Diagnosis and management of severe infections in infants and children: A review of experiences since the introduction of sulfonamide therapy

DIAGNOSIS AND MANAGEMENT OF S~]VERE INFECTIONS IN INFANTS AND CHILDREN: A R E V I E W OF E X P E R I E N C E S SINCE THE INTRODUCTION OF SULFONAMIDE THERAPY I I . I-IEMOLYTIC STREPTOCOC:~AL MENINGITIS

M.D., DOROTHY "WOLFF, P H . D . , FRANCES M. LOVE, M.D., AND BARBARA S. KENDALL

ALEXIS F . HARTMANN,

ST. LOUIS, ~[0.

the period since the first case~of meningitis was treated D URING with sulfonamides in the St. Louis Children's Hospital and the time of this writing (approximately five years), the patients admitted with signs and symptoms sufficiently suggestive of bacteria] meningitis to demand special investigation with such a diagnosis foremost in mind and to suggest sulfonamide drug administration pending accurate diagnosis as to the type of infection numbered approximately 100 and are summarized in Table I. All cases managed by the pediatric service or by the department of otolaryngology with pediatric supervision, particularly in regard to treatment, are included. We have decided to review first our twelve eases of acute hemolytic streptococcal meningitis. In the great majority of cases, such infections are the result of extension of otitiS media, mastoiditis, or petrositis and from the beginning are joint problems of the pediatrist or internist and the otolaryngologist, with much help expected from the bacteriologic laboratory and the x-ray department, just as were the eases of lateral sinus phlebitis reported in the first paper of this series. * REPOI%T OF CASES RECOVERING CASE 1 (Chart 1, and Table I I ) . - - T h i s boy, L. W., aged 20 months, developed an upper r e s p i r a t o r y infection on Dec. 5, 1936. Three days later an area Of eellulitis was seen on his left leg, and on Dec. 11 a stiff neck was noted. On Dec. 12 the initial hospital examination confirmed the p r e s e n c e ' o f ee]lulitis and suggested an associated septicemia and possible meningitis. The blood culture grew hemolytic streptococci. A spinal tap, however, was negative, revealing clear spinal fluid which proved to be without organisms on smear, with but six cells, and sterile. The infection iu the r e s p i r a t o r y t r a c t had largely subsided and the ears seemed uninvolved. I t was decided to t r e a t this i n f a n t with the first of the sulfonamide drugs then avaEable, pro~tosil~ i f his course, a f t e r the institution of other measures of treatment, suggested t h a t he was not progressing as f a v o r a b l y as hoped for. As a result of this plan, observation was continued through Dee. 17, during which time the t e m p e r a t u r e gradually diminished, and the area of cellulitis on the leg showed signs of localizing. A new metastatic area of infection, however, had appeared on the right hand and the blood culture continued positive for the first two days, became negative Dec. :15~ and positive again on Dec. 16 and 17. Late in the eveFrom the Departments of Pediatrics and Otolaryng'ology of the Washington UniVersity School of Medicine. and the St. Louis Children's Hospital. 591

592

TttE JOURNAL OF PEDIATRICS

TABLE I INCIDENCE AND MOICTALITY OF ACUTE PURULENT AND NONPURULENT MENINGITIS AND MENINGO-ENCEPHALITIS (DECEMBER, ]936, TIIROUGH MAY ]5, 1942) PUEULENT NO.

Pneumococcal Meningococcal It. Influenzal t t e m o , strep. B. P r o t e u s l~riedlander's S t a p h . + Strep. B. coli + Strep. v i r i d a n s Sterile Total

*]~y excluding the hospital.

