American Academy of Pediatrics

Proceedings

S E V E N T H A N N U A L M E E T I N G O F T H E A M E R I C A N

A C A D E M Y O~ ~ P E D I A T R I C S

NEW YO~K, JUNE 3, 4, AND 5, 1937

Round Table Discussion of Meningococcic Meningitis

C h a i r m a n : A r c h i b a l d L. H o y n e , M.D. , C h i c a g o , I l l .

A s s i s t a n t s : E d w a r d B. S h a w , M.D. , S a n P r a n e i s e o , Ca l i f .

G i l b e r t H . L e v y , M.D. , M e m p h i s , T e n n .

F r a n c i s F . S e h w e n t k e r , M.D. , B a l t i m o r e , Md.

Mentngecoccic Meningitis Archibald 1",. Hoyne, M.D.

Meningoeoeeie meningit is is our topic for discussion. Possibly greater la t i tude in deliberations will be afforded i f we assume tha t our subject is menlngocoecic infection. The la t ter term carries the inference that meningit is does not neces- sarily accompany or follow infection with the meningococcus. The presence of meningoeoeeemia without clinical evidence of meningitis is not an extremely rare occurrence. The meninges as a rule are not the pr imary seat of infection, nor is blood stream involvement usually secondary to meningitis.

In terpre ta t ions which one places on this disease are likely to exert a marked influence in the choice of methods for t reatment . Shall we apply therapeutic measures directly to the involved meninges, or should we a t tack the disease as a systemic one and indirect ly relieve the meninges os their inflammatory products?

From the time tha t antimeningoeoeelc serum was introduced some th i r ty years ago, i t has been customary to administer the remedy by the intraspinal route in almost all instances. I t seems that this was regarded as a necessity on the theory that the only value possessed by the specific serum was i ts ant ibacter ial aetlon. True, serum was sometimes injected by other routes, but generally intraspinal t rea tment was insisted upon as the standard procedure.

During a period of twenty-five years there has been considerable fluctuation in our mortal i ty figures for meningococeic meningitis pat ients at the Cook County Hospital, in Chicago. With exception of one year in which there were but six eases, the fatal i ty rate was seldom less than 40 per cent until the year 1933~ when we began to make a change in our old established form of t reatment .

Ferry in 1931 reported a soluble toxin of the meningococcus and developed a meningoeoeeus ant i toxin which he used experimentally in t rea t ing laboratory animals. In the fall of 1933 we began t reat ing menlngococcic meningit is pat ients with F e r r y ' s ant i toxin at the Cook County Hospital. Soon af terward we rapidly increased the intravenous dosage and at the same time diminished intraspinal therapy. Eventual ly a l l intraspinal t rea tment was abandoned. Now af ter a

863

864 TItE JOUR.NAL OP PED~ATI~ICS

period of about three years, during which no serum of any kind has been admin-

istered intraspinally, we feel more convinced than ever of the superiority of

intravenous treatment exclusively.

We had success with intravenous treatment alone. Variations in fatality

rates for the different age groups were noted. As in most diseases~ the prog-

nosis is particularly grave ill the two extremes of life. This is especially true

in meningocoecie meningitis and is more apparent ill those of advanced age

than in the very young. Year~ season, virulence of the organism~ and degree

of susceptibil i ty of the individual are often given consideration in evaluating the success of any form of treatment. I t is sometimes claimed the fatality rate is higher during an epidemic than when only sporadic or endemic cases are en- countered. This has not always been our experience in Chicago.

When we consider such fa ta l i ty figures as 95 per cent reported by the Ministry of Heal th of Great Bri ta in for the year 1930 and the more recent report of Tripoli for New Orleans wi th a rate of 65 per cent, we fee] tha t great improvement has been made during the past few years in the contagious disease hospitals of Chi- cago Where intravenous therapy has been adopted exclusively.

Whether meningococcus ant i toxin or s tandard antimeningococcus serum is used, the remedy is given in large doses- - f rom 70~000 to 150,000 units of anti toxin or from 100 to 300 c.c. of serum--di lu ted in 10 per cent glucose in normal saline of at least twice the volume. To the mixture administered at body temperatnre, there is added about 10 minims of adrenalin. The rate of flow is of ten s tar ted at 10 drops per minute and gradually increased to 60 drops per minute. In this way we have sometimes given as much as 1~200 e.c. of serum to a pa t ient within four days without unpleasant reactions. Some of our pat ients have received more than 2,000 c.c. of serum during their illness.

We feel there is no great emergency about making lmnbar punctures i f the clinical diagnosis is fair ly certain. Blood cultures are made in every instance and, i f they are negative, at least one lumbar puncture is done for the purpose of confirming the clinical diagnosis. We have t rea ted fifteen or sixteen pat ients without resorting to any lumbar puncture, and in the group there was but one dea th - - a fulminat ing case. ]~ost pat ients have two or three lumbar punctures. Since discontinuing intraspinal therapy we have found no occasion to perform cisternal or in t raventr icular punctures.

Among the advantages noted with intravenous therapy exclusively are (1) al- most a tota l absence of opisthotonos, (2) avoidance of difficult problems due to blockage, (3) fewer complications, (4) rarely any septic complications, (5) less discomfort for the patient , (6) more rapid recovery, and (7) lower death rate.

In respect to a choice between Fe r ry ' s ant i toxin and a s tandard antimenin- gococeic serum, we no longer note the marked difference in the recovery rates originally observed. Possibly this may be due to some improved methods in pro- ducing the antimeningocoeeic serums. Nevertheless, among several hundred pa- t ients t reated with the ant i toxin thus fa% we have not witnessed a single instance in which loss of hearing or loss of vision developed a f te r ant i toxin t rea tment was begun. This s ta tement does not hold true for antimeningococcic serum treated patients.

A common objection to the mode of t rea tment described is i ts cost. There is no doubt tha t large quanti t ies of ant i toxin or antimeningococcus serum are expen- sive. But they are no more so than funerals.

However, we seem to be making real progress in the t rea tment of meningitis. We believe tha t intravenous therapy applied in the manner described reduces the death rate. Now ehemotherapy~ which has had advocates for many years~ seems

AMERffCAN ACADEMY OF PEDIATRICS 865

to offer a means of reducing the cost of t rea tment without loss of efficiency. Fever therapy has also been resorted to, and a few sa t is fac tory results have been reported.

There are others here to give you the benefit of theh" experience and to make more valuable presentat ions of thi's subject than I have been able to do.

The Theory of Treatment of Meningococcus Infec t ion E. B. Shaw, M.D.

The problem of t reatnlent of meningococcus infection is directly concerned with peculiarities in their pathogenesis. Production of meningococcus disease proceeds through three phases, which may be sharply differentiated or may merge in several manners one with the other. Successively there is a period of onset, a second stage of dissemination (which may be t ransi tory or indefinitely prolonged), and a final stage of localization (which is usually in the meninges). Certain observa- tions indicate the manner in which the disease proceeds through these phases of infection.

Intense invasion of the blood s t ream by pyogenic organisms is commonly ac- complished in a number of ways. Organisms are readily poured into the circula- tion from an infected lymph channel, vein wa]]~ or heart valve, or they may be disseminated by means of infected emboli extruded from small thrombosed vessels which thus bridge the gap between local infection and the general circulation.

The nature of the pr imary focus of menlngococcus infection suggests no such explanation for the extraordinary degree of blood stream infect ion which some- times occurs. During the stage of sepsis menlngococcl may occur in the blood in tremendous numbers, are readily recovered by blood culture, and in contrast to almost any comparable condition are not infrequent ly demonstrable by careful direct examination of s tained blood smears. The initial foci in the upper air pas- sages are usually minute and obscure. There is l i t t le to suggest infect ion of vessel walls or thrombosis of vessels in a manner readily to explain the sepsis. Second- ary disseminating foci are unusual.

