressure dropped to 120. Serum, 5 c. c. slowly injected. Blood-pressure rose to 130. 8 c. c. of serum caused a rise to 135. 15 c. c. brought a drop to 120. An injection of 30 c. c. of serum caused a drop in blood-pressure to 110. Case 2. Persistent rise. Man, aged 63. Chronic case of meningitis. Blood-pressure 150 — 25 c. c. of fluid removed. No change. Serum injected 20 c. c. Blood-pressure rose to 165. B.P 14-0 135 130 125 120 115 £ u— 3 a— o 7D -2 C 9- C-2 72 scrum injecte •-*£) o , 1^ , /00a. 5 ex. 10 a. I5c.c 20a 30 a 35cjt Chart IX. Chart IX. Note the initial rise in blood-pressure after removing 100 c. c. of fluid. Also note the relatively small drop in blood-pressure after the in- jection of a large dose of serum. The steadily increasing fall in blood- pressure was here an indication to stop the further injection of serum. Case Illustrating the Usual Control of Serum Dose by Blood-Pressure. — Child, aged 10. Severe case of meningitis; unconscious. Jan. 15. Blood-pressure 120. Pulse 144. 40 c. c. of turbid fluid removed under high pressure. Blood-pressure dropped 5. Further withdrawal of fluid which was still under slightly increased pressure was stopped. 27 c. c. of serum were injected by gravity method. Total drop of 17 mm. in blood- pressure. Pulse 92. 218 EPIDEMIC CEREBROSPINAL MENINGITIS. Jan. 16. Blood-pressure 110. Pulse 96. 25 c. c. of fluid removed. Drop of 10 in blood-pressure. Serum injected, 15 c. c. Total drop in blood-pressure 18 mm. Pulse 90. Jan. 17. Blood-pressure 110. Pulse 130. 10 c. c. of fluid removed under low pressure, till pressure was normal. No change in blood-pressure. Serum injected, 15 c. c. Blood-pressure dropped 10. Pulse 130. No further injection necessary — prompt recovery. Chart X illustrates the reaction of the blood-pressure in properly con- trolled cases. Note the fall of 10 mm. in blood-pressure on removing 60 c. c. v> _ s> a 9- B.P~-° no 105 too 55 90 o 3 o n3 60c.c. 5u. 7c.c. 9c.c. 10 cc IH-CC I5c.c \ \ m Chart X. of fluid. Note the progressive fall in blood-pressure on injecting the large quantities of serum. After 15 c. c. of serum were injected, there was a total drop of 20 mm., indicating the limit of safety for the serum injection. TABLE XVI. Blood-Pees sure Curves in a Series of Cases, Showing Change on Removing Fluid and Injecting Serum. Case 1. Age 2 years. Initial pressure 40 20 c. c. withdrawn no change 6 c. c. injected , dropped to 30 Case 2. Age 1 year. Init'al pressure 90 30 c. c. withdrawn 85 15 c. c. injected 75 TREATMENT. 219 Case 3. Age 5 years. Initial pressure 80 25 c. c. withdrawn 74 12 c. c. injected 68 Case 4. Man, aged 25. Initial pressure 145 80 c. c. withdrawn 138 30 c. c. injected 122 Case 5. Man, aged 28. Initial pressure 120 40 c. c. withdrawn 110 15 c. c. injected 60 15 c. c. withdrawn 100 12 c. c. injected 90 Case 6. Woman, aged 30. Initial pressure 80 35 c. c. withdrawn 100 20 c. c. injected 80 Case 7. Man, aged 20. Initial pressure 140 10 c. c. withdrawn 140 20 c. c. injected 120 Case 8. Man, aged 25. Initial pressure 125 80 c. c. withdrawn 135 30 c. c. injected 120 Case 9. Woman, aged 28. Initial pressure 145 45 c. c. withdrawn 140 35 c. c. injected 148 Repeating Doses of Serum. — It has been advocated by Flexner, Dunn and others, that the serum be arbitrarily injected daily for the first four days, later being guided by the clinical condition of the pa- tient. In bad cases, it has been recommended by many, that the patient be injected at first twice daily. In view of the demonstration of considerable depression on injecting serum, it is apparent that ad- ministering serum oftener than once every 24 hours would be very undesirable. Only on very rare occasions have I in recent months, injected oftener than once in 18 to 24 hours; the special indication was in cases with very thick exudate, where one could inject only very small quantities of serum at a time, under pressure ; or in very bad fulminating cases. The arbitrary periods established for repeating injections, in a general way, are efficient; most cases requiring daily 220 EPIDEMIC CEREBROSPINAL MENINGITIS. treatments for the first few injections at least. It is desirable, however, to be guided by more accurate indications. There are two main guides : 1st — the findings in the cerebrospinal fluid at each puncture. 2nd — the clinical condition of the patient. 1. During the course of treatment with serum, the cerebrospinal fluid has a tendency to clear up macroscopically as the disease im- proves. While this is the rule in most instances, at times it is very misleading, since the cerebrospinal fluid will become more turbid and still the patient be recovering. This happens in cases that have only slightly turbid fluid before the injection of serum, and is due to the excitation of a leucocytosis by the serum with resulting cloudy fluid. I have seen the same condition occur when serum was injected in serous meningitis, and in polioencephalitis, under mistaken diagnosis, where a subsequent puncture gave a turbid fluid, containing many pus cells but no bacteria as demonstrated in spread or culture (in other words, really corresponding to the condition of aseptic meningitis). Accurate information is obtained by microscopic examination of the cerebrospinal fluid, especially in the direct stained smear of the sedi- ment. The smear will indicate, in a general way, the total number of bacteria and their relative diminution in number, and, most important, will show the relation of the bacteria to the leucoctytes. In fresh cases and in acute cases, not responding to treatment, the bacteria are princi- pally extracellular and numerous. As a case responds whether under serum treatment or spontaneously, the organisms diminish in number, and become intracellular, frequently appearing clumped together and failing to grow in culture. Remembering that one of the principal func- tions of the antimeningitis serum is its local opsonic action to stimulate the leucocytes to pick up and digest the bacteria, one can see how much information is imparted by studying not only the number of organisms, but their relation to the leucocytes. Thus, where one finds many or- ganisms in spread, the indication is to tap the following day. If the organisms are few in number, but extracellular, again the indication is to tap the next day even if the clinical condition of the patient is appar- ently good and temperature is down. If the organisms as determined by examination of the smear are few in number and intracellular, one should then be guided more by the clinical condition of the patient. If septic symptoms continue, as evidenced by signs of active meningeal irritation and high temperature, the dose should again be repeated the following day, since it is possible that some extracellular organisms may have been overlooked. If, however, clinical signs of sepsis are im- proved and only a few intracellular organisms be found, then one may TREATMENT. 221 wait 24 hours or longer, depending upon the clinical course of the disease. 2. The clinical condition alone as an indication for repeating the doses of serum cannot be depended upon since at times one sees aggra- vation of the disease as evidenced by the condition of the cerebrospinal fluid, even when the clinical condition is apparently improved and tem- perature is down. The clinical course is, therefore, only of value when taken in conjunction with the examination of the cerebrospinal fluid. I have repeatedly punctured patients at a time when the clinical condi- tion was apparently much improved, being guided by the examination of the cerebrospinal fluid obtained at the previous puncture, and have found a serious condition on examining the cerebrospinal fluid. In treating the average case of moderate severity, being guided by the conditions just discussed, one usually has to puncture the patient daily for the first three days, then on alternate days, depending upon the course of the disease. Some cases require daily consecutive injections for six or more days. The total number of injections to be given in any individual case is difficult to determine. The average case, how- ever, requires from 3 to 5 or 6 injections, if treatment is begun during the acute stage; the subacute and chronic cases requiring many more treatments. During the treatment of the severe forms of meningitis, it may be desirable if the signs of general sepsis are marked and persist, and if only a moderate quantity of serum can be introduced into the subarach- noid space, to inject, in addition to the spinal treatment, 20-40 to 60-100 c. c. of serum either subcutaneously or intravenously. CASES WITH VERY THICK PLASTIC EXUDATE. Cases with thick plastic exudate are usually very severe and are apt to terminate fatally. The exudate is too thick to flow through the needle and the injection of serum under pressure is very dangerous. Sometimes the flow of the exudate may be started by gently irrigating with sterile warm water injected under pressure. Two needles may be introduced into the spine at different levels, the water injected at the upper level and draining out at the lower. If the flow of fluid cannot be started, or if very little fluid can be obtained, one is war- ranted in taking the risk of injecting small quantities of serum under pressure, repeating the treatment, if necessary, at 8 to 12 hour intervals. 222 EPIDEMIC CEREBROSPINAL MENINGITIS. SERUM TREATMENT OF CASES WITH DRY CANAL. Some cases respond to serum treatment by an apparent drying up of the whole canal, the cerebrospinal fluid becoming very scanty. In many cases there is a coincident improvement in the local meningeal symptoms and the general constitutional symptoms. In some cases, however, toxemia and signs of local and general sepsis persist. These cases may be treated by injecting small doses of serum into the sub- arachnoid space under pressure, repeating the treatment as necessary. It is very important, however, to differentiate this condition of drying up of the canal from the dry canal one meets in posterior basic menin- gitis in which there is shutting off of the communication between the ventricles and subarachnoid space. Intraspinal serum treatment in the latter condition is useless and very dangerous. WHEN TO DISCONTINUE THE FURTHER INJECTION OF SERUM. The question of judgment is probably the most important element, determining the course to pursue in repeating the injections of serum. The indications to stop the further injections of serum are the same as those indicating an injection. 1. Bacteriological examination of the cerebrospinal fluid. 2. Clinical condition of the patient. 1. Cerebrospinal Fluid. — These changes have already been de- scribed, consisting in most instances of a clearing up of the fluid and a total disappearance or tliminution of the bacteria, which are found principally to be intracellular. 2. Clinical Condition of the Patient. — Extremely important in- formation is obtained by noting the patient's appearance and general symptoms. His mind is clear, he is cheerful, no longer apathetic, irri- table, hypersensitive or delirious. His neck and spine may still be very stiff, but his headache is gone, he feels better, his color and skin look more normal and his appetite returns. Temperature drops to normal and loses its irregularity. Fever, however, as previously de- scribed is a very uncertain guide. RELIEF OF HYDROCEPHALUS IN ACUTE STAGE. During the course of serum treatment of the acute stage of epidemic meningitis, the hydrocephalus (excess of exudate in the cerebrospinal fluid) is relieved by the withdrawal of the fluid by lumbar puncture before the serum is injected, thereby treating the hydrocephalus and TREATMENT. 