patients

24 20 16 ]2 1 1 1 1 24 ]O0

dying

NONPUF~ULENT MORTALITY% CORGROSS RECTED* 75.0 25.0 82.0 33.3 O.O 1OO.0 100.0 I0O.0 O.0 41.0

within

63.7 11.1 76.8 11.1

NO. Tuberculous Syphilitic Total

~ ~ -

MORTALITY

%

100.0 16.7 84.4

MENING0-ENCEPHALITIS ] 1ViOldNO. TALITY

%

29.~

Mumps St. L o u i s Measles Undetermined Total

the first twenty-four

hours

i

/~I

after admission

0 0 0 0

0 to

n i n g on Dec. 17 t h e t e m p e r a t u r e rose s h a r p l y a g a i n , a n d t h e n e x t d a y definite m e n i n g e a l s i g n s a n d s y m p t o m s w e r e n o t e d . S p i n a l t a p n o w r e v e a l e d t u r b i d fluid c o n t a i n i n g 4,500 cells, w i t h s t r e p t o c o c c i s e e n on s m e a r a n d l a t e r g r o w i n g o u t on c u l t u r e . W i t h t h i s t u r n of e v e n t s it w a s d e c i d e d to s t a r t c h e m o t h e r a p y a n d to c o m b i n e w i t h t h e i n t r a m u s c u l a r i n j e c t i o n of p r o n t o s i l c o n t i n u o u s s p i n a l d r a i n a g e b y t h e n e e d l e m e t h o d a n d to p r o v i d e c o n t i n u o u s i n t r a v e n o u s fluid a d m i n i s t r a t i o n . S u c h p r o m p t i m p r o v e m e n t f o l l o w e d t h e i n s t i t u t i o n of t h e s e m e a s u r e s t h a t on t h e f o l l o w i n g d a y , Dec. 19, t h e s p i n a l fluid c u l t u r e w a s sterile, as w e r e all l a t e r cult u r e s . T h e blood c u l t u r e s also b e c a m e n e g a t i v e p e r m a n e n t l y , a l t h o u g h i t is to be n o t e d f r o m C h a r t 1 t h a t t h e blood c u l t u r e t a k e n a t t h e t i m e of t h e d e v e l o p m e n t o f m e n i n g i t i s w a s a l r e a d y sterile. I n a b o u t f o r t y - e i g h t h o u r s t h e t e m p e r a t u r e h a d b e c o m e n o r m a l a n d c o n t i n u e d to r e m a i n w i t h no, or v e r y little, e l e v a t i o n d u r i n g a s u b s e q u e n t p e r i o d of s u l f a n i l a m i d e a d m i n i s t r a t i o n . On Dec. 28 a n a b s c e s s w a s d r a i n e d w h i c h d e v e l o p e d at t h e site of t h e o r i g i n a l eellulitis. I t w a s m u c h like a cold a b s c e s s , b u t t h e p u s c o n t a i n e d v i a b l e h e m o l y t i c s t r e p t o c o c c i . T h e s u c c e s s f u l o u t c o m e of t h i s case l e f t a p r o f o u n d i m p r e s s i o n on all of us, s i n c e it w a s t h e first r e c o v e r y in t h e St. L o u i s C h i l d r e n ' s H o s p i t a l o f a p a t i e n t w i t h h e m o l y t i c s t r e p t o coccal m e n i n g i t i s f r o m w h o m t h e s p i n a l fluid n o t o n l y s h o w e d s u c h o r g a n i s m s i n s t a i n e d s m e a r s , b u t also f r o m w h i c h o r g a n i s m s could r e a d i l y be g r o w n on c u l t u r e . I t m i g h t be m e n t i o n e d in p a s s i n g t h a t w h i l e t h e s k i n of t h i s c h i l d b e c a m e q u i t e r e d d u r i n g t h e p e r i o d of p r o n t o s i l a d m i n i s t r a t i o n , no d i s c o l o r a t i o n of t h e s p l n a ] fluid w i t h t h e r e d d y e could be d e t e c t e d . NO e s t i m a t i o n s w e r e m a d e o f t h e conc e n t r a t i o n s o f p r o n t o s i l or s u l f a n i l a m i d e i n t h e blood or s p i n a l fluid s i n c e m e t h o d s were not yet developed for such chemical determinations.

Fo~low-Up Examination.--When e x a m i n e d on A p r i l 4, 1942, s o m e five y e a r s l a t e r , he w a s 6 y e a r s , ]1 m o n t h s old. I t w a s l e a r n e d t h a t a f t e r r e t u r n i n g h o m e he h a d r e n i a i n e d well a n d a p p a r e n t l y w a s d e v e l o p i n g n o r m a l l y b o t h p h y s i c a l l y a n d m e n t a l l y . H e w e i g h e d 45~A p o u n d s a n d w a s 451~ i n c h e s tall. T h e p h y s i c a l e x a m i n a t i o n r e v e a l e d no a b n o r m a l f i n d i n g s . T h e a p p r a i s a l of h i s m e n t a l s t a t u s b y one of u s (B. S. X . ) w a s as f o l l o w s : W h e n s e e n on t h e s a m e date, t h e p a t i e n t c o o p e r a t e d q u i e t l y b u t w i t h s o m e e n j o y m e n t , a n d s u s t a i n e d a t t e n t i o n well, e v e n in t a s k s w h i c h w e r e of l e a s t i n t e r e s t to h i m . T h e r e w a s s o m e s h y n e s s , b u t on t h e w h o l e he a n s w e r e d q u e s t i o n s r e a d i l y .

HARTMANN ET AL. :

SEVERE INFECTIONS IN INFANTS AND CHILDREN

593

The Stanford-Binet examination (Form L) yielded a mental age of 6 years, 6 months and an I.Q. of 94. There was a reasonable degree of uniformity, with best success in logical memory. C'ontrol of the pencil was rather poor in incidental drawings~ in writing, and in the drawing of a man, which, nevertheless, earned (according to the Goodenough norms) a rating of 7 years, 3 months. Largely because of good sense of form relation, the patient earned a rating a year and a half above Binet mental age in a variety of performance tests drawn chiefly from the Pintner-Paterson scale. 1116 O[r163 ~PINAL

.1| . l $ . 1 4 , 1 S , l & l ? , I B , I t ~ O ~ L I , P . I | ~ . A I S I G Z T ,

FLUID

CrLL eou.T Eu,,u~E

6

4soo *

-

S IM Ir A R(ORGAN IS MS) ~ULTUR[ LEU~OCYTr$

41 -

-

4- + . . . . . CON'T. t.v. FLUID ADflINI~iTRATION CON'T, $PI NAt DRAINA4E (NEEDLE) T M ETASTATIC | l 4-

15700

,'4 -

-

44

9v T'C

-

/INF[CTiON OF

J0& .~11

|

,o,.,,

"103 ,oZ : 3 9

JP&I ~ q ~ 3 1 J A M . 3 . 4 ; I .

$ ~ I DAY OF" MENINGITIS

I{

RT, HAND

~ '~/vl

~ ~

a ~,~',I

]

ASPIRATION A N D DIWAINA(~E OF L[&

~,ll

I

'~ i

VW

,.,,

H.I~. GPt/IO0 C.C. q.8 %,/lADLE BLOOD I.V.C.C DEXTROSE iO ~ " " L A C T A T E - RINGER'S C.C.