Not only do the organisms easily gain access to the clrcu]ation, but they readily escape from it along wi th red cells and leucocytes in the production of the pete- chine which characterize the sepsis. Examination of microscopic sections of pete- chine fails to reveal the presence of thrombi or of bacterial or fibrinous em- bolil, ~, 8 but indicates tha t damage to the arteriole and capillary walls has re- sulted in a loss of vascular integrity,~, 5, c permit t ing the escape of cells and organisms in the production of the eruption. In part this eruption is not f rankly hemorrhagic but is due to localized loss of vascular tone; to this la t ter extent it may be blanched by an effective ant iserum in a manner comparable to the effect of scarlet ant i toxin on the rash of scarlet fever.

On several occasions I have seen other organisms enter the circulation or the meninges~ along with the meningococcus, and, although these instances have not ~ been very numerous, I believe that their occurrence is similarly due to vascular damage produced by the meningococcus.

The early pathologic changes in the meninges somewhat parallel the skin mani- festat ions. Ini t ia l ly there are localized perivascular inflammation and minute areas of hemorrhage in the pia-arachnoidS as a pre]imlnary to frank meningitis.

The eonchsion is almost inescapable that in the initial focus of infection in a susceptible subject bacteria] toxin is produced in sufficient amounts to effect vascular damage which permits ready entrance of the organism to the circulation and equally faci l i tates its escape to the perivascu]ar tissues of the skin ' and meninges. Af te r the infect ion has been well localized in the meninges, if the pat ient has survived the period of intense invasion, general symptoms of intoxica-

866 T H E J O U R N A L OF PEDIATRICS

tlon, including skin rashes, tend to disappear and the clinical evidence sugges ts t h a t the toxin, in i t ia l ly very impor tant , proceeds the rea f t e r to play a somewhat less impor tan t rSle.

I t would seem likely tha t an an t i serum which was active aga ins t the specific toxin would be effective in a r res t ing many of the man i f e s t a t i ons of toxin act ivi ty , especially during the early s tages of the infect ion. As a ma t t e r of fac t the original an t i se rmn used by Joehmann and Flexner , which was therapeut ica l ly very aetiv% nmst have lind a high degree of ant i toxic act ivi ty . This an t i serum was produced by the immuniza t ion of horses wi th suspensions of f reshIy grown cul- tures of virulent meningococei, no effort being made to exclude the soluble exo- toxin from the suspension. Resul ts of t r ea tmen t wi th the an t i se rum so produced were apparent ly f a r superior to those secured with some later serums. A number of factors were blamed for th is wane of therapeut ic power, the cause commonly ascribed being fai lure of the seruln to include propert ies specific aga ins t the clini- cal s train. At one t ime efforts were made to employ type-specific serum~ but this proved not to be feasible because of the delay in t r e a tme n t thus involved. Agglu t ina t ion tes ts were formerly employed as a measure of the specificity of the serum aga ins t clinical s t rains, but it gradual ly became apparent tha t therapeut ic propert ies did not paral lel the s t reng th of agglu t ina t ion . Meanwhile methods of manu fac tu r e of serums had been Mtered so as to exclude toxin filtrates f rom im- nmniz ing suspensions. This practice el iminated unp leasan t reactions and high mor ta l i ty among immunized animals , and a serum was produced which was high in agg lu t ina t ing ac t iv i ty but was therapeut ica l ly of re la t ively less value. A reversal of the t r end in serum manufac tu re was accomplished by Ferry, who in 1931 dis t inguished the soluble toxin of the meningocoeeus and succeeded in pro- ducing an ant i toxin . The applicat ion of th is agen t to t he rapy by Hoyne and others has led to excellent resul ts wi th great d iminut ion of mor ta l i ty rates and the prevent ion of complications. I hope to learn in th i s round table a great deal more about these resul ts and the indicat ion for and technique of ant i toxin admin- is t rat ion.

Most of us have though t of the t r ea tmen t of mcningocoecus infect ions in terms of baeteriolysis by serum. The theory of t r e a tme n t with an ant i toxin raises a great m a n y questions which I should like to propose for discussion al though I cannot pretend to answer many of them.

The actual onset of the disease is usually so obscure tha t no t r ea tmen t can be proposed. I n the s tage of disseminat ion, sepsis, there is l i t t le question tha t a toxin is largely concerned wi th the breakdown of the h o s t ' s resis tance aga ins t invasion. In this s tage an t i tox in is ext remely efficacious and the demonstrable value o f any sermn is largely dependent on i ts content of an t i toxin . This stage of infec t ion has a lways given the best evidence of the efficacy of s e rmn- - i n an- swer to those observers who have sometimes held tha t untimeningoeoecie serum was lacking in therapeut ic powers. Neut ra l iza t ion of toxin opposes the very proper ty of the organism which is responsible for extension of the infect ion and for invasion of the meninges.

Ear ly meningi t i s is a late s tage of sepsis; at this t ime neut ra l iza t ion of toxin diminishes fu r the r flooding of the meninges. When the infect ion is well localized, organisms finally are eradicated f rom the blood stream, perhaps through increased res is tance developed by the pa t ien t aga ins t the toxin. The presumpt ion would be so great t ha t at th i s final s tage the an t i tox in would be much less valuable al- though clinical resul ts indicate t ha t even at this t ime an t i tox in is therapeut ica l ly

active.

Clinically we recognize many infect ions in which the disease-produclng ac t iv i ty of the causat ive organism is largely effected th rough the product ion of bacterial

AMERICAN ACADEMY O~ PEDIATRICS 867

toxins. The diphtheria bacillus produces a powerful toxin which is presumably nearly the entire cause of symptoms of diphtheria; early neutralization of this

toxin completely arrests the progress of the disease. The streptococcus of scarlet fever produces a toxin which is responsible for many of the symptoms of scarlet fever but a f te r neutral izat ion of this single toxin there remain addit ional patho-

genic activit ies of the streptococcus which may produce a var ie ty of addit ional symptoms. A toxin is also produced in the course of erysipelas, but even more str ikingly than in scarlet fever there may be progressive symptomatology a f t e r its neutralization. Certain s t rains of pneumococei produce specific soluble sub- stances which may be neutral ized wi th str iking therapeutic effect, but thereaf te r pleural exudates may develop which are not str ikingly affected by the use of anti- pneumococcus horse serum, which will not demonstrably enter or effect an empyema pocket. (In pass ing- - i t has recently been observed tha t rabbit anti- pneumococcus serum will enter a n d effect these cavities.)

Jus t where, among the various possibilities of ant i toxin activity, does the action of meningococcus ant i toxin belong? Clearly it is valuable in the early stages but is presumably less valuable at a later time. There are those who prefer to t rea t intravenously with ant i toxin to combat sepsis and toxemia but who feel that in the meninges an ant ibacter ia l serum must be directly applied to affect this stage of localization. No completely sat isfactory answer can be given to this question at present but there are several s tatements which are probably justified:

]. I have heard Dr. Fe r ry s ta te tha t anti toxin serum is as strongly ant ibacter ial as any of the serums in common use although the thera- peutic usefulness of this proper ty is difficult to evaluate.

2. Dr. Hoyne ' s results wi th intravenous t rea tment are just as satisfac- tory as any of the results wi th intraspinal therapy, and he thus avoids the production of intense meningeal reactions which are caused by intra- thecal administrat ion of serum. In the presence of meningococcus sepsis introduction of antiserum into the meninges before there is actual men- ingit is will not prevent invasion of the meninges but seems rather to accelerate it.9 I t is certainly not illogical to believe tha t an antiserum may reach infected portions of the meninges.

3. I suspect tha t the best answer at present is tha t neutralization of toxin is the only therapeutic result which can be effected wi th certainty and tha t once this is accomplished the pa t i en t ' s likelihood of recovery can be measured only by his own capacity to resist the fur ther pathogenic activi t ies of the meningococcus. I t is not unlikely tha t somewhat af ter the manner of the streptococcus of scarlet fever, the meningoeoccus pro- duces a toxin which injures the patient, is responsible for a fulminant onset~ and prepares the way for later septic complications. Neutral izat ion of this toxin material ly benefits the patient, but there remains a residuum of additional pathogenic act ivi t ies which may not be completely combated by antitoxin.