223 sepsis at the same time. It is important to arrange to perform the lumbar puncture at such time during the day when hydrocephalic pressure symptoms are most marked. In treating many hospital cases, I have been in the habit of carefully watching each patient during the day and have attempted to select the time when treatment would do most good, rather than choose any arbitrary time each day for the treatment. Occasionally, severe, acute, alarming hydrocephalic pressure symp- toms develop a few hours after serum treatment; the patient grows more stuporous or delirious, the breathing becomes irregular and ster- torous, the pupils dilate and Macewen's sign becomes very pronounced. These symptoms should be carefully watched. Not infrequently -they subside after a few hours, other times they grow rapidly worse, cause convulsions and even death. The patient should be studied carefully, and, if necessary, lumbar puncture with simple withdrawal of fluid performed. Similarly hydrocephalic pressure symptoms may develop during the acute stage even with improvement or complete recovery in the local suppurative condition, so that the cerebrospinal fluid may contain only a few bacteria or be entirely sterile. Thus, for example, a patient who has had daily serum treatment for three days, with con- siderable improvement in the cerebrospinal fluid, and in his clinical condition, may, on the following day, suddenly develop pressure symp- toms, while temperature may remain normal and the neck rigidity and Kernig's sign be less pronounced. The immediate indication, if symp- toms so warrant, is to puncture and relieve pressure by removing fluid, and, if necesary, follow with a dose of serum. Early recognition of pressure symptoms and their prompt relief during the acute stages of meningitis, tend to shorten the course of the disease, and to prevent the dangerous subacute and chronic stages of meningitis. To recapitulate, serum treatment should be actively administered during the first few days of the illness and kept up until bacteria dis- appear from the cerebrospinal fluid. If treatment is stopped too soon, there is danger of a subacute or chronic condition complicating. After the patient has been well saturated with serum, administered by daily injection for 2, 3, 4 or more doses, with considerable improvement in the local suppurative condition, one should be alertly on the watch for pressure symptoms, and, if necessary, relieve by puncture. In cases which show a complete disappearance of septic symptoms, after the first few days of serum treatment (even though a few intra- cellular meningococci persist in the cerebrospinal fluid) while pressure symptoms are pronounced, one may tap with simple removal of fluid one day and the next day, if necessary, repeat the treatment, this time 224 EPIDEMIC CEREBROSPINAL MENINGITIS. also injecting a small dose of serum. Cases with pressure symptoms from large quantities of cerebrospinal fluid may have to be treated in this way for a week or longer. If a few organisms persist in the cerebrospinal fluid, but cause no septic phenomena, serum may be ad- ministered only on alternate days. Case 1. Ill six days when admitted to the hospital. Throughout course of treatment was suffering as much from pressure symptoms as from sepsis. Three punctures were done on successive days, removing from 30 to 40 c. c. of fluid and injecting from 15 to 20 c. c. of serum. The fourth lumbar puncture was done 48 hours after the previous one, as was the fifth, the patient being injected with serum each time. The last fluid had entirely cleared up. There were no bacteria. Twenty-four hours after the last puncture, the note on the chart was as follows: General con- dition is very good. Temperature is down, but the patient is not convalescing rapidly. Signs of simple hydrocephalus are present. Macewen's sign pres- ent. Patient is stupid. Forty-eight hours after the last treatment the patient was punctured for simple relief of pressure and 40 c. c. of fluid were removed. Convalescence was rapid and patient was up and about five days later. Case 2. Moderately severe case of meningitis. Lumbar puncture with removal of fluid and injection of serum on three successive days. Last fluid was under very high pressure and showed only an occasional intracellular organism. On the fourth day the temperature was down. General condition was good, but pressure signs were marked. Patient complained of very severe headache and vertigo. Macewen was marked. Pupils were dilated. Neck was still retracted. 60 c. c. of almost clear fluid were removed. No serum was injected. On the fifth day the patient was much better, but pressure signs were still present. Temperature had also continued. Last fluid still showed a few intracellular organisms. Another lumbar puncture was performed, 40 c. c. of fluid were removed and 15 c. c. of serum injected. Convalescence was prompt. ACUTE MENINGITIS. General Treatment. — 1. Prophylaxis is the first step in general treatment. a. Care of secretion of nose and throat, urine and stool, herpes, and conjunctivitis secretion. b. Care of all who are exposed. Wear muzzle, gloves, gown. Care of nose and throat. Vaccination and other prophylactic treatment desirable. 2. Patient must be kept absolutely quiet in bed. Sitting up or get- ting out of bed is extremely dangerous and may result fatally. It is TREATMENT. 225 very important to turn the stuporous patient frequently from side to side to prevent hypostasis. Most patients feel more comfortable with the head slightly elevated by a pillow. 3. Diet should be liberal. Nourishment should be kept up, giving plenty of eggs, milk, sugar, farina, cocoa, and beef juice. Delirious and stuporous patients can be fed easily by nasal gavage every 3 to 4 hours. 4. Bowels have a tendency to be constipated. Distention frequently becomes marked. This should be treated as in any disease. The bowels can be moved by castor oil, calomel or any of the vegetable laxatives ; enemas, as necessary, help. Stouping the abdomen, pepper- mint by mouth and abdominal massage are an aid in controlling, the distention. Incontinence of the Bladder. — Paresis of the vesical sphincter is quite common. The bladder should be watched very carefully for retention even if there is incontinence. In many cases the apparent incontinence is really an overflow of a little urine but there is a •retention of most of it. I have not infrequently found 40 and 50 ounces of urine in the bladder of a patient who had been reported as emptying his bladder by incontinence. It is very important to watch this condition, especially in delirious and stuporous patients. It is a wise plan to catheterize the patient every now and then to determine if any retention be present. Restless and delirious patients will become quiet and fall asleep when a distended bladder is emptied. There is also the danger of possible rupture of the bladder. Restlessness — Delirium. — Warm sponges, occasionally warm packs and alcohol sponges relieve. The ice-helmet quiets many cases and controls the headache. The helmet is otherwise of questionable benefit in actually benefit- ing the disease. Sedatives are very often necessary. Bromide and chloral help. Combinations of phenacetin and aspirin and codeine, codeine and veronol, help and may be tried. Morphin is imperative in some cases. Occasionally hyoscin may have to be used. Paraldehyde in alcoholics is sometimes effective. Local Pain and General Symptoms After Puncture. — General symptoms of restlessness, vertigo, headache, vomiting, local pain in the back, hips, abdomen and down the legs are usual after injecting serum. The same measures as for restlessness may be employed. Morphin is frequently necessary. An ice-bag at the site of punc- ture gives relief at times. Raising the head of the patient when the 226 EPIDEMIC CEREBROSPINAL MENINGITIS. injection of serum is begun and after the treatment will often con- trol the headache and vertigo. Fever. — Usually the fever is only moderate and does not require special treatment. Hyperpyrexia should be treated by cool sponges or packs. Medication. — 1. Urotropin. — 40 to 60 grains daily adminis- tered in large quantities of water is advisable during the infective stage of meningitis and should be the routine drug in all cases, watching the urine during its administration. 2. Other drugs are symptomatically indicated. Good stimu- lants, especially with low pressure are ergot, adrenalin, digitalis. Other stimulants, such as camphor, caffeine and whiskey are effec- tive in cases with bad circulation. Treatment During Convalescence. — One must be careful not to allow a patient out of bed too soon. Where possible the patient should be kept in bed at least a week after convalescence has begun and sitting up should be gradual. Iron and other tonics may be used. Diet should be liberal. Iodid internally, even without symptoms, is advisable. TREATMENT OF SUBACUTE AND CHRONIC FORMS OF MENINGITIS. This form of meningitis not infrequently occurs in untreated cases, or in cases which have not had sufficiently active treatment during the acute stage. The course of this condition as previously described is not uniform, causing an extremely irregular febrile course, intermitting with days of normal temperature and similarly giving irregular pressure signs lasting for hours or days and inter- rupted by periods free from pressure. There are two essentially different forms of the disease. One form is mostly hydrocephalic with the resulting pressure symptoms. Active signs of meningeal irritation have entirely disappeared, the neck is limber, Kernig gone, mentality perfectly clear and general condition good. The cerebrospinal fluid is considerably improved, cells are less numerous and show a preponderance of the lymph- ocytes. No organisms may be demonstrable in smear but culture will yield a growth after a few days. The second form of chronic meningitis is a protraction of the acute active meningitis into a chronic condition and, if anything, shows an aggravation of all of the active, irritative, meningeal signs. This is the type which was frequently encountered before the days TREATMENT. 227 of specific serum treatment and is illustrative of the extreme emaciation, the boat-shaped abdomen and the hydrocephalic cry. The treatment may be divided into 1. Relief of hydrocephalus. 2. Relief of sepsis. 1. Treatment of Hydrocephalus. —Hydrocephalus not only accounts for the temporary pressure symptoms but can, per se, account for the febrile reaction. The immediate treatment, there- fore, is lumbar puncture with removal of as much cerebrospinal fluid as is safe, using blood-pressure as control. This operation may have to be repeated a number of times at intervals of days or a week or longer, depending on the rate of accumulation of fluid. Some cases will respond without any other treatment, the infec- tion dying out of itself. These cases, however, are long, lingering and persistent and usually require more active treatment, otherwise they continue for weeks, in some cases for months. The patient becomes more and more emaciated and asthenic and finally succumbs. 2. Treatment of Sepsis. — a. Serum Treatment. — Serum treat- ment at this stage is advisable but will often result in only moderate improvement, other times no apparent reaction occurring. The striking response evident in the acute cases is absent in this stage. Serum should be administered in the same manner and. in the same doses as in the acute case, the dose being repeated at intervals of a few days, depending upon the symptoms and the rapidity of the accumulation of the fluid. b. Vaccine. — The use of vaccine in the subacute and chronic stages of meningitis appears to be more efficacious, in some cases at least, than serum. I have tapped a number of these protracted, chronic cases as often as sixteen times and injected serum with apparently no response in some, in others reaction was immediate and striking though temporary, and in still others recovery ensued. The indolent, chronic infection, however, is well suited for treat- ment by vaccine with hope of setting up an active response against the disease. The remedy is surely worth trying and will occa- sionally give beautiful results. The vaccine should be autogenous, if possible, and should be repeated at intervals of 4 to 6 days, the dose varying between 100 and 1,000 million or more, depending upon the reaction produced. The treatment of the severe form of chronic meningitis is prac- tically the same as in the milder form except that it must be more 228 EPIDEMIC CEREBROSPINAL MENINGITIS. active and regular both against the hydrocephalus and against the sepsis by serum and vaccine. The outlook is very bad. General Treatment. — 1. Supportive. — Plenty of nourishment and care of the patient. 2. Iodid in moderate doses appears to help at times. Relapse. — Many cases of supposed relapse are really the sequelae of simple hydrocephalus. One does, however, occasionally see what purports to be a true relapse. The treatment should be the same as that in the acute condition. These cases are apt to lapse into the chronic stage and should be watched carefully. Hydrocephalus, frequently, is one of the most important conditions to look for and treat. Vaccine should be introduced if the condition show a tendency to pass over into the subacute or chronic stage. Cases Illustrating Chronic Meningitis.— Case 1. Mr. H., aged 68. Typical acute form of epidemic meningitis. Three punctures during the first four days of treatment, each time serum being given. Slight temperature con- tinued, last fluid still showed a few extra and intracellular organisms. Gen- eral condition improved very considerably. Further treatment was discon- tinued because patient had complained bitterly of the punctures and it was thought that he might recover without further injections. A week later tem- perature rose to 104° (temperature had been running up to 100° or 101° daily). Severe pressure symptoms developed — very severe headache, vertigo, deafness, diplopia, stupor, irritability, vomiting. Rigidity of the neck became more marked. Kernig slight. Lumbar puncture — about 35 c. c. of almost clear fluid were removed. Fluid showed a moderate number of cells — polynuclears 50%, a few intracellular organisms. All symptoms cleared up, temperature dropped. All continued well for one week, when a similar con- dition recurred. Lumbar puncture was again performed, 30 c. c. of fluid were removed, 20 c. c. of serum injected. Blood-pressure at beginning 150. No change on removing fluid. Rose to 160 on injecting serum. Fluid ex- amination still showed organisms. Prompt improvement again, only for the symptoms to return five days later. Lumbar puncture was again resorted to. Blood-pressure 140. 