4O0 250 5O0 4(015(,0

HEMOLYTIC STREPTOCOCCIC MENINGITIS, SEPT|Cs CELLULITI$. CASE LA'~/RENCE ~/. , ~ G E ~ 0 M O

Z 0 m

I< I--o

CELLULiTi5 OF LEFT LEG IP.-8 STWF NECK(P1ENINGISf'tUS~ I~'-ll

o

H

.8 7

r

V

180 100

B .0 DAY

OF

5ULFONArllDs TRs

Chart

i.

iil

CASE 2 (Chart 2 and Table l I ) . - - T h i s 3-year-old boy, W . B . , developed acute bilateral purulent otlt]s media on Feb. 15, 1939. A p p r o x h n a t e l y one month later, because of continued suppuration, bilateral simple mastoidectomy was performed. E x t e n s i v e cellular destruction was noted, and hemolytic streptococcus was cultured from b o t h mastoids. A t this time the dura and lateral sinuses appeared normal. Tt should especially be noted t h a t no preoperative chemotherapy was employe d but t h a t beginning on the Second postoperative day 1.3 Gin. of sulfanilamide were administered d a i l y f r o m March 14 to 22. Both ears were t h e n dry, the wounds were healing well, and the p a t i e n t was discharged from the hospital. However, on May 5, ]939, meningeal symptoms developed without associated symptoms of acute r e s p i r a t o r y infection. Adm)ssion to the hospital occurred on ~r 8, the

594

THE

JOURNAL

OF P E D I A T R I C S

WABLE

APPARENT

TOTAL

DAY O F MENINGITIS WHEN TREAT-

DATE OF ADMISSION

GM. BEFORE FIRST NEGATIVE SPINAL FLUID

MENT WAS STARTED

12/12/36

Second

IM, O,

5/ 8/39

Fourth

O, O, R,

3/30/39

ADMINISTERED

G1Vi.

Fifth

2.3 P 9.0 S

C U L T U R E AND PERMANENT STERILIZATION

12 days IM,

0.8 P

1.8 S 18.5 SP 21.6 SP

22 days

8.5 SP

O, 69.0 SP IS, 0.4 S SC, 0.3 S

13 days

O,

IS and SC, 3.1 S O, 6.0 SP

10/24/40

Fifth

O, 1.5 S 0, 114.0 SP IS, 0.5 S IV, 32.4 S IV, 3.0 SP

IV.

4.5 SP

12/25/39

First

O, IS, SC, IV,

32.1 1.3 0.3 0.8

S S S SP

O, IS, IV,

2.4 S 0.2 S 0.8 SP

Third

O, O, SC, IV,

33.1 3.2 7.0 2.3

S SP S SP

O, IV,

3.0 SP 1.5 SP

Third

O. O, IV, IV.

81.8 40.0 38.0 0.8

SMT ST S SMT

O, 17.5 SMT IV, 15.0 S IV. 0.4 SMT

Fourth

O, O, O, IV, IV,

15.0 2.4 21.0 14.0 2.6

S SMT ST S SMT

O, O, IV, IV,

Fourth

O, O, IS, IV, O,

56.1 S 1.1 SP 1.5 S 0.3 S 5.5 SP

?

IS, SC,

0.4 S 2.8 S

Fourth

O, IS, SC,

0.6 S 0.3 S 2.5 S

Second

IS, IV,

0.2 S 0.~ SC

1/16/40

2/15/40

3/12/40

12/21/39

6/ 2/38 1/29/39 2/12/42 ~Organism found at autopsy. U.R.T. = Upper respiratory tract. T.B. - - Temporal bone. O = Orally. fourth

day

from

which

was

negative

ministration

of meningitis. the

hemolytic

IM = Intramuscularly. IS - - Intrasplnously. IV = Intravenously. Purulent

spinal fluid containing

streptococcus

at this time. of sulfapyridine.

Rapid The

grew

on culture.

improvement

followed

temperature

dropped

6,400 cells was noted Tobey-Ayer

the oral and to normal

S SMT S SMT Na

Never negative

SC = Subcutaneously. R = Rectally. S = Sulfanilamlde.

The

3.5 0.7 2.5 2.5

rectal

test ad-

in less than

forty-eight hours, and the spinal fluid became sterile on the third day. On the eleventh day of treatment, w h e n t h e c e l l c o u n t w a s s t i l l a t h o u s a n d o r so, b u t after four successively negative spinal fluid cultures had been obtained, sulfapyridlne administration was discontinued because the blood leucocyte eount had

HARTMANN

rlIERAPu

ET, AL. :

OTHER

CONCENTRATION (MG. PER 100

SEVERE INFECTIONS

IN

INFANTS

AND CHILDREN

THERAPY

RANGE c.c,)

MASTOID-

]

SPINAL

DAY!

DAY O F TREATMENT WITH SULFON-

SIDE

4.9

0

-

-

to 18.5

-

0

to 21

0

to 13.7 3.1 to 11.2!

4.6 to 19.2

4

to 10

2

to

20

N, 3 -

6.4

0.8 to

1

--I_-

iL

--

7.6

~o.

NO.

POS*

I~EG,

N,'4

Seventh

recurred,

culture

proved

leucopeMa, rose

to

sumed,

At

-

7

I

already

with

the

very

and

the

sterile. the

had

day,

the

spinal

time,

tap

should

recurrence

high

level

temperature

R

I,+

Fifteenth

+

~hird

40

R

I,+

First

+

irst

28

R

Second

+

ixth

126

R

~cond

20

R

29

D

-

C,+

Second

+

9

-

I,+

Never negative

+

0

1

-

I,

0

1

-

I,+

been

again

fell

41,000.

-

sharply, purulent

could be

of meningitis,

of

+

in amount

showed

especially

D

not

noted

the blood

Sulfapyridine

promptly

to

13/24

+

normal,

for

severa]

days.