We must distinguish two varieties of meningococcus disease. In one, toxic signs predominate, petechial rashes are the rule, the pat ient may quickly succumb to the disease before there is meningeal invasion or ear]y a f te r . i t supervenes. Death is due in these cases to intoxication rather than to meningitis. These pa- tients constitute a fulminant form of disease with high and early mortMity, account- ing for many of the forty-eight-hour deaths, but are especially--and often rlra- matically--susceptiblc to adequate treatment with antitoxin. Certain epidemics, per- haps certain localities, are especially characterized by this form of the disease, and it is the form most frequently encountered in epidemics.

868 THE JOURNAL OF PEDIATRICS

In a second variety of the infection, generalized toxic symptoms are less notable; eruptions are less common; the diagnosis is usually made on the basis of signs of meningitis. These patients are not unaffected by serum therapy, but their response is less gra t i fy ing no mat te r by what route serum is applied. Such pat ients are especially encountered in interepidemic periods and although it is possible that their nature may be accounted for by delays in diagnosis I do not believe that this is the case.

I t hush,been suggested that differences in strain of the causative organism are responsible for some of the differences in clinical behavior. The antitoxin is active against the toxins of all the various strains of menlngococci, but some strains are bet ter toxin producers than others. I t has been s ta ted that Types I and I I I are abundant producers of toxin, that in infection with these organisms characteristic toxic symptoms are the rule, and that they are more susceptible to antitoxin treat- ment. Types I I and rV are said to be poorer producers of toxin, a r e more re- sponsible for the sporadic form of the disease, and are less susceptible to antitoxin treatment.lo

We need to know a great deal more about the relationship between strains and clinical behavior, the amount of toxin present in the given case and the rapidity with which it increases, and the quantita".~ive relationships clinically present between toxin and a~ti toxin--the sort of information which is gradually being accumulated for the problem of pneumococcus therapy. How may the dosage of antitoxin be com- puted? Serum is expensive and large and repeated doses are not always well tolerated. How much is enough? Why should repeated doses be given? Diphtheria antitoxin is commonly given in a single dose. Should antitoxin be given only in- travenously, or must we finally differentiate a form of the disease which must be ,dealt with as an empyema of the meninges?

I do not believe it is easy to answer all of these questions, but I think the clinician must finally supply the answers. I should very much like to hear the opinion of those with more experience in the use of antitoxin in the clinical management of these cases.

REFERENCES

J. Benda, C.: Berl. klin. Wchnsehr, 53: 449, 1916. 2. Gruber, G. ]3.: Deutsehes Arch. f. klin. Med. 117: 250, 1914-15. 3. Pick, L.: Deutsehes Meal. Wehnschr. 42: 994, 1916. 4. Tbomsen, O., ~nd Wulff, ~r Comp. rend. Soe. de biol. 83: 701, 1920. 5. Brown, C. L. : Am. J. Dis. Child. 27: 598, 1924. 6. R.enault, J., and Cain, A. : Ann. de m6d. 7: 114, 1920. 7. Shaw, E. B., and Thelander, H. E.: J . A . M . A . 101: 746-752, 1933, Tables

3, 5, 6. 8. Westenhoeffer, M.: Berl. klin. Wchnschr. 42: 737, 1905. 9. Netter, A., and Selanier, M.: Comp. rend. Soe. de biol. 79 :670 and 973, 1916.

10. Branham, Sara E.: J. A. M. A. 108: 692, 1937.

Meningoeoccus Meningit is

Report of 176 Cases Treated With F e r r y ' s Ant i toxin

Gilbert H. Levy, M.D.

The increased inci.denee of meningococeus meningitis with its high fatality rates in ~he United States during the past ten years is worthy of due consideration. For the year 1934 United States Public Health reports listed 2,186 cases with 1,272 deaths, a mortality rate o2 57.3 per cent. For ~[935 the United States Public Health reports show-5,378 cases with 2,657 deaths, a mortality of 49.9 per cent, and for 1936 the number of cases were recorded at 7,203. The large cities of the country account for nearly 80 per cent of the annum deaths listed. Hoyne reports 4,028 cases for Chicago from 1916 to 1935, inclusive, with 47.7 per cent average yearly

AMEI~ICAIN- ACADEMY OF Pt~DIATI~ICS 869

fatali ty. Tripoli reports a mortal i ty rate of 65.15 per cent for 221 cases t reated at Charity Hospital, ~ e w Orleans, in the years 1925 to :1935. Gordon reported a fa ta l i ty rate of 50.5 per cent for 1,686 eases at Detroit during the outbreak of 1928 to 1931. ]~fortallty ra tes dur ing 1929 for New York City, Salt Lake City, and Indianapolis were 58.6, 53, and 63 per cent~ respectively.

A t ~[emphis dur ing the period of 1925 to 1933 the number of cases reported were 537 wi th 280 deaths. The f a t a l i t y percentage var ied from 35, the lowest, to 80, the highest . The average mor ta l i ty was 52.1 per cent.

Clinicians identified wi th these various outbreaks pr ior to 1934 were disap- pointed wi th results obta ined f rom s tandard po]yva]ent an t ibac te r ia l serums. In the ]929 outbreak Anderson found ordinary commercial ant imeningococcic serum therapeut ica l ly inadequate wi th a marked var ia t ion in the therapeut ic value of the commercial serums. Hoyne has made similar observat ions at Cook County Hospital , Contagious Disease ,Department . We found in the 1930 out- b reak at Memphis t h a t in tens ive t r e a t m e n t wi th a l t e rna t ing inject ions of men- ingoeoccic serums, both intraspina] and intravenous, from fi~,e biologic firms, showed no specific differences in the sermns. In t ravenous in jec t ion of s t andard meningococcus serums was emphasized in the t r ea tmen t of all eases seen early. The overwhelming toxemia and septicemic nature of our many pa t ien t s justified i ts use. From such experience we believe, and have state(], t h a t in all cases there is an early meningococcemia~ admit t ing , however, the difficulty of proving this s ta tement . Shaw and Thelander in a series of 58 consecutive cases of cerebro- spinal fever in childhood over a ten-year period showed a h igh incidence of sys- temic invasion. These same authors suggest t ha t vascular damage by manifes ta- t ions of the infec t ion permi t t ed the character is t ic blood s t ream infes ta t ions and the disseminat ion of the organisms. They conclude wi th the s t a t ement t ha t " s u c -

cessful the rapy should proceed from. recognit ion of signs apa r t from those of meningi t i s and must be designed first to combat the in toxica t ion and second to a t t ack the organism more directly. ~'

Fer ry and his coworkers in 1933 studied the properties of bouillon filtrates of the meningococcus which resulted in the production of extracel lular toxins specific to the four recognized Gordon types of the meningococeus as well as a toxin eon~- men to all types. When animals were in jected individualIy wi th these four toxins~ they developed an t i tox ins specific to the type in jec ted as well as some an t i tox in of the other types. They fu r the r demonst ra ted t ha t meni ngococcus meningi t i s convalescent serums possessed neutra l iz ing propert ies apparen t ly specific toward homologous soluble toxins. Fe r ry showed t h a t meningococcus an t i tox in prepared by immuniz ing horses wi th meningococeus soluble toxin ob - ta ined from all four recognized Gordon types of the organism protected guinea pigs prophylact ical ly and therapeut ica l ly against f a t a l doses of l lve cultures. A comparison was made wi th a lot of commercial tes ted ant imeningococeic serum and controlled wi th normal horse serum. The exper imenta l an t i tox in afforded be t te r prophylact ic protect ion t han the regular antimeningococ~ic serum. Anti- meningocoecic serum when in jected in the same sized dose as the an t i tox in failed to protect guinea pigs therapeut ica l ly aga ins t the fa ta l dose of culture, while the an t i tox in protected the animal.