20 c. c. of fluid were withdrawn with no change in blood-pressure, but there was a drop of 25 in blood-pressure upon injecting 15 c. c. of serum. Fluid showed the presence of 95% polynuclear. A few or- ganisms still present. Some response, but four days later there was again a return of signs which were not, however, so marked. Temperature fluctuated between 102° and 103°. Emaciation was becoming pronounced. Vaccine treatment was begun. Three injections, of 500 m. per dose, were given at intervals of four days. Several days after the first injection there was a marked improvement. Convalescence was well established by the time the third injection was given. Discussion. — This case illustrates the irregular chronic course of the disease; the hydrocephalic symptoms, the temporary response to the removal of fluid alone, followed by an immediate reaccumulation. Apparently very little response to serum. Prompt response to vaccine. TREATMENT. 229 Case 2. Chronic persistent active meningitis. Girl, aged 16, had ordi- nary course of acute meningitis. Treatment had not been actively pushed during the beginning of the illness. I saw her four weeks after the onset. She was very stuporous, but still responded at times. She had a typical boat belly and bed sores. She was extremely emaciated and emitted an occasional hydrocephalic cry. There was marked retraction of head and opisthotonos. Respiration was irregular and pulse 50, intermitting. Knee- jerks were not obtained. Macewen was marked. Pupils were dilated, Ac- tive treatment was again begun. She was punctured six times, daily for the first three injections, then every other day, serum being injected each time. The fluid showed 70% polynuclears and a few intra- and extracellular organ- isms at first. After serum treatment polynuclears rose to 100%, but organ- isms persisted. There was no apparent response to the treatment. Vaccine was given twice, but with no avail. She succumbed about two weeks later. Discussion. — This type of patient has a very bad prognosis, even with any form of treatment. Occasionally, however, even these apparently hopeless cases will recover. Case 3. Relapse. Child, aged six. Typical acute case of meningitis. Three punctures were done on successive days, with prompt clearing up of meningeal symptoms, drop in temperature and clearing up of fluid, which, however, at the last puncture was very much increased in quantity and still showed a few intracellular organisms. The condition progressed so favorably that after a few days the child was allowed out of bed, then discharged. A week later, or almost two weeks after the last puncture, the child again developed active meningeal symptoms. For a few days previously had been also complaining of headache and malaise. Lumbar puncture was performed, when 30 c. c. of turbid fluid were re- moved under high pressure, and 20 c. c. of serum were injected. There were many organisms in the fluid. Two more treatments were given with prompt clearing up of all of the symptoms and of the cerebrospinal fluid, so that no organisms could be found by spread or culture. Convalescence now was uninterrupted. Discussion. — Note how these cases correspond to chronic meningitis. Case 4. Mr. H., 45 years old, had active violent form of meningitis and responded very well to treatment. He had four successive lumbar punctures with serum injection. On the sixth day was punctured for relief of pres- sure. Convalescence set in, but did not progress as rapidly as expected. Patient was irritable at times and had occasional headache. About ten days after the last puncture his temperature rose to 103°. He complained of severe headache and became stuporous. Pupils were dilated. When he slept there was a marked irregularity in breathing. Pulse was 140, of good quality. Lumbar puncture was done and 70 c. c. of clear fluid removed. There was a prompt improvement in all of the symptoms. A similar condi- tion, however, developed four days later, again requiring lumbar puncture. Convalescence continued more rapidly now, but the patient complained of headache, occasional vertigo and impairment of hearing at times for six weeks after. He was unable to attend to his business. No puncture was done. Iodides were given. In two months he was apparently entirely well. 230 EPIDEMIC CEREBROSPINAL MENINGITIS. Case 5. Boy, aged 8. Responded very well to three serum treatments, apparently with immediate recovery. No further treatment was given. Pa- tient, however, did not appear entirely well, had daily headache, did not convalesce rapidly. A week later he again developed temperature preceded by a chill. Had moderate headache, otherwise appeared well. Physical ex- amination showed no retraction of the head, no Kernig and a perfectly clear mentality. Pupils were slightly dilated and did not respond well. Macewen was distinct. Lumbar puncture was done and 40 c. c. of clear fluid were removed. Cellular elements were very few. Spread and culture were sterile. Two days later temperature again rose, with similar conditions present. Again 20 c. c. of clear fluid were withdrawn. Culture gave a growth of meningococcus after 48 hours. There was a recurrence of the condition 48 hours after the last puncture. This time 30 c. c. of fluid were removed and 20 c. c. of serum injected. There were no further symptoms. Convalescence was rapid. This case closely corresponds to the simple post meningitic hydrocephalus. Most of the symptoms were hydrocephalic, but there was a persistent slight infection. There was prompt response to puncture with a serum injection. TREATMENT OF COMPLICATIONS AND SEQUELiE. 1. Hydrocephalus. — A moderate, sterile hydrocephalus persists in many apparently recovered cases of meningitis. Most cases have only mild symptoms, such as occasional headache, vertigo, unusual irritability at times, inability to concentrate on studies, weakness of the eyes, which symptoms may appear irregularly, occurring principally after active mental and physical strain. These cases do not require special treatment except mental and physical rest for several weeks or months after convalescence. Severe general symptoms due to hydrocephalus which may first make their appearance during convalescence require special treat- ment. The irregular general symptom-complex, even in these cases of simple hydrocephalus with sterile cerebrospinal fluid is very sim- ilar to the symptoms occurring in chronic meningitis except that this condition has a tendency to recovery after a varying length of time and is not accompanied by emaciation, while chronic menin- gitis is accompanied by increasing wasting and asthenia, and the general appearance of a chronic sepsis frequently terminating in death. One form of chronic meningitis as described, is character- ized principally by occasional pressure signs, by considerable in- crease in the quantity of cerebrospinal fluid which may be clear or slightly turbid and shows a few meningococci which may only be demonstrated by culture. Active signs of meningeal irritation such as rigidity and retraction of the neck, opisthotonos and hydro- cephalic cry are missing. This form of chronic meningitis is very TREATMENT. 231 similar, therefore, clinically, to the sequelae of simple hydrocephalus alone. The treatment of this condition is similar to the treatment described for the like condition in chronic meningitis, omitting, however, the serum and vaccine therapy. The involvement of the special senses resulting from hydro- cephalus will be discussed under separate headings. General treatment is supportive ; mental and physical rest. Iodids. Case 1. Male, aged five. Had a moderately severe attack of epidemic meningitis, ■which responded promptly to one dose of serum treatment, so that the family physician decided that further serum treatment would he unnecessary. The patient made a rapid, uneventful recovery and was appar- ently convalescing. Temperature was normal for ten days, when the patient suddenly developed a chill, followed by a sharp rise in temperature to 105°, which dropped to normal in eight hours. During the febrile period the patient vomited, was irritable and restless. The pupils were widely dilated and Macewen's sign was marked. In view of the absence of other evidence of meningeal involvement, it was decided to watch the patient for a few days. A similar condition recurred daily. Lumbar puncture was performed after the third febrile attack. 50 c. c. of clear fluid under high pressure were withdrawn. No meningococci could be found either in smear or culture of the sediment. There was decided improvement in the general condition after the puncture, but daily intermitting fever continued. Another puncture was done three days later. 40 c. c. of fluid were removed. This was fol- lowed by recovery with no subsequent fever. Posterior Basic Meningitis. — It is most important to immedi- ately recognize this condition, so that no direct harm be done, even if nothing curative be possible. The futility of lumbar puncture for relief of pressure, the danger of aggravating symptoms by injecting serum under pressure must be recognized. The pathological con- dition is an encapsulation of fluid within the ventricles with shut- ting off of the communication between the ventricles and the sub- arachnoid space. Treatment can only be effective, even if only temporary, by direct puncture of the ventricles. There are two forms of this condition ; the more common is the form with sterile fluid in the ventricles, the other contains infected fluid with pus cells and live meningococci. Symptoms in both types are principally those of extreme pressure, with the addition of some septic febrile symptoms in the infected form. In the sterile form simple removal of fluid is indicated; in the other form, serum is injected by the same apparatus and controlled in the way as in the spinal treat- ment. It is desirable to tap both ventricles alternately at intervals of several days depending upon the reaccumulation of fluid with 232 EPIDEMIC CEREBROSPINAL MENINGITIS. pressure symptoms. In most cases, there is apparently free com- munication between both ventricles, drainage appears, however, to be incomplete in the untapped ventricle and at times the communi- cation appears to be shut off. Dangers of" the Operation. — The direct puncture of the ventricles is well borne, usually causing but little shock. The very strictest asepsis must be employed. The two great dangers are injury to vital centers and hemorrhage. The operation can be performed without risk, if sufficient care is used in selecting the proper site for puncture, so that the cavity may be entered without penetrating the basal ganglia, or without producing hemorrhage from injury to the choroid plexus or the pial vessels. Except in one instance I have always chosen the anterior site for trephining and where the anterior fontanel is open, have punctured directly through it. I have made some sixty punctures in about fifteen cases. I have never had a death on the table nor severe hemorrhage. I know of instances, however, where both of these complications occurred, even when the greatest care was employed in choosing the proper site. The puncture after all is a pretty blind one through the brain tissue. In most cases, however, one can apparently perform the puncture with little risk of severe hem- orrhage. In only one instance was there evidence of local involve- ment of tissue following the puncture. In this case, a child of four years, a complete spastic hemiplegia occurred a few hours after ventricular puncture. The operation is apparently the only possible hope for these cases, and certainly should be done. The few cases of recovery absolutely warrant this procedure. Technic of" Operation. — In children with open fontanel, the operation is a very simple one. The ventricles are usually ex- tremely dilated, the cortex thinned and introduction of the needle at the lateral border of the anterior fontanel in most any direction, will usually strike fluid. The needle must ordinarily be introduced to a depth of an inch and a half or more, directing the needle down- ward, slightly backward and inward. The ordinary lumbar punc- ture needle with the trocar may be used, a blunt-edged needle being- preferable. One must be careful to keep the stylet in, until the ventricle is reached, otherwise the lumen of the needle will fill up with brain tissue. In older cases with closed fontanel, the skull must be trephined. These cases are usually very stuporous so that little anesthesia is necessary. Kocher's point may be chosen. This roughly corre- TREATMENT. 