On

meningeal

signs

and

fluid be

that

seen

leucocyte and

containing on smear

despite

therapy

- D -

2/24 I D

--Incorrect. R = Recovered. D = Died.

rose

organisms

Never negative

-~

iC.+

reduced

temperature

however,

It

62

Second

]

1 1 0 Na : Sodium salt. N = Needle method. C ~ Correct.

and

this

I irst

I, +

1

symptoms

+

Second

7 i

leucocytes.

Second

I2

1

It

R

2

0

thirteenth

13

I, 0

9

to 3,400.

', .'cond

-

N, 4

20, tile

+

1

1.7 to 12.9 2.8 to 15

3gay

R

0

0

dropped

13

I

2

-

', .~cond

I,+

N,'4

Sulfapyridine. ~ Sulfamethylthiazole. Sulfathlazole. Prontodl.

+

-

0

L AASS T L '' O O SS II T TIVE

LAST POSITIVE

R

7

-

gTA'I

21

0

2

OU'ICOME

PITA

irst

7

-

OF HOS-

+

--First

0

WHEN

C, + First

5

2

CULTURE __ _ _ DAY DAY O F TREATTREk MENT NfEI~ WH~ F I R SgTT[ WHEN

DAY O F TREATMENT

+

4

to 13

SP : SMT ST ~ P =

DAY OF TREATMElgT l WtlEN L A S T :- F I R S T POSITIVE

9

Second

-

--

IX TA

~"~

__

1.i to

FLUID

ECTONIY

I

-107 2.4 to .

59~

7,100 and

a

the

previous

count

promptly

was

repeated

promptly spinal

refluid

596

T H E JOURNAL OF PEDIATRICS

e x a m i n a t i o n c o n t i n u e d to s h o w fluid f r e e o f o r g a n i s m s on s t a i n e d s m e a r s a n d sterile, a n d on :May 28 t h e cell c o u n t d r o p p e d to 136. A f e w d a y s later~ a n irregu l a r l o w - g r a d e t e m p e r a t u r e w a s n o t e d w i t h a n o r m a l blood c o u n t a n d w i t h subs t a n t i a l l y n o r m a l s p i n a l fluid. No c a u s e f o r t h i s f e v e r could be f o u n d , a n d it w a s p r e s u m e d d u e to th~ d r u g , w h i c h w a s t h e n d i s c o n t i n u e d . T h e p r o m p t falI o f t h e t e m p e r a t u r e to n o r m a l s t r o n g l y s u g g e s t e d t h a t t h e f e v e r w a s d u e to d r u g a d m i n istration.

~

I

2~z

P R G ~ z

-

O=~O K U ~ m m ~

,

"5

BmmQmw

>-

Bm~B]

t,~

a

~.~

2

lii i' ..~

b- J , J , I . I

I

ec

/.

.>"

~...

o

~

i'

~o

z5

o..J

0 0 ~ 0 ~ 0 ~ --

...... "14~ -- "~Q|~,WliNV3qN~ / "M ~ - - 3 N IO t "l:JN<:iY.J "1N~ ~.

5

I-~V~IO I--"1~_ 0 "IV.LD3W

Iv~O P~)-

T h e m o s t i n s t r u c t i v e p o i n t s a b o u t t h i s case w e r e t h e f o l l o w i n g : (1) 1VIeningitis d e v e l o p e d t w o m o n t h s a f t e r b i l a t e r a l m a s t o i d e e t o m y i n t h e a b s e n c e of s y m p t o m s or f i n d i n g s i n d i c a t i v e e i t h e r of l a t e r a l s i n u s p h l e b i t i s or of p e t r o s i t i s a n d i n t h e a b s e n c e of a n y a c u t e r e s p i r a t o r y i n f e c t i o n ; (2) r e c u r r e n c e o f m e n i n g i t i s r e s u l t e d a p p a r e n t l y f r o m t h e too e a r l y r e d u c t i o n a n d c o m p l e t e d i s c o n t i n u a t i o n o f s u l f o n a -

H A R T M A N N ET AL. :

SEVERE INFECTIONS IN INFANTS AND CHILDREN

597

mide t h e r a p y w h i c h was prompte.d b y the development of l e u c o p e n i a ; (3) t h e blood l e u c o c y t e c o u n t of 3,400 c e r t a i n l y could n o t be i n t e r p r e t e d a s d u e to d a n g e r o u s b o n e m a r r o w d e p r e s s i o n , s i n c e w i t h t h e r e c u r r e n c e of m e n i n g i t i s j u s t t h r e e d a y s l a t e r t h e l e u c o c y t e c o u n t rose to 41~000; (4) t h e l a s t b o u t o f f e v e r o c c u r r e d w h e n t h e r e w e r e v e r y low c o n c e n t r a t i o n s of s u ] f a p y r i d i n e in t h e blood a n d s p i n a l fluid a n d s i m u l t a n e o u s l y w i t h a c h a n g e f r o m s u l f a p y r i d i n e to s u l f a n i l a m i d e , w h i c h w a s g o i n g to be g i v e n u n t i l we w e r e c e r t a i n t h a t t h e i n f e c t i o n w a s t h o r o u g h l y eradic a t e d a n d d i s a p p e a r e d p r o m p t l y a f t e r c o m p l e t e ',cessation o f d r u g a d m i n i s t r a t i o n . A n o t h e r p o i n t of i n t e r e s t is t h a t w h e n p n e u m o e n c e p h a l o g r a m s w e r e - m a d e j u s t one y e a r l a t e r , on M a y 22, 1940, t h e y w e r e e n t i r e l y n o r m a l a n d t h e i n t e r v a l h i s t o r y w a s in k e e p i n g w i t h c o m p l e t e r e c o v e r y f r o m t h e m e n i n g i t i s w i t h o u t r e s i d u a l d a m a g e of a n y sort.