Fu r t he r studies by Fe r ry and Schornack on guinea pigs, rabbi ts , and monkeys wi th meningococcus toxin and an t i t ox in indicated very eonc]usively t h a t " t h e symptoms of meningococcus cerebrospinal meningi t i s in l abora tory animals was due in large to the act ion in the cent ra l nervous system of a soluble specific toxin e laborated by the meningocoecus and t h a t these symptoms can be modified or ent i re ly prevented by the neutra] iza t lon of this toxin wi th a specific a n t i t o x i n . "

870 TttE JOURNAL OF PEDIATRICS

Experimental meningocoecus antitoxin prepared by Dr. ~ . S. ~'erry was fur- aished us at the Isolation Hospital at Memphis in 1933. A preliminary report on twenty-four cases in 1933 and 1934 was read before the Georgia State Pediatr ic Society in December~ 1935. Fourteen eases were t reated in i933 with two deaths and ten cases in 1934 wi th four deaths, result ing in a combined mortal i ty of 25

per cent. The first eleven cases t reated in 1933 resulted in only one death. Four of the six deaths reported occurred within twenty-four hours a f te r admission. The ages represented ranged from eleven months for the youngest to forty-three

years for the oldest. The average number of lumbar punctures required for treat- ment was 5.1 as compared to 6.9 in the 1930 series.

The average number of intravenous anti toxin injections was 1.1 as compared to 2.5 in the 1930 series. The average total spinal ant i toxin injected was 86.7 c.e. (30,000 units) compared with 133 c.c. of s tandardized serum. All intravenous ant i toxin was given well diluted in 10 per cent glucose solution. Sensit ivi ty tests were made on all pa t ients before administrat ion of the anti toxin. The average injection was 10,000 units, or 30 c.c. Of part icular interest in this small initial series was the short time, 4.8 days, required for the clearing of the spinal fluid from positive to negative cultures.

The apparent success of our first two years ~ experience wi th Fe r ry ' s anti toxin received an unexpected upset during January, 1935, when eight of the first nine pat ients admit ted to Isolation Hospital died wi thin a short period of time. Two of these pat ients were infants , one five months old and one eight months old.

Seven of the eight were comatose on admlssion~ extremely septic with advanced meningitis.

Our failure to combat the infection in the eases just mentioned was due to our lack of appreciation of sufficient intravenous dosage. I t has been the custom since 1925 for all pa t ients assigned to my service at the Isolation Hospital to receive antimeningococcie serum intravenously in small dosage, never averaging

more than 30 r This of course was in addit ion to the usual intraspinal serum treatments .

Hoyne in XVfarch, 1935, reported his observations on 296 cases of meningococcus meningitis, 85 of which were t rea ted with experimental ant i toxin (Ferry) . The mortal i ty for this entire series t reated with ant iserum and ant i toxin was 39.5 per cent. ~orty-thrce per cent of the deaths occurred within forty-eight hours after ad- misslou to the Cook County Hospital. The mor ta l i ty of 85 cases t reated with ant i toxin was 23.5 per cent, whereas the morta l i ty of cases t rea ted with anti- serum was 49.9 per cent. Twenty deaths occurred in 85 pa t ients t reated with anti toxin, and 97 deaths occurred in the sermn-treated group comprising 211 pa- t ients. Hoyne advocated the intravenous use of 60 to 100 c.c. of anti toxin in 120 to 200 c.e. or more, respectively, of physiologic solution of sodium chloride or I0 per cent dextrose solution. The smaller dose for a child, the larger dose for an adult. This form of t rea tment may be repeated daily i f the condition of the pat ient requires it.

Encouraged by the above results, we rapidly increased our average intravenous anti toxin t o 81.3 e.e. or 28,000 units as compared wi th 30 c.e. or 10,000 units dosage used in 1933 and 1934. The intraspinal therapy average was 95 c.c., or 30,160 units, about the same quant i ty used in 1933 and 1934. Sixty of these pa- t ients with 29 deaths gave a fa ta l i ty of 46 per cent. Excluding the 13 deaths in less than twenty-four hours and 4 deaths in less than for ty-eight hours, the fa ta l i ty was 26 per cent.

AMERICAN ACADI~Mu OI~ PEDIATRIC~ 871

The smallest intravenous dosage in any single case in 1935 was 10 c.c. or 3,300 units. The largest intravenous dosage for one case was 525 c.c. or 175,000 units. Two eases in this group were recurrent, and both pat ients died. One of these pa- t ients, a white female, aged nineteen years, on her second admission received a total of 525 c.e. or 175,0'00 units intravenously and 285 c.c. intraspinally. This pa t ient developed a bacterial endocarditis, suppurative pericardi~is, optic neuritis,

and complete deafness before death. At autopsy 200 e.c. of perieardial pus was obtained.

Of interest was a seventy-four-year-old white male, a t ransient , admitted in emma, who was given 100 c.c. of the experimental anti toxiu intravenously and 150 e.c. intraspinaily. This pat ient developed a right panopthahuit is which neces- s i tated an enueleatlon. The pat ient made an uneventful recovery.

During 1936 seventy pat ients were t reated with twenty-three deaths, giving a fa ta l i ty of 32.8 per cent. Included in this group were seven pat ients who died within twenty-four hours and 4 wi thin for ty-e ight hours af ter admission. Ex- cluding these eleven eases~ a mortal i ty of 20.3 per cent would have been obtained.

At this time our average intravenous anti toxin therapy was increased to 159 e.c., or 53,000 units. This is five and one-half times the dosage employed in 1933 and 1934. The intraspinal ant i toxin average dose was decreased to 60 c.c., or 20,000 units. The number of average lumbar punctures was decreased to 3.5.

Attention is directed to the ten-year age groups, one to thirty years. Forty- eight cases were t reated with a mor ta l i ty of 23.7 per cent. Included in the fifteen deaths were ten in which death occurred within forty-eight hours af ter admis- sion. A high mortal i ty for the oldest age group, for ty to seventy yettrs, mani- fested i tself as it did in 1935. In the age group forty-one to fif ty years, there were five cases with four deaths, and in the age group sixty-one to s e t en ty years, one case and one death.

Tucker reported an epidemic of meningococcus meningit is in Spri~gfield~ Ill., and vicini ty during 1935. IIis first sixteen cases wer~ treated intraspinally with antimeningoeoecic serum with ten deaths or a mortal i ty rate of ,62.5 per cent. Sub- sequently fifty-three eases were t reated with ant i toxin (Ferry) intravenously and intraspinal ly with fifteen deaths, or a mortal i ty rate of 28.3 pcr cent. Complica- tions were surprisingly few in this last group.

Occasionally during 1936 patients were treated by intravenous antitoxin only with excellent results. A five-year-old white male admit ted in coma, slow in responding to therapy, received a tota l of 263,000 units (790 c.c.), a total of ~f teen intravenous injectious before recovery was complete. A six-month-old infant recovered following three intravenous injections, a total of 60,000 units (180 c.c.).

Ho?/ne, in 1936, reported a total of ninety-slx pat ients t reated exclusively by the intravenous route wi th a fa ta l i ty of 15.9 per cent. t i e also reported nine meningocoecic pat ients t reated intravenously without any lumbar punctures and wi th only one death. I-Ie likewise urges massive doses of ant i toxin intravenously, the init ial dose ranging from 50,000 to 100,000 units. The samller dose for a child and the larger dose for an adult.

During 1937, to ]YIay 1, we treated nineteen patients with intravenous anti- toxin only (Ferry) . The age groups represented ranged from eight months to for ty years. Two deaths occurred under one year despite massive doses of anti- toxln~ and one death occurred at eleven years. The average mortal i ty for this group was 15.7 per cent. There were fifteen white pat ients and four colored pa- t ients.