233 sponds to the lateral border of the anterior fontanel in a child. This, like the puncture through the open fontanel, traverses the frontal lobe. The point is situated 2]/ 2 c. m. from the middle line and 3 c. m. anterior to the central fissure — a point lying somewhat in front of the bregma. The needle must penetrate 4 or 5 c. m. before it reaches the ventricle and should be directed somewhat downward and backward. The ventricle at this situation is broad, extending fulfy 2 c. m. from the middle line, and there is practically no risk of hemorrhage during the passage of the needle. One side may be trephined at one sitting and the other side when necessary at another. The skin flap is entirely closed up and subsequent punctures are done through the scalp. Keene's point may also be chosen, it having the advantage of better drainage. The site of election is at a point corresponding with the posterior end of the temporal line, about 3 c. m. behind and an equal distance above the external auditory meatus. In this situation the needle should enter .the posterior part of the first temporal convolution and should be directed toward the summit of the opposite pinna. At a depth of about 5 c. m. the ventricle will be entered at its widest part ; namely, where the lateral and posterior cornua are given off from the body of the ventricle at the posterior end of the thalamus. Case 1. Child, aged four. Five days under intraspinal serum treatment of epidemic meningitis, developed all of the typical symptoms of posterior basic meningitis within 24 hours after the fourth puncture, which had showed a free communication between the ventricles and subarachnoid space. Pres- sure signs were marked. There was exophthalmos on the right side. Spinal puncture gave a dry tap. The right ventricle was trephined in Kocher's point. Dura appeared tense. Ventricle was tapped and about 40 c. c. of clear, amber fluid were removed. A fine, urethral catheter was introduced through the needle and left as drain. On the second day the child was brighter and there were practically no pressure signs. Exophthalmos had disappeared. Breathing was regular. Pupils were contracted. Dressing over the catheter was wet. On the third day pressure signs were again as marked as at first. 35 c. c. of clear fluid were removed from the left ventricle also. This side was also drained. Condition seemed somewhat improved for 48 hours, then pressure signs again appeared. There was no drainage from either catheter. The right ventricle was tapped — 30 c. c. of fluid were removed. There was temporary improvement for 24 hours, then a recurrence of symptoms. The child was tapped three more times, each time with tempo- rary improvement, but immediate recurrence of symptoms. Became more and more emaciated, became totally unconscious and died three weeks after developing the condition. Case 2. Infant, aged two months, was ill five days. Was very stuporous, had staring expression and slight exophthalmos. Opisthotonos was extreme: 234 EPIDEMIC CEREBROSPINAL MENINGITIS. fontanel showed marked bulging; respiration was irregular All signs of marked pressure and meningeal irritation were present, with occasional clonic convulsions and constant tonic spasms. Lumbar puncture at three levels gave a dry tap. Brain Puncture. — From the right side of the fontanelle 30 c. c. of very turbid fluid were removed and 20 c. c. of serum injected directly into the ventricle. The fluid showed pus-cells and many intra- and extra-cellular or- ganisms. On the second day pressure signs were still present — fontanelle bulging. Left ventricle was tapped, 25 c. c. of slightly turbid fluid were removed and 15 c. c. of serum injected. Catgut drain was left in the ventricle. Only a few intra-cellular organisms were now seen. On the third day there was marked improvement in the pressure symp- toms. The child was brighter, opisthotonos was less marked, breathing was more regular and there were no convulsions. On the fourth day the condition was good. On the fifth day the child was more stuporous, tonic spasms of the ex- tremities were again marked. The right ventricle was tapped — 30 c. c. of clear fluid withdrawn. No serum was injected. Fluid failed to show any organisms in spread or in culture. The child was subsequently tapped six times at intervals of 2 to 3 or 4 days, each time with temporary relief, but subsequently followed by relapse of symptoms. At one sitting the right ventricle was first tapped and 40 c. c. of fluid were removed. The needle was allowed to remain in situ. Then the left ventricle was drained and 10 c. c. of fluid were removed. Serum was then introduced into the left ventricle and after 15 c. c. were injected the fluid began to flow out from the needle in the right ventricle, showing that there was a free communication between the ventricles. The fluid remained sterile. The patient finally died four weeks after treatment was begun. Discussion. — There was marked temporary improvement here, which, however, was promptly followed by reaccumulation of fluid. All of my other cases of post basic meningitis were treated in the same way. Some who had sterile fluid were simply tapped, as indi- cated, for relief of pressure; others were injected with serum into the ventricles. In all there was undoubted temporary improvement. One case in the Kansas City Hospital had posterior basic men- ingitis. The canal was dry and the fluid in the ventricles was very purulent. Serum was injected three times into alternating ventri- cles on successive days. Apparent recovery followed and the child was sent home well. I heard of similar case in Ft. Worth. After several tappings with injection of serum, the patient recovered. This patient was older and skull trephine was necessary. Louis Fischer reported a case in March, 1910, which corre- sponded to the clinical picture of post basic meningitis with dry canal. This was an infant two months old. The ventricles were TREATMENT. 235 tapped a number of times, were irrigated with saline solution, then injected with serum. There was apparently complete recovery in this case. Flexner in discussing this case believed that it was the first on record to recover. Treatment of Complicating General Symptoms of Sepsis. — 1. Arthritis. — The acute, temporary arthritis requires only general treatment — simple immobilization, hot applications, methyl salicy- late or wintergreen. Internally, aspirin in moderate doses appears to help. The condition clears up quickly, usually within a few days to two weeks. 2. In joints with extreme distention which have a tendency to grow worse rather than improve, the advisability of tapping must be considered. I have never had occasion to resort to this pro- cedure though I had it under consideration in a number of cases for a time. Lord and Netter reported cases in which tapping followed by injection of the antimeningitis serum resulted in prompt recov- ery. I have record of an extremely interesting case in a young woman. The disease began as a polyarthritis, apparently as an attack of rheumatism. Several weeks later meningitis developed. The joint condition persisted and the right shoulder became more and more distended. The meningeal condition responded promptly to treatment but the shoulder became more distended and painful and apparently accounted for a persistent, irregular temperature. It was decided to aspirate. A large quantity of turbid fluid contain- ing many pus cells and meningococci was removed and a moderate dose (about 20 c. c.) of antimeningitis serum was injected. Tem- perature promptly dropped to normal and the joint cleared up with no further trouble. This case not only illustrates the occurrence of true infective meningococcus arthritis but also the benefit of local serum treat- ment in this condition as in meningitis. 3. Subacute and chronic polyarthritis, characterized by slight swelling, with disability of the affected joint and irregular, persist- ent temperature. This condition is an ideal one for vaccine therapy, an autogenous vaccine in repeated, moderate doses between 100 and 1,000 m. being indicated. Local treatment of heat and massage is beneficial. Internally, urotropin may be given for a time. Aspirin frequently controls the acute paroxysms of pain. Phlebitis and neuritis usually are mild and clear up quickly, no special treatment being necessary. 236 EPIDEMIC CEREBROSPINAL MENINGITIS. Pericarditis, pneumonia and endocarditis should likewise be treated in the usual way. Endocarditis. — If endocarditis can be demonstrated, especially if it be associated with a chronic sepsis, such as I have illustrated, causing a condition like chronic, infective endocarditis due to the streptococcus, it should be actively treated by vaccine in repeated dose and in sufficient quantity to obtain reaction. Serum Sickness. — The symptoms of serum sickness are the same after using this serum as after other preparations of horse serum. It is a very frequent complication in serum treated cases of menin- gitis, probably due to the fact that the serum is unrefined and very large doses are used. The symptoms have occurred in about 60% of many cases under my treatment. They usually appear on the eighth to tenth day after the first dose of serum. Not infrequently one sees the accel- erated reaction on the fourth to sixth day after the first injection in cases where the dose of serum has been repeated. I have met with a number of cases who have had the immediate reaction within ten minutes to one-half hour after the injection of serum. These cases had probably been sensitized by a previous injection of horse serum for some other disease. Ordinarily the symptoms are annoying but not alarming. They are, chiefly, marked general, giant urticaria, at times a general errythema or errythema multiformis or angio-neurotic edema. Edema of the tongue is occasionally observed but I have never seen edema of the larynx. Fever is moderate, sometimes chilly feeling is experienced. There may be nausea and vomiting. Headache and vertigo may be marked. Slight arthritis and alubuminuria are common. General moderate adenitis may occur. In those who have had serum subcutaneously, as for prophylactic injection, there may be some local reaction and local adenitis near the site of injec- tion. These symptoms last from several hours to several days and are usually at no time alarming. Occasionally, however, the severe symptoms of serum sickness which have been described following the use of serum for other diseases may appear and cause apprehension for a time. Severe chills followed by very high temperature may occur. Prostration may be marked and the patient be in shock with feeble pulse and cold, clammy skin. One case had pulmonary edema which cleared up in several hours. This condition usually responds readily to treatment and appears ordinarily to be more grave than it actually is. During the course of treatment of an acute case of meningitis, the development of these symptoms may TREATMENT. 