Follow-Up Examination.--Thls b o y w a s a g a i n s e e n on F e b . 2, 1942, w h e n he w a s 6 y e a r s , 2 m o n t h s old; a l m o s t t h r e e y e a r s a f t e r r e c o v e r y f r o m t h e m e n i n g i t i s . Exc e p t f o r a n a t t a c k of a c u t e c e r v i c a l a d e n i t i s a f e w m o n t h s p r e v i o u s l y , he h a d b e e n well s i n c e d i s c h a r g e f r o m t h e h o s p i t a l . H e w a s in t h e first y e a r of school a n d g e t t i n g a l o n g well. H i s w e i g h t w a s 47 p o u n d s , h i s h e i g h t , 451/2 i n c h e s . T h e p h y s ical e x a m i n a t i o n w a s e n t i r e l y n e g a t i v e . A m e n t a l a p p r a i s a l m a d e b y one of u s ( B . S . I ( . ) w a s as f o l l o w s : T h e child w a s s e e n on Feb. 14, 1942. H e c o o p e r a t e d w i t h v e r y s e r i o u s i n t e r e s t , b u t w a s too s h y to s p e a k s p o n t a n e o u s l y a n d p r e f e r r e d to a n s w e r w i t h a n o d or a s h a k e of t h e h e a d w h e n e v e r t h i s w a s possible. T h e m e n t a l a g e s c o r e in S t a n f o r d - B i n e t ( F o r m M ) w a s 6 y e a r s , 2 m o n t h s , a n d the I.Q., 100. T h e r a n g e was n a r r o w , a n d t h e lowest f a i l u r e s seemed very p o s s i b l y due to s h y n e s s in s p e a k i n g . M i d s c o r e in a s e l e c t i o n of p e r f o r m a n c e t e s t s w a s a b o v e 10 y e a r s ; c u b e i m i t a t i o n s c o r e d a t t h e 12-year level, a n d o n l y t h e m a n i k i n t e s t s c o r e d b e l o w a v e r a g e . T h e d r a w i n g of a m a n e a r n e d a score of 9 y e a r s , 9 months. I t is p r o b a b l e t h a t b e c a u s e of s h y n e s s t h e p a t i e n t f a i l e d to do h i m s e l f f u l l justice where verbal responses were required. It was reported by the mother that school w o r k in t h e first g r a d e w a s s a t i s f a c t o r y , e x c e p t f o r w r i t i n g . CASE 3 ( C h a r t 3 a n d T a b l e I I ) . - - J . M. S., 7 y e a r s of a g e , d e v e l o p e d a n u p p e r r e s p i r a t o r y t r a c t i n f e c t i o n on ~r 13, 1939. T h e l e f t e a r r u p t u r e d s p o n t a n e o u s l y on ~V[arch 16, a n d t e n d a y s l a t e r m e n i n g e a l s y m p t o m s w e r e n o t e d . On t h e f i f t h d a y o f s u c h s y m p t o m s , M a r c h 30, s h e w a s a d m i t t e d to t h e h o s p i t a l . T h e i n i t i a l e x a m i n a t i o n r e v e a l e d t h e f o l l o w i n g : P u r u l e n t s p i n a l fluid w i t h o u t o r g a n i s m s to be s e e n on s m e a r b u t f r o m w h i c h t h e h e m o l y t i c s t r e p t o c o c c u s g r e w on c u l t u r e ; a n e g a t i v e T o b e y - A y e r t e s t , p u r u l e n t d r a i n a g e f r o m t h e l e f t ear, which~ on c u l t u r e , g r e w o u t t h e h e m o l y t i c s t r e p t o c o c c u s ; a n d x - r a y e v i d e n c e of m a s t o i d i t i s on t h a t side. T h e b l o o d c u l t u r e p r o v e d sterile. Treatment was started with a single i n i t i a l s u b c u t a n e o u s dose of s u l f a n i l a m i d e , f o l l o w e d b y a n i n t r a s p i n o u s i n j e c t i o n a n d t h e n w a s c o n t i n u e d a l m o s t e n t i r e l y b y oral a d m i n i s t r a t i o n o f s u l f a p y r i d i n e w i t h t w o m o r e i n j e c t i o n s of s u l f a n i l a m i d e i n t r a s p i n o u s l y on t h e t h i r d a n d f o u r t h d a y s . F r o m C h a r t 3 it m a y be n o t e d t h a t p r o m p t l y f o l l o w i n g t h e i n s t i t u t i o n of c h e m o t h e r a p y t h e t e m p e r a t u r e b e c a m e m u c h l o w e r a n d t h e s p i n a l fluid b e c a m e s t e r i l e a n d r e m a i n e d so. M a s t o i d e e t o m y w a s p e r f o r m e d on t h e d a y a f t e r a d m i s sion, a n d a c o a l e s c e n t t y p e of m a s t o i d i t i s w i t h b o n e n e c r o s i s w a s n o t e d . C u l t u r e s f r o m t h e m a s t o i d p r o v e d sterile. N e i t h e r t h e d u r a n o r t h e l a t e r a l s i n u s w a s exposed during this operation. The temperature remained normal after the fifth day of treatment, which was continued altogether for thirteen days. Cyanosis from m e t h e m o g l o b i n e m i a d e v e l o p e d p r o m p t l y a f t e r t h e i n s t i t u t i o n of e a r l y a n d i n t e n s i v e s u l f a n i l a m i d e a n d s u l f a p y r i d l n e t h e r a p y . On t h e s e c o n d d a y m e t h y l e n e b l u e

59~

THE JOURNAL OF PEDIATRICS

was given intravenously and later orally w i t h good control of methemoglobinemia, which must have been due chiefly to the original dose of sulfanilamide, since subsequent administration of sulfapyridine was not associated with clinically significant degrees of methemoglobinemia.