872 TI~E JOURNAL. OF PEDIATRICS

TABLE I

INTRAVENOUS ANTITOXIN ONLY

(WHITE AND COLORED) COh~BINED DISTI~IBUTIOI~ lVOl~ 1937

AGE GROUP CASES DEATHS ~ORTALITu RATE PER CENT U n d e r 1 Yea r 2 2 100

1-10 8 0 0 11-20 5 1 20 21-30 3 0 0 31-40 1 0 0 To ta l 19 3 15.7

M ass i ve in t r avenous doses were cons t an t ly given. The ave rage for each pa t i en t was 132,000 uni ts , or 396 c.c. The smal les t a m o u n t admin i s t e r ed to one pa t i en t was 30,000 un i t s , or 90 c.c. The l a rges t a m o u n t g iven to one pa t i en t was 260,000 uni ts . The in i t ia l dose fo r adu l t s in th i s smal l series was a t leas t 50,000 un i t s or 150 c.c. d i lu ted in a t least two or th ree t imes i ts volume of 10 per cent glucose. Adrena l in in dosage o f 10 m i n i m s h a s been added wi th each dose of i n t r avenous ant i toxin . ~ e n t l o n should be m a d e o f a severe sickle-cell a n e m i a irL a five-year-ohl negro male child wi th an associa ted meningococcic mening i t i s . This pa t i en t made .a complete recovery f r o m his m e n i n g i t i s wi th 110 c.c., or 36,000 un i t s , of F e r r y ' s an t i tox in given i n t r avenous l y on two successive days.

Table I I g ives a s u m m a r y of the ten-year age g roups of pa t i en t s t rea ted wi th an t i t ox in ( F e r r y ) f r o m J a n u a r y , 1933, to May 1, 1937. The h i g h mor t a l i t y under one year o f age ave rages 76.9 per cent and shows l i t t le change f r o m a s imilar g roup t r ea t ed wi th s t a n d a r d meningoeoccus se rum f rom 1930 to 1932 (77.7 per cent ) . The th ree decades on to t h i r t y yea r s include ] 35 an t i t ox in - t r ea t ed cases wi th an average mor t a l i t y o f 23.8 pe r cent as compared wi th 161 se rum- t rea ted cases f rom 1930 to 1932 when t he mor t a l i t y was 42.4 per cent. Fo r the older groups , f o r t y to seventy- ilve years , ~he mor t a l i t y was 08.6 per cent in t he an t i t ox in cases as compared wi th 79.6 per cen t in the s e rum- t r ea t ed cases.

TABLE I I

ANTITOXIN-TREATED CASES ACCOROING TO 10-YEA~ AGE GROUPS (1933 TO 1937)

AGE CASES DEATHS MORTALITY RATE PER CENT

U n d e r 1 yr. 13 10 76.9 1-10 57 14 24.5

11-20 50 11 22.0 21-30 28 7 25.0 31-40 12 6 50.0 41-50 10 9 90.0 51-60 3 2 66.6 61-70 1 1 100.0 71-80 2 1 50.0 Tota l 176 61 34.6

The ave rage mor t a l i t y was 34.6 per cent for 176 an t i t ox in - t r ea t ed cases between 1933 and 1937. E x c l u d i n g the 24 dea ths wi th in twen ty - fou r hours , a ra te of 24.3 per cent and excluding the 8 dea ths wi th in fo r ty -e igh t hours , a r a t e of 20.1 per cent would have been obtained.

Tab le I I I summar i ze s all eases t r ea t ed with an t i t ox in ( F e r r y ) both in t r a sp ina l ly and in t r avenous ly for tile yea r s 1933, 1934, 1935, and 1936, as well as the smal l series of n ine teen cases t r ea ted exclusively by in t ravenous ant i toxin . Conspicuous is the sha rp increase in the in t r avenous dose f rom an average of 10,000 un i t s in 1933 and

AMEIglCAI~ ACAD]g2CIY OF PEDIATI~IOS 873

1934 to 27,000 uni t s in 1935 and 53~000 un i t s in 1936. The ave rage i n t r avenous t h e r a p y for the n ine teen cases in 1937 was 132~000 units . The decrease in the n u m b e r of in t r a theea l t r e a t m e n t s d imin ished f r o m an average o f 5.1 pe r cent in 1933 to none in 1937.

TABLE I I I

ALL -~-NTITOXIN TREATED OASES

AVERAGE AVEI~AGE I.S. % YEAR CASES D E A T H S UNITS UNITS INJ. 1Vf 0RTALITY

I , S . I .V.

1933 t 4 2 30~000 1'0,000 " 5.1 14.2 1934 10 4 30j000 10;000 5.1 40.0 1935 63 29 30,160 27,000 5.0 46.0 ] 936 70 23 20~000 53,000 3.5 32.8 1937 19 3 0 132,000 0 15.7 Tota l 176 61 Ave rage 34.6

The complicat ions a m o n g these an t i tox in - t r ea ted eases have been few in n u m b e r compared wi th fo rmer series of se rum- t rea ted cases. Se rum reac t ions have occurred in 40 per cent of all cases. I n the smal l group of n ine teen ea se s t r ea ted only wi th in t r avenous ant i toxin , s e rum sickness ha s occurred in 74 per cent of the eases.

A survey of a b u s y seventeen-year service a t the I so la t ion Hosp i t a l recalls t he a l toge ther too n u m e r o u s i n t r a theea l punc tu r e s and s e rum t r e a t m e n t s which were admin i s t e red a t in te rva ls of every e igh t or twelve hours . U n q u e s t i o n a b l y in cases of sepsis in the pa s t wi th a low degree of meningi t i s , we have ac t iva ted the menin- g i t i s by all too f r equen t l u m b a r punc tu res . L u m b a r punc tu re s m a y well serve the i r :purpose for d iagnos is and for t he re l ie f of i n t r ac ran i a l p res su re symptoms . Our a t t en t ion should be di rected toward the toxic i ty of the disease, and we should look upon the men ing i t i s as be i ng secondary to a sys temic infec t ion . This a t t i t ude m i g h t be l ikened to t h a t a s sumed now in the t r e a t m e n t of t e t a n u s and d iphther ia . There fo re we should concen t ra te our effor ts in t e rms of how m u c h an t i tox in ( F e r r y ) is requi red for t r ea tmen t .

SUMMARY

A t t e n t i o n is directed to the i nc reas ing incidence and mor t a l i t y of meningococcus men i ng i t i s a m o n g cer ta in la rge cit ies in the Un i t ed S ta tes over a per iod of t en years , especial ly du r i ng the las t th ree years . In the Un i t ed S ta tes the ave rage f a t a l i t y fo r 1934 and ]935 was 53.2 per cent. F i g u r e s are cited showing t h a t 3/[emphis f a t a l i t y ra tes f r om 1925 to 1933 ave raged 52.1 per cent.

Tables are shown wi th var ious age groups r a n g i n g f rom :five m o n t h s to seventy- five years . The f a t a l i t y r a t e s fo r ]76 an t i tox in - t r ea ted ( F e r r y ) patienq~s was 34.6 per cent. J0~or 135 pa t i en t s r a n g i n g in age f rom one to t h i r t y years , the average was 23.8 per cent.

F i g u r e s and tables a re cited to d e m o n s t r a t e t h a t wi th increased mass ive in- t r avenous doses of an t i tox in , a decreased f a t a l i t y is obtained.

REFERENCES

1. U n i t e d S t a t e s P u b l i c H e a l t h Repor t s , Deeeinber~ 1934, 1935, 1936. 2. D e p a r t m e n t of Commerc% B u r e a u o f t he Census, 1934, 1935. 3. H o y n e , A. L. : J . A. 3I. A. 107: 478, 1936. 4. Trlpoli~ C. 5.: J . A. 31. A. 106: 175, 1936. 5. Gordon, & E. : M e d i c a l R e p o r t o f t h e H e r m a n K i e f e r H o s p i t a l , De t ro i t , fo r

t he five y e a r s 1927 1931~ Sec t ion X X I I .