237 be very confusing in that one may be in doubt as to whether the severe, general symptoms and high fever are due to meningitis or to the serum sickness. If one be on the watch for serum sickness, the cause of the symptoms can usually be determined. If the men- ingeal condition had been responding as could be expected, it is wise to leave the patient alone rather than to puncture him unnec- essarily and further depress him. Case. — Girl, aged 10. Moderately severe case of epidemic meningitis. Had been injected with the antimeningitis serum subdurally on two successive days with considerable improvement so that the attending physician thought further serum treatment might be unnecessary. Four days later (six days after the first dose of serum) a moderate relapse was observed and the patient was sent to the hospital. Her general condition was very good. Lumbar puncture was performed and 15 c. c. of the antimeningitis serum were administered. The condition at the end of the operation was good. Four hours later, a severe, giant urticaria suddenly broke out, being accom- panied by delirium and symptoms of intense shock. Pulse was rapid and weak; color was cyanotic and within an hour a severe, general, pulmonary edema developed. The immediate condition of meningitis was not aggra- vated. Active general treatment fortunately brought notable response in a few hours. The patient made an uneventful recovery from her meningitis. Case 3. Moderately severe case of meningitis. Injected with serum on three consecutive days following his admission to the hospital, then on the fifth day, and tapped for simple removal of fluid on the seventh day. Symptoms were very much improved, child was brighter, stiffness of the neck was only slight, Macewen was slight, temperature was 100°, cerebrospinal fluid had cleared up, yielding only a few intracellular organisms. On the eighth day temperature suddenly rose to 104°. General condition was not so good. The patient vomited, appeared stupid, pulse was weak but there were no other pressure signs. The onset of such violent symptoms in the face of previous steady improvement made me suspicious that possibly the meningitis was not accounting for the symptoms. General treatment was given. About two hours later a marked urticaria appeared all over the body. General condi- tion became worse and pulmonary oedema quickly developed. It was notice- able, however, that while the general condition was not good, that it was not as bad as it would be usually with terminal pulmonary oedema. Active general treatment with cupping of the chest gave immediate response in a few hours. The following day urticaria was still present, but general condi- tion was good and oedema entirely gone. Treatment of Serum Sickness. — Externally. — Local sedatives, such as acetic acid, alcohol, warm sponge or sometimes ice-cold sponge, bicarbonate of soda, menthol, and anesthezine ointment prove beneficial. Internally. — Laxatives. Salol and menthol appear to do some good. Diet should be light. Sedatives, such as codein, at times 238 EPIDEMIC CEREBROSPINAL MENINGITIS. morphin, are sometimes necessary. Atropin 1/100 of a grain in some cases appears to check the attack. ANALYTICAL STUDY OF THE EFFECT OF SERUM TREATMENT OF EPIDEMIC MENINGITIS. General Remarks. — The response to serum treatment in many cases is immediate, with disappearance of many of the severe symp- Name Age DaU > 191 / a ^ i 9 * i Pulse Re«p. -Lj 6 10 2 6 >9 i A io 2 6 10 I 6 10 2 6 io 2 6 IC 2 6 10 2 6 10 A H -«- 106 4 -& — 1 - -wo— -65- 3J ,r *». tos 60 X -*; 7 .p Of ^5 r\ ■T" 10} L - - 440- -40- t i V- 102 * - 4J0- —45- V* "\ ~ii' >o J "irf 101 3 1 = ^ — - -m- —40- 4 F ^= - - l ~^— 100 3! E — V Stf" i -tar •—95- H 1 5X 99 NORMAL *3 3 _ * = ^F ■ * m '- ff -Ar =t =te* - -90-^ -30- _l — 98 97 V TT ■ 3 - — - — | 1 i * ^ - -^60- —20- M 95 :- _ 4t>- — «- •— Chart XI. Child aged 4. This chart illustrates a pronounced perature after the first dose of serum with no subsequent rise. Note following for a few days. critical fall in tem- the subnormal curve toms. In most cases, recovery occurs by lysis. A number, how- ever, recover by crisis, as evidenced not only by a critical fall in temperature, but also by clearing up of all of the active symptoms. Flexner and Jobling reported that symptoms disappeared by lysis in 200 of their cases and by crisis in 73 or 25%. In my experience true, critical recovery, in 24 to 36 hours after treatment, occurs in cases treated at the very inception of the disease, either during the primary septicemic stage, or just at the onset of the meningitic TREATMENT. 239 stage. Cases diagnosed and treated during this period are rela- tively few. Many cases of meningitis respond in a startling manner, after only one dose of serum, with very considerable im- provement in all symptoms and a fall in temperature. Some men- ingitic symptoms, however, persist for a number of days, clearing up gradually. I have not referred to these cases in my classification as true critical recoveries, though a study of a later analysis of the Name Age Date 191 / a 4 ^ ? ar ? ; Pulie Re«p. 2 6 10 2 A ^ \v \ iru V; IIM IV ^ jh ^\ ^ ~\ o t_ § *» t; _f % j t Tl "1 ~* t £~ 1 V"S XJ ' 4/ Jl SZ t 100 jr :fc ' \ \ L <¥* •M \ -^_ — "Y — ± V, \ LZ v — • 1 r L . vv V Q7 60 20 % 95 — Chart XII. Child aged 12; marked immediate response to serum treatment, accom- panied by rapid lysis in temperature. total duration of the disease in many recovered cases shows that one would be justified in referring to many as critical recoveries. The effect of serum treatment in epidemic meningitis, may be classified according to its effect on 1. Sepsis — local suppurative meningitis and general sepsis. 2. Hydrocephalus. 3. Complications. 4. Shortening of illness. 5. Change in prognosis. 240 EPIDEMIC CEREBROSPINAL MENINGITIS. 1. Effect on Sepsis. — a. EFFECT on Temperature. — The change in the febrile curve is very striking in many cases. Fully one-third of the cases respond by a sharp, critical drop to normal after the first injection, some of the cases remaining at normal- until complete re- covery. Most cases, however, again develop a little fever 12 to 24: hours after the initial critical fall, then gradually drop to normal by lysis during the following few days. Other cases show a rapid Name A«e Date _ 1»1 / a ; 4 "i 7 * ? PuIm Rap. 2 to j '6 10 2 6 10 2 6 10 2 6 10 2 6 10 2 J 6 10 2 6 10 2 6 10 ' / X 75 || / i S J : i w \ \ s 10$ $ - Jni If l" S3 fc ■ i 41 <*•> 5^ i\ / 103 \* / a 3 * \ a rz XI \ f\ 102 ±: V "■ \j 3 Y d 3 M IAI zs sS . f v ri" too X| , / 1 E ■fl ZJ 4v ~_ Mm / ^v IE j / ; / [j ■f a* B 96 j 1 c 1 •Jr 97 20 1 ■ 1 so" 96 I . 95 l_ i Chart XIII. Chinese boy aged 13; marked accompanied by rapid lysis in temperature. immediate response to serum treatment, lysis. The largest group of cases display an irregular fever chart characterized by sharp, considerable fall after each injection of serum, followed by a moderate rise several hours later. With im- provement, there occurs a lowering of the extent of the fluctuation with each new treatment, and a gradual lytical fall to normal. The recorded fever curves reproduced from some charts best illustrate these changes. TREATMENT. 241 b. Effect on Cerebral Symptoms. — The rapid clearing up of many of the most violent cerebral symptoms is especially remark- able. It is a common occurrence to have a change from a violently delirious or completely comatose patient one day to a rational, quiet patient 24 hours later. The picture is a noteworthy transition from an overwhelming sepsis with marked, local cerebrospinal and men- ingeal symptoms one day to a normal condition the next. The sub- sidence of mental symptoms is the most prompt and is of consid- Name Chart XIV. Child aged 5. Prompt improvement after serum treatment. No change in temperature, however, until after the fourth puncture. erable prognostic importance. A rational, quiet, pleasant patient is a cause for great relief, even though other signs such as rigidity of the neck, Kernig and fever may continue unchanged. c. Effect of Serum Treatment on the Rigidity of the Neck and Kernig's Sign. — Many cases show improvement clinically by disappearance of neck tenderness and a relaxation of the muscles with gradual return of free movement. There is usually a coinci- dent improvement of Kernig's sign. Absence of improvement in 242 EPIDEMIC CEREBROSPINAL MENINGITIS. these two important diagnostic signs is no index, however, as to the course of the disease. Not infrequently, considerable stiffness of the neck and Kernig's sign persist well into convalescence. It is very probable that this may be explained by fear on the part of the patient rather than by a persistent local meningeal irritation. General Improvement. — Improvement in the general condition is remarkably rapid, with favorable response to treatment. Patients who are extremely prostrated and cyanosed with very weak circu- Name - Agi Date 191 / 2. 3 4 l 7 * Pu!.e Reap. 2 b 10 2 6 10 2 6 2 6 10 2 6 10 2 6 — * 10 2 6 10 2 6 10 6 10 4 75 IJ < is ,; 3 ' * 3 _Q tJ ^ j , CI . * IE Tl L 3 3 J\ 3 Z5 ^ 7^ ( ^ 1 y S^ V Zi ini E i XL t n ^3 f ¥ X- ' n •r ZI r) A* S- V nf 3a A ^% i H \ > \1 3 \fi ii . .1 "ft cz I \" .1 t Ni tfc SL ?»" zt IAI - — 5: ^ zt i*hi u\ 3 3 s - 1 "•M _: j 3 1 3 ZJ ^ . r I ZS 53 __; ^ _L_ f 10 9* / i ZS I /\ fa Z3 3 \ J \ *r S3 Z3 z; J \ * \ / 35; §5 5 w I Aj H L j !5 3 *t — 4- — , r^ 1 V -r» 4 -V ~Z NORMAL 96 =! 1 -80- -*- 1 , 1 \ J \v *- — VI ., % | R 95 — i i— Ml J Chart XV. Man aged 60. Illustrates an ascending febrile curve, which, on the fourth and fifth days, was accompanied by some general improvement. Febrile curve here during the first three days was very misleading as to the course of the disease. lation, in a few days, often feel well enough to eat everything and ask to sit up. This apparent well-being is very deceptive. Several weeks usually elapse before normal health returns. d. EEFECT on Cerebrospinal Fluid.— The significant evidence of improvement as noted by clearing up of the cerebrospinal fluid— the total diminution in quantity of the exudate, the phagocytosis of the meningococci and their prompt disappearance— has already been described. TREATMENT. 243 It must be remembered, as noted before, that these changes must be weighed together with clinical evidence of improvement, since chronic meningitis and posterior basic meningitis both show find- ings in the cerebrospinal fluid very similar to the changes occurring with improvement in acute meningitis. (See page 245.) 2. Effect on Hydrocephalus. — Improvement in pressure, hydro- cephalic symptoms are often first indicated by the clearing up in the mentality as above described. Coincidently there is the disappear- Name. Age. Date. .191. / a 3 4 6 * Pulie Reap. 2 10 2 6 10 2 6 10 2 6 10 2 6 10 2 6 10 2 6 10 2 6 10 2 .6 10 75 3 160 60 Z3 _j Z3 n \ A 73 • r ,. z: §j . IAJ jv / t ILM -S f zt :§ ft- 1 , j \ r V 1 ZJ 3 ?» V 1 ' \ j 3 v. j ^ s *t \J ^ ^ Tr * i u* A V * 1 !* l 'vJ TTTTT I J ' il 2 1 ^ ' T a ^ * ! \ I '* „ II j /n 2 T T 1 *> „ I l ; , , 1 ill §1 .,JXJ LU gkJc i •< ^ * 5i-i:::i 1 1 II 2 ^v^&tpA ''?3? N .11.1.1., O ctf ^ ^ - I III 2 r~ * •m3Z& > "-'7i f*"'> "2* « -ll-l-t- 1 2 ■ + + ■ + »■» %l[ l«a -ltt-1 ■"'1 p™ 414.1- k --.j 1 ' ■SfK lOs * i \wi/ 1 r?-r2f.->n?fo *.* "nisi -U""+t 1 2 i f .-•"'' 1 \Q -o <;^ ' " ^5 TT e 4 ^^ Q i"N il *V[' ; ff f' '" r, '"H!1 „ © tt::;^! i T Si * .t-±t<. „ .--I.--.II::: ---it--- 1 III o ::;:;;::n:;: (q * ""jzC a>3 BJI .^igl:: « 2 > . '4pr?r ;]'3^"|I '' N T > o 1 1 co •. ""WasL ;' «>._r ::i::"ii_i T^'iSn 1 .2 c» - ff "|f ;>ii t;Xxww « 1 2 -Il„„±.-*' ■ > >^ o TT "iS^T* !:j;:;::!jm4! y ''' r \W " _LT -m i 1 III S 3 3 g ~ _ s ? | $ 5 I s S E ■ Z a 1 c 2 .2 3 Q 3 .5 >> bo' 55 i- a 3 3 II 3 W) Q. J^ 3 £o £ + j rt 00 n r ~^ r\i ^^ O rt .5 3 CD T3 * U ■m , U 3 a. 5 rt ^ >. 00 u T3 Ph X O i; w. a J; u. TREATMENT. 245 It has been elsewhere noted, however, that there is a tendency for many cases to recover with a temporary, mild, simple hydro- cephalus. This, of course, is really to be expected as a result of the extensive cerebrospinal inflammation. Series of Microphotographs Illustrating the Change in the Cerebro- spinal Fluid Under the Influence of Serum Treatment with Improvement. Fig. XX. Fig. XXI. Fig-. XXII. Fig-. XXIII. Fig. XX. Stained sediment of cerebrospinal fluid removed from a case of epidemic meningitis at the beginning of the disease, before serum treatment was instituted. Note the presence of intra- and extracellular diplococci and pus-cells. Fig. XXI. Appearance of sediment 24 hours after 30 c. c. of serum had been injected subdurally. Note the marked diminution in the total number of bacteria and the fact that most of them are intracellular, only a few being extracellular. This condition was asso- ciated with evidence of clinical improvement in the disease. Fig. XXII. Stained sediment of cerebrospinal fluid obtained 24 hours after the second dose of antimeningitis serum. Most of the bacteria have disappeared, the few remaining diplococci being intracellular. The pus-cells are more numerous, probably as a direct result of the beneficial action of the serum. Fig. XXIIT. Sediment of the cerebrospinal fluid 48 hours after the third dose of serum. Bacteria have totally disappeared and the cytological picture is changing. A moderate number of lymphocytes are beginning to appear. The patient at this stage was rapidly recovering. 246 EPIDEMIC CEREBROSPINAL MENINGITIS. 3. Effect of Treatment in Preventing Complications. — Next to a reduction of the mortality, the great benefit of serum treatment has been in the prevention of the terrible complications of the disease, previously so common. The complications and sequelse of blind- ness, deafness, imbecility and extensive paralysis were far more to be dreaded than the existing high mortality. These complications have been almost entirely eliminated in cases receiving the benefit of early serum treatment, before the disease has caused serious damage. Chronic meningitis, which formerly was frequent, is now uncommon. Posterior basic meningitis is also probably far less frequently encountered than formerly. 4. Effect of Serum Treatment in Shortening the Period of Illness. — Prior to the use of serum treatment, epidemic meningitis was either rapidly fatal or a long-drawn illness, frequently ending in death. In his tabulation of 350 cases which occurred during the New York epidemic in 1905-6, before the introduction of serum treatment Holt showed that the disease lasted one week in less than 3% of cases that recovered, and five weeks or longer in 50% of the cases. Against these figures are significantly contrasted those of Flexner and Jobling who found that the average duration of active symptoms in 288 serum treated cases was 11 days. In my personal experience with several hundred cases, I have found that most acute cases responding to serum treatment were convalescent five to six days after the beginning of treatment. Most of my cases so treated during the last Dallas epidemic were discharged as well, two weeks after they were placed under treat- ment. Even older patients over 50 years of age, showed prompt and wonderful change after treatment. The following cases illustrate : Case 1. V. J., aged 25. Ill 48 hours. Admitted to the hospital in com- plete coma and in collapse. Pulse rapid and weak. Respiration stertorous and irregular. All meningeal signs marked. Temperature 105 c . Lumbar puncture on admission. Had to be actively stimulated during the operation. 