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FoZlow-Up J~xamination.--This girl was seen again on Feb. 7, 1942, when 10 years, 5 months old, and some three years a f t e r recovery from the a t t a c k of meningitis. Her parents stated t h a t she had r e t u r n e d to school shortly a f t e r her discharge from the hospital and t h a t her teacher expressed herself as feeling t h a t the girl behaved just as she had before her illness. During the w i n t e r following discharge f r o m the hospital, there was again purulent drainage from both ears. Subsequently she remained healthy. Physical examination was negative, l~[ental appraisal by one of us (B. S. I<.) was as follows: This girl was seea Feb. 9~ 1942; at t h a t time she was in the fifth grade. She cooperated willingly and seemed fully self-confident.

~IART~VIANI~ ET AL. :

599

SEVERE INFECTIONS IN INFANTS AND CHILDREN

The Stanford-Binet examination (Form L) showed a mental age of 13 years, 8 months, and an I.Q. of 131. There was some scatter, with lowest failures in similarities, in interpreting a picture, and in constructive visual imagination, and best work in reversed digits, in the code ~est, and in arithmetic reasoning. Performance work scored at the same level as the Binet. lVs dexterity was no more than average, and cube imitation scored at 15 years. The Goodenough, scoring at 13 years, 3 months, was a normal adolescent drawing, well proportioned and well executed.

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CASK ~t ( C h a r t s 4A a n d 4B and Table I I ) . - - C . W. was a S-year-old boy ~vheu a d m i t t e d . A p p a r e n t l y he h a d h a d his iirst resph'ato~'y i n f e c t i o n , a r h i n i t i s , at 1 y e a r o f age, a n d h i s a d e n o i d s h a d b e e n r e m o v e d a t 2 y e a r s o f a g e b e c a u s e of r e p e a t e d colds. On Oct. 16, 1940, he a g a i n d e v e l o p e d am a c u t e u p p e r r e s p i r a t o r y t r a c t i n f e c t i o n a n d b e c a m e v e r y i l l . lV[eningea] s y m p t o m s a p p e a r e d on Oct. 20.

600

THE JOURNAL OF PEDIATRICS

Admission to the hospital occurred on Oct. 24, the fifth day of meningitis. The initial examination revealed an extremely ill boy whose spinal fluid was purulent, the smear showing many gram-positive dip]ococci iz~ short chains. I t could not be certain f r o m this smear whether these organisms were streptococci or pneumococci. The Tobey-Ayer test at this time was negative. I a addition to the meningitis,

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there was a severe generalized upper respiratory t r a c t infection w i t h tonsillitis and sinusitis. The ears, however, were almost normal in appearance. There was also pericarditis with pericardial effusion (Fig. ]). Cultures from throat, blood, and spinal fluid on admission grew out hemolytic streptococci. The pericardia] fluid, however, proved sterile, even though purulent.

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pyridlne which was changed to sulfanilamide the following, day when the cultures revealed the presence of hemolytic streptococci. At this stage in our experience we f e l t as others did at the time, t h a t perhaps sulfanilamide was without question the drug of choice f o r hemolytic streptococcal infections, an idea which now is no longer tenable. I t is to be noted t h a t promptly a f t e r the administration of sodium sulfapyridine the temperature dropped critlca]ly, almost to normal, and although the spinal fluid cell count increased, the numbe$' of organisms on smear diminished and even on the second tap the culture already was sterile and continued to remain so. The blood culture remained positive until the tblrd day. A f t e r substitution of sulfanilamide for su]fapyridine therapy, the spinal fluid cell count continued to diminish until a low count of 140 was noted on Nov. 1, the ninth day of t r e a t m e n t . Throughout this period of sulfanilamide therapy, however, the temperature continued gradually to mount, and the blood leucocyte counts remained at a very high level. The sulfanilamide was administered b y the continuous intravenous injection method along with dextrose and l a c t a t e - R i n g e r ' s solution.

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On the f o u r t h and fifth days of t r e a t m e n t blood drug concentrations of approximately 20 rag. per 100 c.e. were obtained w i t h ahnost as high spinal fluid concentrations. Because of the rising temperature with falling cell count in the spinal fluid, which continued to remain sterile, drug f e v e r was thought possible, and the dosage of sulfanilamide was gradually reduced until on the eleventh day of treatment the blood concentration fell Mmost to zero. On this day, Nov. 3, the temperature rose sharply, meningeal signs and symptoms again appeared, and a spinal tap revealed purulent fluid with two thousand cells. Organisms, however, could not be seen on smear nor could they be cultured. Sulfapyridine therapy was then resumed, the drug being given orally this time with v e r y prompt control of the f e v e r and w i t h rapid clearing of the spinal fluid. The dosage of the drug was cut in h a l f when the t e m p e r a t u r e had been normal for a p p r o x i m a t e l y five days and when the spinal fluid cell count had reached 34. Shortly a f t e r w a r d s the temperature again mounted with, however, a continued low cell count of the spinal fluid. Drug fever was again thought possible, and sulfapyridine administration was discontinued completely. There followed still higher fever, so su]fapyridlne t h e r a p y