The exper imentM ant i toxin (Fe r ry ) was provided th rough the cour tesy of the Parke~Davls & Company Laborator ies .

874 TItE JOURNAL OF PEDIATRICS

6. Levy, G. J. : South. IV[. J. 24: 232-238, ]931. 7. Anderson, J. Mercer: J. A. M. A. 93: 1613, ]929. 8. Shaw, E., and Thelander, H.: Endemic Cercbrosplnal Fever in Childhood,

5. A. M. A. 101" 746, 1933. 9. Ferry, N. S., Norton, J. F , and Steele, A. I t . : J . Immunol. 21: 293, 1931.

10. Fcrry~ N. S.: 5. Immnnol . 23: 315, ]932. I t . Ferry, N. S., and Schornack, Phi l ip J . : J . ImmunoL 26: 143, 1934. 12. ]-Ioyne, A. L.: J. A. 3d[. A. 104: 980, ]935. ]3. Tucker, Wins ton tI . : I l l inois ]V[. 5. 71: 328, ]937. 14. Hoyne, A. L.: J. A. 3/I. A. 107: 478, 1936.

Treatment of M'eningococcic Meningit is With Sulfanilamide

Francis r . Schwentker , M.D.

During 1935 and 1936 an epidemic of meningococeic meningit is in Baltimore caused the admission of over 400 eases to the Syndenham Hospital. In the fall of 1936 sulfanilamide was introduced as a chemotherapeutic agent. Encouraged by good experimental results in animals we administered sulfanilamide to two patients with meningoeoccie meningitis whose course under serum therapy had been un- favorable. Both pat ients showed immediate improvement and recovered. Since tha t t ime sulfanilamide has been used in the t reatment of all pat ients admitted to the hospital with meningococcic infection.

Method of Treatment--The drug is usually administered both intraspinally and subcutaneously. To some patients i t has been given by mouth. For parenteral injection, ] per cent solution of the powdered crystalline sulfanilamide (Merck) is prepare,d in physiologic solution of sodium chloride. This solution is injected intraspinal ly in amounts varying from 10 c.c. ~o 30 c.c. and subcutaneously in volumes of 100 to 500 c.c., according to the weight of the patient. Both the intraspinal and subcutaneous injections are repeated every twelve hours unti l there is definite im- provemen% in the pa t i en t ' s condition and thereaf ter at twenty-four-hour intervals for a few injections. The t reatments are usually discontinued when the cultures of two or three consecutive specimens of spinal fluid have proved sterile.

In order to control the effectiveness of the t rea tment we have found it advanta- geous to follow the concentration of sulfanilamide in the blood and spinal fluid. The dosage of the drug ~s regulated to mainta in a concentration of sulfanilamide not less than 5 rag. per 100 c.c. in the spinal fluid and preferably as near 10 rag. per

100 e.c. as possible. These values are given for specimens taken twelve hours a f te r the last inject ion of sulfanilamide. Because of the rapid absorption and excretion of the drug, the ~ime elapsing between adminis t ra t ion of the sulfanilamide and withdrawM of the specimen for analysis must be consl.dered. I f spinal fluid is analyzed six hours af ter int raspinal injection of sulfanilamide, from 15 to 25 rag. per 100 c.c. will be found present. This value exceeds the level in the blood. At twelve hours, however, the spinal fluid vMue is slightly less than the concentration in the blood.

l~esults.--Up to the present time 52 patients consecutlve]y admit ted with meningo- coecic infections have been ~reated with sulfanilamide. In the major i ty of cases the spinal fluid became sterile fol lowing the first inject ion of the drug~ the spinal fluid cell count fell rapidly to .normal, the proportion of polymorphonuclear cells decreased progressively, the sugar content increased; and the pat ient showed rapid recovery. In a few ~patients several t reatments were required to sterilize the spinal fluid; the maximum number has been five, representing two and a ha l f days of treatment.

Of the 52 patients t reated with sulfanilamide, eight died. This is a mortal i ty of 15 per cent. Two of ~hese patients were moribund on admission and died-thrQe

A1VfER.ICAN ACAD]~Mu OF PEDIATRICS 875

and seven hours , respect ively, a f t e r admiss ion. I f these cases are excluded the re r ema in 50 cases wi th 6 deaths , a m o r t a l i t y of 12 per cent. Of 278 consecutive pa- t i en t s t r ea ted with an t imen ingoeoeeus serum in the mon ths immedia t e ly preced ing the i n s t i ga t i on of su l f an i l ami de the rapy , there were 85 deaths , or 30 per cent mor- ta l i ty , compared wi th 15 per cenZ for the drug. E x c l u d i n g cases in which dea th occurred wi th in t wen t y - fou r hours , the re were 237 se rum- t r ea t ed pa t i en t s wi th 44 deaths , or 19 per cent mor ta l i ty , compared wi th 12 per cent m o r t a l i t y wi th su l fan i la - mide.

There have been too few pa t i en t s t r ea ted with su l f an i l amide to draw any com- par i sons as f a r as compl ica t ions are concerned. Ar th r i t i s and t r an s i en t dea fne s s were observed, bu t all pa t i en t s were d i scharged well.

I t is of in te res t t h a t no repor t of a case has yet reached our a t t en t ion in which the su l f an i l amide fa i led 'to s ter i l ize t he sp inal fluid prompt ly . Even in those pa t i en t s who died, the o rgan i sm could not be recovered a f t e r the first few t r ea tmen t s . These pa t i en t s had considerable encephal l t ic involvement and cont inued m o r i b u n d t h rough - out *heir course.

ToociciCy.--Certain toxic effects for su l f an i l amide have been no ted by m a n y ob- servers. Sulphemoglobinemia , hemoly t ic anemia , acidosis, and mor ib i l l i fo rm r a sh have been described, b u t only su lphemoglob inemia ha s occurred in t h i s series of pa- t ients . None of these compl ica t ions is ser ious i f cons t an t ly expee*ed and t r ea ted appropr ia te ly .

Concluaion.--It seems reasonable to conclude t h a t s u l f a n i l a m i d e is as effective in the t r e a t m e n t of meningocoecic in fec t ion as specific a n t i s e r u m and ha s the ad- v a n t a g e o f f reedom f r o m fo r e i gn p ro te in propert ies .

D I S C U S S I O N

DR. E. E. M A R T M E R (DETROIT, MICH.).--Since commercia l s e rums conta in about 50 per cent as much an t i tox in as does the commercia l antitoxin~ why do l a rge doses of s e rum fa i l to reduce case rascality r a t e s?

C H A I R M A N H O Y N E . - - I t h i nk se rum does reduce case f a t a l i t y ra tes when used in l a rge enough doses. Mos t of the s ta t i s t i cs on se rum t h e r a p y have been based on t he use o f re la t ively smal l doses o f se rum as compared wi th the doses of ant i -

toxin now be ing used.

DR. L. S. F R I E D M A N (CINCINNATI, O H m ) . - - D o you a t t e m p t to tes t all cases for horse se rum sens i t iv i ty?

C H A I R M A N t I O Y N E . - - ~ V e do no t tes t rout inely. We star~ our se rum very slowly and always give ad rena l in mixed wi th it. W e do tes t pa t i en t s who give a suspic ious his tory.

DR. F ' R I E D M A N . - - W h a t procedure do you follow i f a pat ien ' t is sensitive.~

C H A I R M A N H O Y N E . - - W e give t he se rum by the i n t r a m u s c u l a r route be fore in- t r avenous admin i s t r a t ion . F o r example , recent ly we h a d two pa t i en t s who re lapsed after h a v i n g had in t r avenous t r e a t m e n t . One was a se rum- t r ea t ed patient and the other an an t i t ox in t r ea ted pa t i en t . A n a t t e m p t Was m a d e to give i n t r avenous t h e r a p y a g a i n and both had react ions . Anr was then g iven i n t r a m u s c u l a r l y on th ree successive clays; s ter i le cu l tures r e su l t ed ; and bo th p a t i e n t s recovered.