28 c. c. of turbid fluid withdrawn under high pressure. 23 c. c. serum in- jected. Many diplococci, extra- and intra-cellular organisms and pus-cells. 2d day. Much improved, though still very ill. Very stupid. Temper- ature had dropped within six hours after first puncture to normal. On morn- ing of second day temperature 100°. Lumbar puncture — fluid much less turbid. 30 c. c. withdrawn, 20 c. c. of serum injected. Fluid showed only a few organisms to a field and almost all intra-cellular. 3d day. General condition very good. Temperature normal. Perfectly clear and rational, asked for food. Rigidity of neck and Kernig only slight. TREATMENT. 24? No further treatment was necessary. Patient was discharged five days after admission to the hospital. It was not considered advisable to allow the patient to get up so soon, but for some reason it was done. She looked per- fectly well at the time of her dismissal and convalesced rapidly at her home. Discussion. — A remarkable transition from almost dying condition to re- covery in two days. Case 2. C. A., aged 19. Ill 12 hours. Admitted to the hospital in very bad condition, unconscious and very delirious. Color was bad, breathing very irregular. All signs of meningeal irritation marked. Temperature 103°. Lumbar puncture — 65 c. c. of turbid fluid withdrawn under very high pres- sure. 35 c. c. of serum injected. Fluid showed many extracellular or- ganisms. Twenty-eight hours later, temperature normal (had dropped in one, hour after operation). Patient was bright and rational. Felt well. Had some headache and felt dizzy. Neck still very stiff. Macewen distinct. Lumbar puncture — 55 c. c. of turbid fluid withdrawn, 25 c. c. of serum injected. Fluid now showed only a few meningococci — these intracellular. 3d day. Temperature normal. Felt well. No complaints. All signs much less marked. Discharged seven days later. Case 3. Mr. C, aged 55. Ill 24 hours. Admitted to the hospital in wild delirium. Was given every known hypnotic without effect. Chloroformed and held by ten assistants before puncture could be performed. 70 c c. of turbid fluid under terrific pressure were withdrawn, 30 c. c. of serum in- jected. Fluid was overloaded with meningococci. Twenty-four hours later, delirium had passed. Patient wished to know why he was in the hospital. Complained of severe headache and vertigo. Temperature continued high. Active meningeal irritation still present. Lumbar puncture — 40 c. c. of much less turbid fluid under higher pressure withdrawn, 25 c. c. of serum injected. Fluid yielded a moderate number of organisms, some being extracellular. 3d day. Temperature down. Felt well. Neck was still very rigid. Still had slight headache. General condition was very good. Respiration was regular. Pulse good. Mind clear, not irritable. In view of the findings in the previous cerebrospinal fluid, I decided to puncture. Lumbar puncture — 30 c. c. of slightly turbid fluid withdrawn, 20 c. c. serum injected. Fluid showed only a few organisms, all intracellular. 4th day. Temperature normal. All symptoms very much improved. Slight neck rigidity. 7th day. Patient apparently well. Insisted upon getting out of bed so as to be prepared to leave for business the following day. 8th day. Patient left hospital for business, he said. He reported several weeks later that he was well, though at first felt very weak, was unable to stand very long and was subject to headache and vertigo. 348 EPIDEMIC CEREBROSPINAL MENINGITIS. PROGNOSIS. In the preceding pages we discussed the remarkable effects of the antimeningitis serum, in curing the disease in many cases, in preventing the serious complications and sequelae and in shortening the course of the disease. We will now study the various influences which determine the ultimate course and prognosis of epidemic meningitis. For simplicity, I shall classify the study of prognosis into 1. Factors influencing prognosis : A. Early diagnosis. B. Age of the patient. C. Character of treatment employed. a. Acute. D. Type of disease 4 b. Chronic. c. Posterior basic meningitis. 2. Prognosis of complications and sequelae: A. Septic complications. B. Injury of special senses- 3. Causes of death: a. Deafness. b. Blindness. c. Paralysis. d. Imbecility. A. Sepsis. B. Hydrocephalus. C. Complications. 4. Summary of mortality statistics : A. Before the days of serum. B. With serum treatment. 1. Factors Influencing Prognosis. — A. Early Diagnosis. — The importance of early diagnosis with prompt institution of treatment before the disease has made too much headway is apparent. Epi- demic meningitis, is in most cases, a virulent, very acute disease. It is extremely important to begin treatment before the meningeal suppuration has advanced too far, before the hydrocephalus has become alarming and especially before there has occurred destruc- tion of important structures, which will cause permanent disability. The following statistics are mute witnesses of this fact : TREATMENT. 249 TABLE XVII. Mortality, per cent. Day of the disease when treatment was begun. Flexner's cases (712). Dopter's cases (402). Netter and Debre's cases. (99) Author's cases (180). Author's corrected statistic cases (161). First to third day 25.3 27.8 42.1 8.20 14.40 24.10 20.9 33.3 26.0 13.0 23.6 37.1 9.0 Fourth to seventh day Later than seventh day 14.9 22.6 Average mortality 34.1 16.44 28.0 25.0 15.5 During epidemics, if sufficient suspicion exist, the patient should be given the benefit of the doubt, and exploratory puncture done. If possible, diagnosis should be made during the accumulative stage, when immediate treatment may promptly abort the disease. B. Influence of Age of Patient. — Flexner, in his exhaustive studies, called particular attention to the influence of the age of the patient on the prognosis. Note the following statistics : TABLE XVIII. Gross Percentage Mortality in Epidemic Meningitis Under Serum Treatment, Cases Analyzed According to Age of Patients. - - Reported by Flexner i Netter Dopter Author 50.0% 50.0% 48.6% 50.0% 42.1% 0.0% 20.1% 21,2% 23.5% 16.6% 9.3% 17.5% 11.4% 12.5% 8.5% 9.0% 23.8% 0.0% 10.2% 18.0% 26.4% 0.0% 14.1% 32.0% Under one year One to two years. . . Two to five years. . Five to ten years . . . Ten to twenty years Above twenty years The very high mortality in infants and in adults over 40, is to a very great extent, influenced here as in other diseases by their lowered vitality and resistance. An additional factor in young chil- dren is their greater tendency to develop extreme hydrocephalus and convulsions. C. Influence of Character of Treatment Employed. — The persona] element of judgment when to treat actively and when to 250 EPIDEMIC CEREBROSPINAL MENINGITIS. leave the patient alone, often determines the ultimate course in many cases. The recognition of the proper. indications for repeat- ing the injections of serum, especially in the information obtained by proper laboratory examinations of the cerebrospinal fluid, the importance of recognizing and promptly treating hydrocephalic pressure symptoms often determine the prognosis. The proper control of the dose of serum administered under control of blood- pressure observations, if possible, is all important. All of us who have administered serum in the old arbitrary way, judging the dose solely by the volume of cerebrospinal fluid removed, can recall in- stances of serious results which occurred either on the table or shortly after the operation. These results were probably due to the quantity of serum injected. The great importance of causing as little shock as possible during the operation is apparent and can- not be overestimated. I believe that the control by blood-pressure observations will undoubtedly prevent many unfortunate accidents. Dr. Nash, City Health Officer of Dallas, who used the blood-pres- sure control in about 400 cases of meningitis now says "I could not do without it." Such has also been the experience of many others who have employed this method of control. The best proof of the value of all measures above mentioned is seen in comparing the mortality statistics in many of the different cities in Texas during the last epidemic. Thus, in one city there had been at one time a general mortality of over 70% in serum treated cases, later when serum treatment, properly regulated and controlled was generally introduced, the mortality dropped to less than 30% in a large series of cases. In a tabulation of the statistics of about 2,800 cases at the end of the epidemic, one finds very high mortality in some districts as against low mortality in many others. In a gross tabulation of serum treated cases at the end of the epidemic in Texas, the mortality was only 37%, whereas there was a mortality of over 50% in a large city in the West among over 400 cases. The disease in that city did not appear to be any more vir- ulent than in Texas. These wide variations in statistics can be readily explained by the greater experience in treating the disease in different sections and especially by the important influence of careful, experienced hospital treatment, where constant attention can be given. D. Relative Prognosis of Different Forms of Meningitis. — a. Acute Meningitis. — This form of meningitis offers the best hope. The influences previously considered apply especially to this form of the disease. TREATMENT. 251 b. Chronic Meningitis. — -The chronic simple hydrocephalic type, which is a simple hydrocephalus plus a very low grade attenuated infection, has a fair prognosis, if active treatment be employed. The other form of chronic meningitis, which is a. protraction of the acute active meningitis with all of the active lesions and symp- toms, has a very bad prognosis, most cases dying in spite of all treatment. Occasionally, however, after all hope has been aban- doned, these cases may begin to gradually improve and utimately recover. c. Posterior Basic Meningitis. — This condition has an extremely bad prognosis. Untreated it is probably fatal in every case; treated it is fatal in most. 2. Prognosis of Complications. — (Refer to the special discussion of this subject in chapter on "Complications.") 3. Causes of Death in Meningitis. — A. Immediate. — General sepsis, especially in the petechial, fulminating cases, may kill even before an active meningitis occurs. Local sepsis, from suppuration in the cerebrospinal meninges, may kill in several days, or more slowly as in subacute and chronic meningitis, where it causes steady progressive wasting, marked asthenia with ultimate exitus. B. Hydrocephalus. — Hydrocephalus with its pressure symp- toms, next to sepsis, is the great cause of death in meningitis. In untreated protracted cases, in which the cerebrospinal fluid not in- frequently becomes sterile, in subacute and chronic meningitis in which there is frequently only an attentuated low grade infection, hydrocephalus is the immediate cause of death. In acute menin- gitis, severe hydrocephalic pressure symptoms, stupor, convulsions, cyanosis, respiratory embarrassment which appear to immediately threaten the life of the patient, are of frequent occurrence. The immediate relief of symptoms after lumbar puncture with simple removal of cerebrospinal fluid, forcibly demonstrates the great influ- ence of hydrocephalus in determining the prognosis. C. Secondary Causes. — a. Pneumonia. — Septic pneumonia is one of the most frequent secondary infections, which is the immediate cause of death among meningitis cases. During the 1912 Texas epidemic, a number of my meningitis cases, especially among the negroes, were responding very favorably to treatment, when they developed broncho-pneumonia and were carried off. I fear a sec- ondary complication of pneumonia among my meningitis patients more than anything else. 252 EPIDEMIC CEREBROSPINAL MENINGITIS. b. Other Septic Complications. — The rare complication of chronic meningococcus sepsis accompanying meningococcus ulcerative en- docarditis, is probably a highly fatal condition. The other general septic complications, such as otitis media, pyelitis, polyarthritis, are usually free of serious menace to life. 4. Summary of Mortality Statistics. — The striking results ob- tained in the serum treatment of epidemic meningitis, can be best appreciated by a study of mortality statistics before the days of serum treatment and in a comparative study of the results in recent epidemics in cases treated with and without serum. The following interesting chart prepared hy Dunn shows the remarkable change in mortality with the introduction of serum therapy. old treatment serum | * \900 W '01 flj n w u '07 W w '10 fOO 90 M • — ' ^ A r \ 70 V, r V J ' \ (yd V \ 50 1 i • ¥0 A 30 V f i 10 10 - Chart XVIII. Dunn's chart, showing the mortality from epidemic cerebrospinal menin- gitis in the Children's Hospital in Boston, before and after the serum treat- ment, during the eleven years since the diagnosis has been regularly con- firmed by bacteriological examination of the cerebrospinal fluid. The serum treatment was begun after November 1, 1907. Each year shown in the chart is taken as beginning November 1 of the preceding calendar year. The general average of mortality of epidemic meningitis in this country and in Europe, before the serum was used, ranged between 70 and 80%, and in many instances was up to 90%. Thus, in the 1904-5 New York City epidemic, of 2,000 cases, 90% died. During 1906, of 1,032 cases reported during the height of the epidemic, 812 died, a mortality of 78.7%. In 1907, toward the end of the epi- demic, 828 cases were reported, with 642 deaths, a mortality of 77.5%. TREATMENT. 