602

TtIE JOURNAL OF PEDIATRICS

w a s a g a i n resmned. The t e m p e r a t u r e them fell p r o m p t l y to a lower level b u t did not reach normal. On the f o r t i e t h d a y d r u g a d m i n i s t r a t i o n was a g a i n discont i n u e d a n d a g a i n a h i g h e r t e m p e r a t u r e p r o m p t l y followed, w h i c h a g a i n r e t u r n e d to a lower level w i t h r e s u m p t i o n of s u l f a p y r i d i n e a d m i n i s t r a t i o n on the fortyf o u r t h day. The d r u g w a s d i s e o n t i n u e d f o r good on the fifty-third day, a f t e r w h i c h t h e t e m p e r a t u r e r e m a i n e d normal or v e r y s l i g h t l y e l e v a t e d w i t h t h e exception of one single spike on Dec. 17, t h e r e s u l t of a t r a n s f u s i o n reaction. B y Nov. 15 the perieardial effusion h a d completely disappeared, and a normal eardiae silh o u e t t e w a s noted (Fig. 1). A t no t i m e were t h e ears definitely involved, and m a s t o i d i t i s seemed not to be considered as a probable portal of e n t r y for the meni n g i t i s i n t h i s ease. S i m u l t a n e o u s l y w i t h t h e r e c o v e r y f r o m m e n i n g i t i s a n d perieardltis, tonsillitis and sinusitis also subsided. On Nov. 11 all the sinuses seemed clear in t h e c o n v e n t i o n a l x - r a y film, b u t l a m i n a g r a m s showed cloudiness still of the r i g h t posterior ethmoid eells. We f e l t t h a t t h e e o n t i n u e d low-grade fever, w h i c h would so s t r i k i n g l y increase w h e n s u l f a p y r i d i n e t h e r a p y was d i s c o n t i n u e d a n d d i s a p p e a r w i t h r e s u m p t i o n of sueh t r e a t m e n t , was due either to t h i s residual e t h m o i d i t i s or to some residual poeketed m e n i n g i t i s w i t h good walling off b u t c a u s i n g still a c o n t i n u e d slight i n c r e a s e in cells in the spinal fluid.

Follow-Up Examination.--This boy was seen oll J a n . 31, 1942, a little more t h a n a y e a r a f t e r r e c o v e r y f r o m the m e n i n g i t i s , a n d w h e n he was 4 years, 4 m o n t h s old. A c c o r d i n g to his f a t h e r , there were no signs or s y m p t o m s related to the c e n t r a l n e r v o u s s y s t e m d u r i n g t h e i n t e r v a l . He was, however, s u b j e c t to "co l d s" a n d h a d h a d one a t t a c k of sore t h r o a t w i t h fever. He w e i g h e d 391& p o u n d s and w a s 42aA inches tail. On p h y s i c a l e x a m i n a t i o n , large, chronically i n f e c t e d tonsils were f o u n d . There w a s st~ll t h e s t r a b i s m u s due to t h e w e a k n e s s of t h e l e f t sixth i n t r a c r a n i a l nerve, which the p a r e n t s h a d s t a t e d w a s p r e s e n t before the involvem e n t of t h e m e n i n g e s . Mental appraisal by one of us (]3. S. K.) was as follows: IIe came into the room s o m e w h a t u n w i l l i n g l y as he w a s tired f r o m a l o n g wait. IIe w a s overactive, a n d a t t i m e s p l a y f u l l y negative~ a t t e n t i o n s p a n w a s r e l a t i v e l y short. The S t a n f o r d - B i n e t e x a m i n a t i o n showed a m e n t a l age of 3 years, 11 m o n t h s and an I.Q. of 90. The patient did best at tasks t h a t could be grasped and earried out at once, b u t was less successful where prolonged effort was needed. P e r f o r m a n c e work w a s average. There w a s no lack of u n i f o r m i t y in the examin a t i o n w h i c h could not be t r a e e d to r e s t l e s s n e s s a n d v a r y i n g a t t e n t i o n . CASE 5 ( C h a r t 5 a n d Table I I ) . - - T h i s girl, V. B., was b u t 6 weeks of age w h e n a d m i t t e d to the h o s p i t a l on Dee. 25, 1939. F e v e r a n d i r r i t a b i l i t y h a d been p r e s e n t f o r t w e l v e hours a n d convulsions for f o u r hours prior to admission. I n i t i a l exa m l n a t i o n revealed a b s o l u t e l y n o t h i n g other t h a n m e n i n g e a l signs a n d s y m p t o m s . The spinal fluid w a s p u r u l e n t , a n d o r g a n i s m s were seen on s m e a r for t h e first three days, d u r i n g which time t h e y also grew on eu!ture. C h e m o t h e r a p y w a s b e g u n w i t h an i n t r a v e n o u s i n j e c t i o n of sodium s u l f a p y r i d i n e , followed b y i n t r a s p i n a l a n d t h e n oral a d m i n i s t r a t i o n of s u l f a n i l a m i d e . Combined s u l f a p y r i d i n e a n d sulf a n i l a m i d e t r e a t m e n t w a s c o n t i n u e d on t h e second a n d t h i r d days. As in all p r e v i o u s cases, p r o m p t initial f a l l in t e m p e r a t u r e w a s noted. D u r i n g this period t h e s p i n a l fluid first i n c r e a s e d in cell count a n d t h e n showed a p r o m p t d i m i n u t i o n in t h e n u m b e r of cetts. A r e t u r n of f e v e r w a s n o t e d w h i c h r e m a i n e d low grade f r o m t h e f o u r t h to t h e t h i r t e e n t h day, w h e n s u l f a n i l a m i d e only w a s b e i n g administered, a n d w h e n spinal fluid c o n c e n t r a t i o n s of t h e d r u g a v e r a g e d less t h a n 8 rag. per 100 c.c. D u r i n g t h i s time, a l t h o u g h t h e spinal fluid r e m a i n e d sterile a n d without o r g a n i s m s to be seen on smear, an a b n o r m a l l y h i g h cell count, a v e r a g i n g more t h a n 300 per cubic millimeter, w a s c o n s t a n t l y noted. On the t h i r t e e n t h d a y the c o n c e n t r a t i o n of s u l f a n i l a m i d e in the spinal fluid dropped to less t h a n 4 rag. per 100 c.c. The t e m p e r a t u r e rose sharply, m e n i n g e a l signs reappeared, the spinal