DR. A. E. A M I C K (CHARL~dSTON, W. V A . ) . - - W h a t is the m i n i m u m dose o f an t i t ox in ?

C H A I R M A N H O Y N E . - - N o t less t h a n 60,000 uni ts . Th i s m a y be all t h a t is needed. I n severe cases we usua l ly g ive 100,000 un i t s or more as t h e in i t i a l dose.

876 THE JOURNAL OF PEDIATIgICS

DR. A M i c K . - - H o w rapidly is this given~

CHAIRMAN IIOYNE.--Wo begin our intravenous therapy using I0 per cent

glucose solution in normal sa]in6 containing adrenalin and gradually add the anti- toxin to this solution. We start with 10 drops per minute and gradually increase to 60 drops per minute.

DR. H. Y. F I N E (Png,rH A~iBOXr, N. J . ) . - - I s there any objection to giving the serum faster than 60 drops per minute because of the difficulty of staying in the vein .~

CIIAII~MAN H O Y N E . - - I do not think so i f no harmful effects manifest them- selves. The concentration of substances in the spinal fluid is dependent upon their concentration in the blood stream and the ability of those substances ~o pass through the barrier between the two. Any foreign substance introduced directly into tile spinal fluid, as by lumbar puncture, will produce meningitis; this means an increase in the permeability of the meninges. Therefore I feel convinced that patients a re much better off if they have nothing intraspinously.

DR. SHAW.--Can you demonstrate antitoxin in the spinal fluid after it has been given intravenously?

CHAIRMAN HOYNE.--Yes, experimental work (by Philip Miller) on mice has shown that antibo,dies pass from the Mood stream into the spinal fluid. Spinal fluid from patients treated with antitoxin intravenously was used in this investiga- tion.

DR. SHAW.~How about the various types of meningocoeci, do they influence the mortality?

CHAIRMAN HOYNE.--Formerly we paid a great deal of attention to typing the organism. Now very little consideration is given to types and nmch more to toxic effects.

Dig. E. S. PLATOU (MINNEAPOLIS, MINN.).--Have any comparative fatali ty rates resulting from different methods of treatment during a single outbreak of meningitis been made?

CHAII~MAN HOYNE.--Yes, this was done in Los Angeles and also in Detroit, where the patieirts were divided into two groups, one receiving serum intravenously and intimspinally and the other receiving the serum intravenously and intracister- nally. The groups treated intravenously and intraci#cernally showed the better re- sults in both instances. However, the group treated intraclsternally received larger doses intravenously and this might explain the lower fatality rate although credit was given to the intraeisterna] method of treatment.

DR. C. H. SMITH (NEw YORK, N. Y.) . - -There has been an average of 30 to 100 cases :per year on the East Side of New York. Under advice of the New York Department' of Health, we previously treated cases of meningococcie meningitis with a single daily treatment of serum intraspinally. Intravenous serum was not advised. At present at Bellevue Hospital we treat patients intravenously twice a day for one or two days, and intraspinally twice a day for three or four days (using city or state serum), then switch to one intraspinal treatment a day. I f you depend on culture to guide you in slopping or starting treatment, you have to wait too long. Treatment should be determined in this disease by the same methods that one uses in treating a case of appendicitis. In meningococcic meningitis one should be guided by temperature, a daily white blood count, and by the number o f cells in %he spinal .fluid.

A~IEI~ICAN ACADEMY OF PEDIATRICS 877

DR. AMICK.- - t tow is the early diagnosis of meningitis made without a puncture?

CHAIRMAN HOYNE. - - In an epi~demic you can be fairly sure of the diagnosis. We depend upon blood cultures, as a rule, to confirm the clinical diagnosis. I t is true that there are certain types of hemorrhagic smallpox that are almost impossible to distinguish from meningocoecic meningitis. Patlea~s showing petechiae should

always have a blood culture. Sometimes the petechia may be pricked by a needle and the organism obtained on smear. I f the blood culture is negative, an examina- tion of the spinal fluid is required for a certain diagnosis.

(~UESTION.--Do you find a low percentage of negative bloo,d cultures during the first few days?

CHAIRMAN HOYNE.--Seldom do we get a positive blood culture if the patient noes not have petechiae.

DR. MARTMEI~.--What relation do you feel exists between the decline in the outbreak of meningitis in Chicago and the improvement in case fa ta l i ty?

CHAIRMAN HOYNE.- -We are still having a number of cases in Chicago. The severity of the disease (]oes vary during epidemics a, ac] a~so among endemic cases. During 1928-1932 "in Detroitj Dr. Gordon stated the cases were.severe, and he seemed to attribute that fact to the presence of an epidemic. In 1936 we had ]44 cases at the Cook County Hospital with 44 deaths, 20 dying within for~y-eight hours of admission. This gave us a very favorable fatality rate. In 1934 and 1935 the fatali ty rate was also low, but the number of patients was considerably higher than in 1936. I t has been my experience that endemic cases of meningococeic meningitis are frequently as severe as those e~countered during an epic]emi~.

DR. SHAW.--Do you think the reverse is true?

CHAIRMAN HOYNE.--Par with peteehiae were regarded by us as having a very bad prognosis when admitted to our hospitals some years ago. Now we feel the opposite is likely to be true unless the patient is suffering from a fulminating type of infection. A patient with petechiae is likely to be diagnosed earlier, and there ~ a y be little or no apparent involvement of the meninges. Consequently the chances for recovery are favorable. But even with early treatment the morts is always high for fulminating cases.

CHAIRMAN HOYNE. - - I see Dr. Neal in the room and I am sure all of us would appreciate a few words from her.

DR. J O S E P H I N E B. NEAL (N~w Y0aK, N. Y.) . - - Infeet ions of menlngococcus shoul:l be considered ~noningoeoccemla wi~h or without meningitis. I n New York during the last two or three years we have had meniugococcemi~ with very mild meningitis, These cases respond to intravenous therapy. I would not dare treat a case of meningitis without intrasplnous treatment. We use serum intraspinousiy once a day and only give intravenous serum where there is a septicemia. I have only had a limited experience with sulfanilamide and am using it with serum a~ the present time. Much of the confusion with methods of therapy is due to the serum's varying in potency. Some serums tested very l i~le better than horse serum during 1926-30, whereas the New York state serum was good. Naturally rising such serums would give varying results. We must keep clearly in mind the difference in the septicemic type, which responds to intravenous therapy, and the meningitic type of the disease, which responds to intraspinous therapy.

CHAIRMAN HOYNE. - - I am still surprised that Dr. Neal likes to give serum intraspinously.

878 THE JOURNAL OF PEDIATRICS

DR. NEAL.- -Your cases were those of the septicemic type with very mild meningitis.

CHAIRMAN HOYNE.- -Pa t ien ts treated intraspinously usually have opisthot- onus. Our patients de not have opisthotonus, nor do they develop Mocks. We

h a v e fewer complications, such as panopthMmitis or pericarditis. Streptococcic meningitis will occasionally follow intraspinous therapy. We do not have that. There is less likelihood of traumatic complications due to injury of intervertebral discs an,d otlmr spinal tissues as the result of faulty punctures. Our patients are much more comfortable, and there are fewer deaths. ' Whether the patient is seen on the first day of the disease when there may be meningoeoccemia with no apparent evidence of meningitis, or whether tile patient enters the hospital with meningitis of many days ' or weeks' duration and perhaps in a state of extreme opisthotonus, no intraspinal therapy is adopted. During a period of twenty-five years we have had all varieties of meningo~oceie meningitis on my service at the Cook County hospital. The percentage of severe cases treated without intraspinal therapy during any one of the last few years has been as high as in any one year when intraspinal treatment was practiced.

QUESTION.--How about sequelae?