253 A tabulation of all of the meningitis cases at the end of the 1912 Texas epidemic showed a remarkable reversal of mortality statistics in the serum treated as against the non-serum treated cases. Note Dr. Steiner's report (President of the State Board of Health of Texas) : TABLE XIX. Report on Meningitis for Cities. I. Number in cities 1,001 Number in country 307 Total 1,308 II. Color and Sex. White, male 610 cases 278 deaths White, female 359 cases 165 deaths Colored, male 219 cases 111 deaths Colored, female 120 cases 49 deaths Grand total 1,308 cases 603 deaths III. Ages. (Noted in 1,128 cases.) White, Colored, Male. Female. Male. Female. Less than one year 19 22 1 One to four years 69 57 18 8 Five to nine years 91 62 14 Ten to fourteen years 76 52 24 12 Fifteen to nineteen years Ill 50 25 14 Twenty to twenty-nine years 94 46 27 13 Thirty to thirty-nine years 49 18 23 12 Over forty years 63 36 15 6 Total 916 212 IV. Number of instances where more than one case occurred in the same house. 2 cases each in 52 houses. 3 cases each in 14 houses. 4 cases each in 7 houses. 5 cases each in 1 house. V. Number of cases traced to direct contact. 80 cases. VI. Number of cases confirmed bacteriologically. Confirmed, 608. Unconfirmed, 338. VII. Number of cases treated with serum. Cases, 799. Deaths, 314. VIII. Number of cases treated without serum. Cases, 325. Deaths, 299. 254 EPIDEMIC CEREBROSPINAL MENINGITIS. TABLE XX. Report of Meningitis for Counties. I. Number of cases in cities 246 Number of cases in country 635 Total 881 II. Color and Sex. (Noted in 827 cases.) White, male 387 cases White, female 244 cases Colored, male 132 cases Colored, female 64 cases Grand total 827 cases III. Ages. (Noted in 781 cases.) White, Male. Female. Less than a year 18 8 One to four years 42 33 Five to nine years 59 41 Ten to fourteen years 58 25 Fifteen to nineteen years 70 30 Twenty to twenty-nine years ... 95 36 Thirty to thirty-nine years 24 19 Over forty years 43 30 Total 409 222 White. Less than a year 26 One to four years 75 Five to nine years 100 Ten to fourteen years 83 Fifteen to nineteen years 100 Twenty to twenty-nine years. . . . 131 Thirty to thirty-nine years 43 Over forty years 73 Total 631 176 deaths 95 deaths 66 deaths 29 deaths 366 deaths Male 1 Colored, Female. 4 4 30 13 16 7 17 1 30 6 11 1 9 110 40 Colored. 1 8 43 23 18 36 11 10 150 IV. Number of instances where more than one case occurred in same house. 2 cases each in 51 houses. 3 cases each in 9 houses. 5 cases each in 1 house. Number of cases traced to direct contact. 100 cases. TREATMENT. 255 VI. Number of cases imported. 72 cases. VII. Number of cases confirmed bacteriologically. Confirmed, 351. Unconfirmed, 262. VIII. Number of cases which developed after use of sprays and drugs. Sprays, 30. Drugs, 11. IX. Number treated with serum. Cases, 595. Deaths, 292. X. Number treated without serum. Cases, 237. Deaths, 149. Total cases of cities and counties of Texas. Cases, 2,135. Deaths, 969. Number of cases confirmed bacteriologically 959 Number of cases unconfirmed bacteriologically 598 Number of cases treated with serum. Cases 1,394 Deaths 606 Mortality 37% Number of cases not treated with serum. Cases 562 Deaths 446 Mortality 77% Dallas not included in above. TABLE XXI. Statistics of Cases Personally Treated by Author in Texas Epidemic. Total number of cases 180 Deaths 44 Mortality 25% TABLE XXII. Corrected Statistics. Nineteen of the above-mentioned cases were admitted to the hospital in hopeless, moribund condition, dying from a few minutes to 24 hours after ad- mission. Excluding these helpless cases, a number of whom died before serum could be administered, the statistics are as follows: Cases 161 Deaths 16 Mortality 15.5% 256 EPIDEMIC CEREBROSPINAL MENINGITIS. TABLE XXIII. Statistics from Texas Cities Most Affected During the Epidemic. Dallas. — Treated by Dr. Nash, City Health Officer in the City Hospital. Cases 444 Mortality 28% City of Houston. — Reported by Dr. Geo. W. Larendon, Health Officer, and Dr. Felician J. Slataper, Pathologist. Total number of cases 210 Recovered 128 Died 80 Total death rate 38% Total number of cases treated with serum 169 Recoveries 122 Deaths 47 Total death rate 27+% Average number of doses of serum per patient. . 4 TABLE XXIV. Galveston Statistics. (Reported by Dr. Truehart, City Health Officer.) Total number of cases within the corporate limits 93 Color and Sex. White, male 35 cases 14 deaths White, female 17 cases 4 deaths Colored, male 18 cases 7 deaths Colored, female 23 cases 6 deaths White, "Colored, Male. Female. Male. Female. Less than one year 1 1 One to four years 6 5 3 Five to nine years 8 3 2 3 Ten to fourteen years 3 6 2 4 Fifteen to nineteen years 7 1 3 3 Twenty to twenty-nine years 3 1 5 5 Thirty to thirty-nine years 113 3 Over forty years 3 2 1 2 Number of cases where more than one case occurred in same house: 2 cases in 4 houses. Interval between development of cases in same house: 5 days, 6 days, 3 days and 2 days. TREATMENT. 257 Number of cases traced to direct contact Number of cases imported 3 Number of cases confirmed bacteriologically by examination of cere- brospinal fluid 92 Unconfirmed, but symptoms very pronounced 1 Number of cases which developed after the use of sprays 1 Number treated with serum 83 cases Deaths 20 Mortality 24+% Most of the cases in Galveston were treated by Dr. Graves. TABLE XXV. Shreveport, La., Statistics. Total number of cases 112 Color and Sex. White, male 16 cases White, female 12 cases Colored, male 55 cases Colored, female 29 cases Mortality 37+%. 3 deaths 1 death 19 deaths 15 deaths TABLE XXVI. San Antonio, Texas, Statistics. Total number of cases 73 Color and Sex. White, male 43 cases White, female 17 cases Colored, male 12 cases Colored, female 1 case Mortality 49+%. 15 deaths 12 deaths 9 deaths deaths TABLE XXVII. Austin, Texas, Statistics. Total number of cases 13 Color and Sex White, male 2 cases 2 deaths White, female 5 cases 2 deaths Colored, male 4 cases 4 deaths Colored, female 2 cases 1 death Mortality 68%. The following table is a summary of many reported statistics of serum- treated cases. 258 EPIDEMIC CEREBROSPINAL MENINGITIS. TABLE XXVIII. Reported by- Cases treated with serum. Number. Percentage Mortality. Cases treated without serum. Percentage Mortality. Plexner — collective Dunn Chase and Hunt Sladen Fulton Koplik Ladd Morgan and Wilkinson Robb Ker Netter Dopter Schoene Jehle, Weiss, Eder Leick Neglein Kleinschmidt Quenstedt Levy Krohne Tobben Sophian , Steiner (collective for Texas) Nash (City Health Officer— Dallas) Geo. W. Larendon and F. J. Slat aper — Houston Truehart (treated by Dr. Graves) — Galveston San Antonio, Texas Austin, Texas Shreveport, Louisiana 712 40 12 23 22 15 31 10 90 30 100 402 30 64 34 30 21 18 165 59 29 161 2,280 444 169 83 73 13 112 31.4 22.5 25.0 13.0 31.0 13.3 35.5 30.0 30.0 43.0 28.0 16.44 25.0 42.0 32.4 26.6 19.0 22.2 18.18 40.6 34.0 15.5 37.0 28.0 27+ 24+ 49+ 68.0 37+ 70—80.0 70.0 90.0 64.0 78.4 60.0 75.0 80.0 49.0 65.0 53.0 -85.0 66.0 50.0 62.47 56.2 52.14 66.0 56.0 70- 77.0 80.0 BIBLIOGRAPHY. Adams, 178 Albrecht, 24, 47 Alexander, 210 Alzheimer, 112 Ames, 15, 178 Andrews, 54 Arkwright, 40, 42 Barber, 178 Barker, 178 Barlow, 86 Beckmann, 178 Bellot, 116, 130 Bernheim, 118 Bernstein, 118 Bethege, 49, 187 Biot, 68 BlRNIE, 191 Black, 49 Bochalli, 46, 49 Bolduan, 17, 18, 46 Brand, 124 Braun, 107, 124 Brimhall, 18 Brown, 178 Brudzinski, 70 Bruns, 49 Brtjynoghe, 116 Buchanan, 18, 35 Bybee, 107, 109, 123 Carter, 159, 211 Cecil, 45, 54 Chase & Hunt, 258 Churchill, 178 Cole, 178 Colombo, 40 Connor, 68 Costa, 35, 109, 129 Councilman, 14, 19 Crohn, 105 Crowe, 188 Cushing, 105, 148, 178, 188 Davis, 115, 128, 130, 190, 191 Debre, 48 De Lipinay, 70 Dieudonne, 49 Ditthorn, 39, 190 Dixon, 122 Dopter, 11, 33, 40, 41, 178, 250 Dorr, 181 Dow, 127 Draper, 121 Drobe, 48 DuBois, 188 Dunn, 178, 205, 252, 258 Duval, 178 Eberle, 39, 190 Elser & Huntoon, 19, 23, 24, 25, 28, 33, 35, 39, 58, 114, 128, 190 EWALD, 118 Ferrata, 124 Fischer, L., 234 Fischer, O., 110 Flexner, 27, 28, 29, 44, 176, 188, 258 Flugge, 46, 47 Friese, 49 Frohman, 56 Fromme, 39, 190 Fuchs, 109 Fulton, 178, 258 Gay, 123 Gaste, 16 Gee, 86 Geldemeister, 39, 190 Gerstenberg, 165 Ghon, 24, 47 Goodwin, 17, 18, 46, 48 Grysez, 116 Gwyn, 127 Hatchell, 35, 49, 186, 187 Haywood, 35, 49, 186, 187 Heiman, Henry, 174, 204 Hein, 165 259 260 BIBLIOGRAPHY. Hemenway, 118 Herford, 49 Herzog, 178 Heubner, 56, 118 Hill, 163, 164, 191 HlRSCH, 1-14 Hohn, 49 holdheim, 56 Holt, 178 Howell, 112, 164 Houston, 86, 130, 190 Huber, 48 Hugh, 125 Hunter, 56 Husler, 107, 124 hutyra & marek, 18 Jager, 22 James, 178 Jehle, Weiss, Eber, 258 Jobling, 177, 182 JOCHMAN, 175 Joseph, 123 Kafka, 110, 116, 124 Kerr, 177, 258 Key, 165 Kleinschmidt, 258 Koch, 40 Kolle, 48, 175, 176 Koplik, 178, 258 Kovarizek, 178 Krauss, 181 Krohne, 178, 258 Kronig, 105 Krumbein, 39, 40, 190 Krumwiede, 120 Kucera, 48 Kutscher, 39, 47, 48, 190 Ladd, 177, 258 Langer, 118 Laignel, 109 Larendon, 256, 258 Lavastine, 109 Leick, 258 Lenhartz, 56, 118 Lenzman, 178 Leuchs, 29 Levi, 178 Levy, 176, 258 Lewis, C. H., 178 Lewis, M. J., 178 Libman, 20, 24, 58 Lieberknecht, 190 Longcope, 178 Lord, 47 Lorenz, 107, 109, 123 Lucas, 123 Luck, 178 Lusk, 166 MacGregor, 115, 128, 129 Mackenzie, 116, 132, 191 Manges, 178 Manicatede, 118 Marcovitch, 45 Martin, 116, 132, 191 Martini, 45 Mayer, O., 178 Mayerhofer, 108 McNeil, 23, 41 Meakens, 131, 190 Merkel, 87 Meyer, A., 178 Meyer, E., 44, 49, 110 Miller, 178 Monte, 118 Morgan, 178 Morgan & Wilkinson, 258 Moritz, 106 Morse, 178 Moser, 118 MtJLLER, 49 Nash, 53, 256, 258 Neal, 40 Neglein, 258 Netter, 19, 48, 56, 258 Neufeld, 175 Nichols, 125 Nissl, 110 Nonne, 106 northrup, 178 Nuttall, 56 Oseki, 96 osterman, 47, 48 ostertag, 18 Park, 29, 120 Peabody, 121, 178 Pfaundler, 118 POLTAUF, 178 Quenstedt, 178, 258 Quincke, 105, 165, 169, 174 Rabant, 109 BIBLIOGRAPHY. 