CHAIRMAN t IOYNE.- -We have not had a single ease of loss of vision or hearing when the patient was treated before such complications arose, among our antitoxin patients treated without intraspinal therapy. In fact, we have had several cases with endophthalmitis and impaired hearing clear up under intravenous therapy. However, complications do vary in different years.

DR. B. S. DENZER (NEW YORK, N. Y. ) . - -What is ~here in common between serum and antitoxin~ Do immunologists recognize an antibacterial serum?

DR. SHAW.- - I feel that the amoun~ of antitoxin, agglutinins, the opsonie index, and the antileucocidin effect only can be measured in a serum, but farther than that we cannot go. The agg]utinin content of antibacterial serum does not parallel the therapeutic effect.

CHAIRMAN HOYNE.--There is very little difference between antibacterial serum and antitoxin from the standpoint of recovery. Since producers of serum have recently altered their methods of manufacture, now there is probably a higher antitoxin content in the antibacterial serum.

In answer to several questions relative to ,dosage of antitoxin: We have not s'tandardized the optimal dosage of antitoxin. We feel the ideal thing to do would be to give the total dose at one time. A few months ago we had a nurse who developed a headache. Tile next day she had numerous petechiae and was in deep stupor. Immediately she was given 150,000 units of antitoxin intravenously. No lumbar puncture was done. The next day she received another 150,000 units, and the third day~ 100,000 units. Blood cultures were positive during this period. Tile fourth day a spinal tap grew out organisms. She was given more serum and anti- toxin until in all she had received over 2,000 c.c. We frequently repeat the dose on subsequent days to avoid relapse, although cultures of spinal fluid often become negative in thirty-six to forty-eighl; hours. I f one week or more elapses without treatment, and then further treatment is indicated, we often give an intramuscular injection of 10~000 units of antitoxin before resorting to additional intravenous therapy.

DR. SHAW.--We sometimes give 80,000 units during a period of five days.

DR. R. P. ROGERS (GREENWICH, CONN.).--What does the purpuric rash of meningitis look like in a dark negro~

AMERICA~ ACADt~MY OF PEDIATRICS 879

CI.IAIRMAN HOYNE.--Sometimes the rash is hard to see but may be as obvious as smallpox in the negro. The sore throat in meningitis is very important. One member of a family may be a carrier and another may have a pharyngitis or meningoeoccemia but no meningitis. I feel that a lumbar puncture in a case of meningococeemia with no meningitis may favor the development of meningitis.

DR. PLATOU. - - I have slides showing the results of treatment in two cases of meningococeic meningitis, using fever therapy. The first case was a three-and-one- half-year-old child having meningitis with arthritis. Fever therapy alone was used, ancL the child recovered. The other case was one of chronic meningitis in which fever therapy alone was used, and recovery followed. I feel that this type of therapy is contraindicated in acute cases but that it is useful in the chronic type or in serum-refractive cases. Certain strains of the organism may be more thermo- labile than others.

DR. MARTMER.--I-Iow does Dr. Levy explain the failure of improvement ~n the age groups under one year and over twenty to thirty years?

DR. LEVY.--Our results coincide with other statistics. I t is true that the two extremes of life carry the highest mortality.

DR. DENZER.- - I s there any objection to combining sulfanilamide and serum?

CHAIRMAN HOYNE.--2'Io, I have used both with good results.

i)R. DENZER.- -Why not give sulfanilamide intravenously?

DR. SCHWENTKER.--Excret ion of sulfanilamide is too rapid and you do not -ge~ the concentration in the spinal fluid that one gets following the subcutaneous method of a.dministration. Furthermore, dogs show toxic reactions to the intravenous use of the drug and not to the subcutaneous method. The peak of concentration after oral or subcutaneous administration is reached in about four hours.

DR. LEVY.- - I s prontosil in 2.5 per cent solution equivalent to a 1 per cent solution of sulfanilamide?

DR. SCI-IWENTKER.--One can give prontosil and get the same effect, but it has to be broken down into prontylin~ requiring about twelve hours. A 2.5 per cent solution of prontosil is equivalent to about an 0.8 per cent solution of sulfanilamide.

DR. SHAW.--How do you glvc sulfanilamide? How do you figure dosage?

DR. SCHWENTKER.- -The dose of sulfanilamide which we have used runs about as follows: To infants and children under 40 pounds, 2 to 2A gnu per day. To children from 40 to 80 pounds, 3 to 3.6 gin. per day. To children weighing over 80 pounds, 4 to 4.8 gin. per day. This is given by mouth or subcutaneously, at four-, six~ or eight-hour intervals. In very severe infections we double the dose mentioned. On the first day the dose for twenty~four hours may be given at once. The largest dose which has been given is 5 gin. for an infant, ~or older children, 7.5 gin., and for adults, 10 gin. One half of the patients treated will become cyanotic, but this can be .disregarded.

QUESTION.--What are the toxic effects?

DR. SCHWENTKEI=t.--In addition to the cyanosis, which is due to sulphemoglo- binem~a and clears upon stopping the drug, we have seen a morbilliform rash appear af ter two or three days of medication. Acidosis occurs frequently. Transient nausea occurs when the drug is being administered by mouth. Dizziness may occur. Pyrexia may appear and be hard to distinguish from the fever of infection. Hemolytic anemia has been reported, We bavQ ~ever had to interrupt treatment because of toxic effects,

880 THE JOURNAL OF PEDIATRICS

DR. C. L: LAMAR (Brr~INGtIAM, ALA.).--Can sulfanilamide be given intra- peritoneally in infants?

DR. SCHWENTKER.--Yes, if desired.

DR. L E V Y . - - I f optimal results are obtained by maintaining concentration in the blood at a certain level, can the analysis be made easily?

DR. SCt tWENTKER.--Yes , the technic was described by Marshall, E. K., Jr., and his associates: Para-Aminobenzenesulfonamide, J. A. M. A. 108:953 (March 20)~ 1937.

A eolorimeter is required, but we do not buffer the solution. The method is about as complicated as a blood sugar determination.

DR. G. B. HUNT (PITTS~'I~D, MASS. ) . - - In the use of prontolyn what has been the effect on the white blood count.~ In the New England Journal of Medicine, a case was recently reported of a patient who had an extreme ncutropenia and died as a result of the use of the drug.

DR. SCt tWENTKER.- -Al l cases of neutropenia which have occurred have not been proved to be caused by the drug. Agranulocytosis often accompanies a strep- tococcic throat and other infections. I have heard of two patients with agranu- locytosis treated with sulfanilamide, and both recovered.

DR. S. A. ANDERSON (Rre~r~o~rD, VA.).--You mentioned treating a few cases by mlbeutaneous medication only. So far as you have gone, does this seem a better method than combining with the intraspinous treatments?

DR. SCHWENTKER. - - I f it is necessary to keep the spinal fluid content of sulfanilamide high, then this method should be use,d more.

DR. ROGEItS.--Have you found that sulfanilamide-treated eases produce anti- bodies? In other words, is sulfanilamide actually toxic to the organism, or does it merely check the growth of the organism until antibodies are produced? Is it necessary to continue sulfanilamide for as long as two weeks after the spinal fluid is norinal?

DR. SCI:IWENTKER.--Sulfanilamidc cheeks the growth (~f the organism. Phago- cytosis fu~'ther aids the sterilization of the spinal fluid. Treatment is continue~l three or four days af ter the tlrst sterile eult~u:e is obtained,

CHAIRMAN HOYNE.--Perhaps sulfanilamide may supplant eventually all other therapy in the treatment of meningococcie meningitis. I ts lower cost is an important factor.

DR. SCHWEiNTKER.--Dr. Branham has recently published results in mouse pro- tection tests, which show that the protective value in mice of sulfanilamide and of serum was approximately the same. When used in combination, and apparent synergistic ~tction was obtained.

KATHERINE MERI~ITT J. LEwis /3LA:~TON

Recorders,