261 Rankin, 86, 130, 190 Relun, 107 Retzius, 165 Rhode, 45 Robb, 177, 258 Robertson, 53 Robinson, 148 Roemer, 123 Rosenthal, 109 Royer, 176 Ruppel, 178 RlJNEBERG, 106 SCHATLLOFF, 39, 40, 190 Schoene, 258 Senator, 118 Shattuck, 178 Sholly, 48 Shubert, 133 Sicard, 109 Sladen, 105, 114, 178, 258 Slataper, 256, 258 Slawyk, 118 Smith, 191 Solbeit, 133 Solomon, 45, 54 Soper, 54 Steiner, 14, 17, 253, 258 Stetze, 178 Stewart, 175 Still, 86 Stillman, 68 Swift, G. M„ 178 Taber, 144, 146 Taylor, 86 Thacher, 178 Tobben, 178, 258 TORREY, 42 Trautmann, 39, 49, 190 Truehart, 256, 258 Vannod, 40 Vincent, 116, 130 Von Eberts, 191 Von Lingelsheim, 26, 29, 33, 39, 44, 46, 47, 49, 128, 190 Warren, 188 Wassermann, 48, 175, 176 Watabiki, 40 Weichselbatjm, 19, 29, 47 Weil, 116, 124 Westenhoffer, 44, 137 Wickman, 98 WlDAL, 109 Wilkinson, 178 Wilson, 18 Wollstein, 40, 123 Wright, 53 INDEX. Abdomen, boat-shaped, 84 Absorption tests with meningococcus, 40 Acetic acid test, 106 Accumulative stage, 58 treatment of, 200 Agar for meningococcus, 23 Thalmann's, 23 Rockefeller Institute, 23 Research Laboratory, 23 Age incidence in meningtis, 13 influence on prognosis, 249 Agglutination studies, 128 with blood serum, 128, 129, 190, 192 with cerebrospinal fluid, 115, 120 with meningococcus, 35-39 following vaccination, 192, 194 Albumin test, see cerebrospinal fluid, 106 Albuminuria, 133 Analytical study of the effect of the serum treatment, 238-258 effect on sepsis, 240-243 cerebrospinal, 242 cerebral symptoms, 241 temperature, 240 hydrocephalus, 243 in preventing complications, 246 in shortening duration of disease, 246 Anatomy of subarachnoidal space, 165-167 anterior subarachnoidal space, 165 posterior subarachnoidal space, 165 cerebrospinal meninges, 161 lumbar puncture, 161 Anesthesia in lumbar puncture, 175 Animal inoculation in tuberculous meningitis, 120 Antimeningitis serum, 175 complement-fixation test with, 183, 184, 185 Flexner serum, 179-181 history of, 175 homologous serum, 177 immunization of rabbits, goats and monkeys, 176 Jochmann's serum, 178 Kolle-Wassermann serum, 178 opsonic index with, 182, 183 pathogenic tests, 184 preparation of, 178 prophylactic use of, 189-199 standardization of, 181 in curative treatment, see treatment, 199-238 Apnea, see respiration Apparatus for injecting antimeningitis serum, 210 Arterial pressure, 163 effect upon cerebral blood flow, 163 263 264 INDEX. Arthritis, see joints Ataxia, 98 Atropin, 20 B Babinski, see reflexes, 70, 84 Bacillus bubonic plague, 19 coli, 19-27 glanders, 19 influenza, 19 pyocyaneous, 19-27 tubercle, 19 typhoid, 19-27 Bactericidal substances in blood, 131 Bacteriology of cerebrospinal fluid, 108, 113, 114, 118 chromogenic group of bacteria, 32 diplococcus mucosus capsulatus, 32 gonococcus, 30 meningococcus, 21-30 micrococcus catarrhalis, 31, 32 micrococcus pharyngis siccus, 32 parameningococcus, 33 pseudcmeningococcus, 30 Bladder, incontinence of, 225 paresis of, see paralysis Blindness, 144 Blood culture, 127 Blood examination in epidemic meningitis, 127-131 blood cultures, 127 leucocyte count, 127 serological examination, 128 after vaccination, 192 Blood-pressure in meningitis, 148-160 effect of injecting the serum, 154, 206-209 effect of withdrawal of cerebrospinal fluid, 152 rise after injecting serum, 156 symptoms accompanying fall in, 211 usual pressure, 149 variations in pressure at different stages of the disease, 149 Bowels, 67, 83 Brandenberg's test, 107 Brudzinski's sign, 70 C Carrier studies, 34, 35 technic of, 34-35, 186 Buchanan, 35 Costa, 35 Hatchel and Haywood, 35 in quarantine, 186 Cauda equina, 168 Cerebrospinal fluid, chemical examination of, 106-108 Albumin test, 106 Fehling's test, 107 Globulin test, 107 color of, 106, 113 examination of, 60, 104 pressure of, 105, 113, 206 bacteriology of, 108, 113, 114 INDEX. 265 Cerebrospinal fluid, chemical examination of — cont'd cytology of, 109-113 Alzheimer method, 112 Cell types, 112 Fuchs-Rosenthal method, 109 slide method of examining, 109 in tuberculous meningitis, 118 Fibrin content in, 108 in aseptic meningitis, 125 in epidemic meningitis, 113-115 normal, 112 in poliomyelitis, 120-123 bacteriology, 122, 123 chemical examination in, 121 cytology, 121 serological examination, 115 immune bodies in, 116 complement in, 116 tuburcle bacillus in, 119 in syphilitic conditions of the central nervous system, 123-125 spirocheta pallida in, 125 Wassermann reaction, 124 in tuberculous meningitis, 118 agglutination tests with, 120 animal inoculation in, 120 bacteriology of, 118 cytology in, 118 during serum treatment, 220, 242 thick plastic exudate, 221 Chart, illustrating control of dose by blood-pressure, 218 Dunn's, showing mortality statistics, 251, 252 effect of anesthesia on blood-pressure, 216 fall in blood-pressure, 214 Chills, 62, 79 Chromogenic Gram-negative cocci, 21, 32 Group 1, 32 Group 2, 32 Group 3, 32 Cocain, 211 Conjunctivitis, 64, 143 meningococcus in, 132 Complement-fixation, with antimeningitis serum, 183, 184 with blood, 131 with cerebrospinal fluid, 116 with meningococcus, 42, 43 following vaccination, 194-196 Complications, 134-147 general meningococcus sepsis, 134-138 local involvement of the central nervous system, 138-146 treatment of, 230-238 Constipation, see bowels Convulsions, 66, 82, 89 Cri hydrocephalique, see hydrocephalic cry Curative treatment, see treatment, 199-238 Cytology, 60, 109-113, 118 D Deafness, 72, 144, 145 Death, causes of. 251, 252 hydrocephalus, 251 immediate, 251 septic complications, 251, 252 266 • INDEX. Delirium, 65 Diagnosis, clinical differential, 91-101 influence in prognosis, 248 Diplococcus mucosus capsulatus, 32 Diplococcus crassus, 39 Diseases accompanying meningitis, 55 influenza meningitis, 56 pneumococcus meningitis, 56 tuberculous meningitis, 56 typhoid fever, 55 Dosage of serum, see serum, 208-209 Dry cerebrospinal canal, 222 Dwelling infection, 18 E Bar complications, 144-146 deafness, 144-145 labyrinthian involvement, 146 otitis media, 144 Emaciation, 79 Endocarditis, meningocoecic, 137, 236 Epidemiology, 10-13 Eruptions, 63, 64 Eye complications, 143, 144 blindness, 144 conjunctivitis, 143 panophthalmitis, 144 suppurative choroiditis, 144 F Fatigue, influence of, 18 Fehling's test, see cerebrospinal fluid Fever, 62, 79, 240 due to hydrocephalus, 139 Febrin content, see cerebrospinal fluid Flushing, see tache cerebrale, 67 Fontanel bulging, 59, 69, 89 Foramen of Key, 87 of Lushka, 161 of Magendie, 87, 161 of Retzius, 87 Fumigation, 187 G General hygiene, influence of, 16 General paresis, 111, 123 General treatment, 224 Globulin test, see cerebrospinal fluid Glucose solution, preparation of, 25 Gonococcus, 19-20 morphology, 30 staining, 30 fermentation reaction, 30 autolysis, 30 Gram stain, 22 Gravity method of injecting serum, 204 Grysez' test with cerebrospinal fluid, 117 INDEX. 267 H Headache, 59, 65 Hemorrhage complicating lumbar puncture, 169 Herpes, 59, 63, 197 meningococcus in, 132 Historical, 1-10 1st period, 1 2d period, 2 3d period, 5 4th period, 9 Hydrocephalic cry, 82 Hydrocephalus, 65-70, 81, 88, 138 relief of, 222, 227, 230, 243 Imbecility, see mental symptoms, 65-140 Incubation period of meningitis, 53 Infantile paralysis, see poliomyelitis Infections produced by the meningococcus preceding meningitis, 54 general septicemia, 54 nasopharyngitis, 54 pneumonia, meningococcic, 55 rheumatism, meningococcic, 55 Inhalations in prophylaxis, 188 Injection of antimeningitis serum, 204-224 Insanity, typhoidal, 65, 82 Internal medication, 188 Intracranial pressure, 162 Jager coccus, 22 Jaws, tenderness of, 67 Joint complications, 134-136 treatment of, 235 Joint effusion, meningococcus in, 132 K Kernig's sign, 67, 82, 98, 241 Laboratory diagnosis of meningitis, 104 blood examination, 127-132 cerebrospinal fluid, 104-126 examination of other secretions, 132, 133 Labyrinthian involvement, 146 Leishman's method of standardizing antimeningitis serum, 183 Leucocyte count, 127 Low temperature in meningitis, 15 Lumbar puncture, 170-175 anesthesia for puncture, 175 apparatus for, 170 breakage of needle, 174 depth of puncture, 174 hemorrhage, 169 268 INDEX. Lumbar puncture — cont'd level for puncture, 167-168, 173 paralytic sequelae after lumbar puncture, 170 posture of patient, 171 route of puncture, 172 site of operation, 172 M Macewen's sign,- 59, 70, 83, 89, 98 . McNeil's specific antigen, 41 Manometer, cerebrospinal fluid, 105 Meningeal irritation, symptoms of, 65-67, see symptoms Meningeal spaces, 161 Meningismus, 96 Meningitis, epidemic, 11 abortive form, 75-77 acute, classification of, 71 prognosis of, 250 aseptic, 100, 125 chronic, 79, 226 prognosis of, 251 cerebrospinal fluid of, see cerebrospinal fluid dissemination of, 46-51 meningococcus, 11, 21-43, see meningococcus organisms in nasopharynx of meningitis patients, 47, 48 experimental, 29, 176 fulminating form, 77-79 posterior basic, 81, 86 prognosis of, 251 subacute, 222 cerebrospinal fluid of, 118-120, see cerebrospinal fluid usual form, 71-75 Meningitis, influenza, 56, 96 pneumococcus, 96 pyogenic, other than epidemic, 118 streptococcus, 96 tuberculous, 56, 94, 99 Meningitis in domestic animals, 18 Meningococcus, animal tests for differential diagnosis of, 43 autolysis, 27 crystals, 24 culture, 23-25 daylight, effect of, 26 dessication, 26 fermentation reactions, 24 ice box temperature, 26 media, 23 microphotographs, 245 morphology of, 21 pathogenicity, 27 pigment, 24 room temperature, effect of, 26 serum reactions, 35-41 staining, 22 strain differentiation, 42-43 sunlight, effect of, 26 viability, 26 metachromatic granules in, 22 Meningococcus autolysate, 179 Meningo-myeloencephalitis, 140 INDEX. 269 Mental symptoms, 65, 140 change in disposition, 140 imbecility, 140 Micrococcus catarrhalis, 20, 31, 32 Type 1, 31 Type 2, 31 autolysis, 31 fermentation, 32 pathogenicity, 32 Micrococcus pharyngis siccus, 20, 32 Micrococcus tetragenus, 19 Microphotographs, 245 Mortality statistics, 252-258 N Nasopharyngitis, 54 Nationality, influence of, 14 Neck, rigidity of, 66, 82, 241 Neufeld's method of standardizing the antimeningitis serum, 182 Neuritis, 138, 235 Nitric acid test, 106 Noguchi's globulin test, 107 Nonne's albumin test, 106 Normal cerebrospinal fluid, see cerebrospinal fluid Nuclear involvement, 70 Nystagmus, 84 Q Opisthotonos, 88 Oppenheim's sign, 70 Opsonic studies with cerebrospinal fluid, 115 with blood, 129, 130, 190 with antimeningitis serum, 182, 183 Leishman's method, 183 Neufeld's method, 182 Otitis media, 144 meningococcus in, 132 Overcrowding, influence of, 16 Pacchionian bodies, 161 Pain after puncture, 225 Panophthalmitis, 144 Paralysis, 70, 98, 141, 142, 225 facial, 70, 98, 141 of bladder, 142, 225 hemiplegia, 98, 141 monoplegia, 98, 141 ophthalmoplegia, 98, 141 Paralysis following lumbar puncture, 173 Parameningococcus, 21, 33 Pericarditis, 138, 236 Pericardium, meningococcus in, 132 Permanganate reduction test, 108 Perspiration in meningitis, 67 Petechia, 59, 64 270 INDEX. Phlebitis, 138, 235 Photophobia, 59, 66 Pleura, meningococcus in, 132 Pneumococcus, 19 Pneumococcus meningitis, 19, 56, 96 Pneumonia, meningococci, 55 septic, 136, 236 Polioencephalitis, 97 Poliomyelitis, 97, 120 Portal of entry of the meningococcus into the human body, 44 method of invasion, 44, 45 nasopharyngitis, 44 Posterior basic meningitis, 81, 86 treatment of, 231-234 Precipitin test, with blood, 130 with cerebrospinal fluid, 116 Predisposing causes of meningitis, 10 Premeningitic or accumulative stage, 54, 58, 61, 200 Pressure phenomena, see hydrocephalus Previous health, influence of, 18, 53 Prophylactic measures against epidemic meningitis, see treatment Prognosis, 248, 258 factors influencing it: age, 249 character of disease, 250, 251 early diagnosis, 248 treatment, 249-250 Pseudomeningococcus, 20, 30 Pulse, 67, 83 rate during lumbar puncture, 158 Pupils, 67 Purpura, 64 Pyelitis, 136 R Race, influence of, 14 Reaction after vaccination, see vaccination Reflexes, 70 Babinski, 70, 84 contro-lateral-indentique, 70 contro-lateral-reciproque, 70 Rheumatism, meningococcic, 55 Relapse, 101 Respiration, irregularities of, 68-70 Biot's breathing, 68 Cheyne-Stokes breathing, 68 undulatory breathing, 68 Scalp veins, dilation of, 84, 89 Seasonal influence, 15 Serological examination of blood, see blood examination of cerebrospinal fluid, see cerebrospinal fluid Sepsis, symptoms of, 61-65 Serum, dosage of, 208-209 repeating dosage of, 219 Serum sickness, 236-238 Serum treatment, see treatment INDEX. 271 Sex, 14 Shock, 159 Sighing, 59 Signe de la nique, 70 Skull sutures, separation of, 84 Spine, rigidity of, 67 Spleen, meningococcus in, 132 Stains, Eosin-hematoxylin, 112 Jenner, 112 Leishman, 112 Loffler's methylene blue, 112 Nocht, 112 Wright, 112 Staphylococcus, 19-27 Strabismus, 70-84 Strain differentiation of the meningococcus by complement-fixation tests, 42, 43 Streptococcus mucosus capsulatus, 19 Streptococcus mucosus meningitis > 20 Stupor, 70 Subarachnoid space, 161 Subdural injection of antimeningitis serum, 205-224 Suppurative choroiditis, 144 Symptoms of meningitis, 54 accumulative stage, stage of invasion, general septicemia, 4, 58-61 active stage, 61-79 hydrocephalus, 65-70 meningeal irritation, 65-67 nuclear involvement, 70 symptoms of sepsis, 61-64 cerebral, 241 chronic stage, 81 posterior basic meningitis, 88, 89 relapse, 102, 103 with fall in blood-pressure, 211 Syringe method of injecting serum, 204 T Tabes dorsalis, 124, 125 T'ache cerebrale, 67 Temperature, see fever Typhoid fever in epidemic meningitis, 55 Traumatism to head, influence of, 18 Treatment of epidemic meningitis, 185 prophylactic measures, 185-189 quarantine, 186 medicinal, 187 local, 187 internal, 188 specific treatment serum, 189, 190 vaccination, 190-199 curative treatment, 199-2B8 accumulative or premeningitic stage, 200 active treatment, 203-238 serum treatment, 203-224 changes in cerebrospinal fluid, 220 for thick plastic exudate, 221 for dry canal, 222' when to discontinue serum treatment, 222 relief of hydrocephalus, 222 general treatment, 224 272 INDEX. Treatment of epidemic meningitis — cont'd of subacute and chronic meningitis, 226-230 relief of hydrocephalus, 227 treatment of sepsis, 227 vaccination in, 227 of relapse, 228 of complications and sequelae, 230-238 of hydrocephalus, 230 of sepsis, 235-236 of posterior basic meningitis, 231-234 serum sickness, 236-238 influence on prognosis, 249 Trephining for posterior basic meningitis, 232-233 Trophic disturbances, 83 • Twitching, 66, 83 U Urine, analysis of, 133 meningococcus in, 132 Urotropin, 188, 266 Vaccine, meningococcic, 192, 277 Vaccination against epidemic meningitis, 190-199 agglutination studies in, 192-194 complement-fixation studies in, 194-196 reaction following, 196-197 Vasomotor phenomena, 67, 83, 89 Vincent's test, see precipitin test Vomiting, 59, 67, 83 W Wassermann reaction, 124 • 23 *