HARTMANN ET AL. :

fluid again became turbid and for on smear although t h e y would not then doubled f r o m the f o u r t e e n t h the t e m p e r a t u r e again was slowly

--

603

SEVERE INFECTIONS IN INFANTS AND CHILDREN

the next four days continued to show organisms grow on culture. The dose of sulfanilamide was through the twenty-first day of t r e a t ~ e a t ; and brought under control and the spinal fluid grad-

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trolly c l e a r e d , and the organisms disappeared entirely. During this period the spinal fluid sult'anilamide concentrations averaged about 10 rag, per 100 c.e. F e v e r p e r s i s t e d from the twenty-second to the t w e n t y - s l x t h day of t r e a t m e n t despite 6lear spinal fluid w i t h relatively few cells. Because of this, drug fever was suspected and the drug discontinued. The ,temperature t h e n p r o m p t l y fell to normal :and remained so. During the hospital s t a y , the measurements of head cireumfer-

604

THE JOURNAL OF PEDIATRICS

ence remained normal, iNTopneumoeneephalograms, however~ were made. As mentioned previously, nothing at all was noted which would suggest a portal of e n t r y for the meningitis. As in previous instances when sulfanilamide and snlfapyridine were used, considerable cyauosis due to methemoglobinemia developed and was controlled b y the administration of methylene blue from time to time. Also, as in previous cases, anemia was never p e r m i t t e d to develop to any dangerous degree, normal red counts and hemoglobin values being maintained b y suitable transfusions. I n this patient, a s in the patients in Cases 2 and 4, it was very difficult to determine just when it was safe to discontinue chemotherapy.

Follow-Up Examination.~--This girl was seen again on ~[arch 10, 1942, more than two years a f t e r recovery from the meningitis which had developed when she was only 6 weeks old. The parents stated t h a t she had had some difficulty in sleeping for a while a f t e r returning home and then seemed perfectly normal and bright and w i t h good muscular coordination. Physical examination was negative except for enamel defect usually described as ~'hereditary opalescent d e n t i n e . " k'gental appraisal by one of us ( B . S . K . ) was as follows: P a t i e n t was seen w h e n she was 2 years, 4 ~mnths old. Because of her extreme shyness which made it difficult to elicit spoken responses, the I.Q. of 100 (Stanford-Bluet, Form M) was eonss to be minimal. That the rating was at least average suggested that no impairment of intellectual function was present. CASE 6 (Chart 6 and Table I I ) . - - J . It., a 5-year-old boy, complained of pain in his left ear eight days before admission to the h o s p i t a l The ear ruptured two days later, and two days before admission he developed headache and stiff neck. He received his first sulfonamide drug on the second day of meningeal symptoms, 1.5 Gin. sulfapyridine by mouth. When admitted on the third day of meningitis, on Jan. 16, 19~0, the initial examination revealed the fol]owing: Cloudy spinal fluid containing, however, only 750 cells; gram-positive cocci were seen on stained smear and when grown proved to be hemolytic streptococci; the blood culture at this time proved to be sterile; the Tobey-Ayer t e s t was at first questionably positive on the left but later proved f r a n k l y negative on four separate occasions; x-ray examination revealed changes characteristic of mastoiditis on the ]eft. T r e a t m e n t was begun with orally administered sulfapyridine and intravenously administered sodium sulfapyridine, and, a f t e r approximately twenty-four hours, sulfanilamide was also given subcutaneously. A f t e r the third day only sulfanilamide was administered, orally and subcutaneously. As in all of the previous cases, a prompt temperature fall was noted almost immediately a f t e r i n s t i t u t i o n of sulfonamide chemotherapy with, however, a later recurrence of fever. Also, as in other instances, when the initial cell count of the spinal fluid was low and organisms numerous, the earliest change was a decrease in the number of organ~sms w i t h increase in the number of leucocytes. As early as on the second day organisms no longer could be seen, and the spinal fluid proved sterile although the leucocyte count of the spinal fluid had risen f r o m 750 to 5,000. On the n i n t h day of the t r e a t m e n t , a f t e r the amount of sulfanilamide administered had been somew h a t reduced and the spinal fluid concentrations, which had averaged close to 9 nag. per ~00 e.e., had fallen to approximately h a l f t h a t level, a sharp rise in temp e r a t u r e was noted with an increase in the cell count of the spinal fluid fro m a low of 27 on Jan. 21, the sixth day of t r e a t m e n t , to 760 on Jan. 24. The dosage of sulfanilamide was then increased to its previous level of 0.3 Gin. per kilogram per day, again with prompt fall in temperature and cell count of the spinal fluid. I r i s to be noted t h a t a f t e r the first day the spinal fluid continued to remain sterile and w i t h o u t visible organisms on smear. Oa the f o u r t e e n t h day of su]fonamide t r e a t m e n t a l e f t simple mastoidectomy was performed. Mastoid cells were found

HARTMANN ET AL. :

SEVERE INFECTIONS IN INFANTS AND CHILDREN

605

lined w i t h a g r a y pyogenle membrane but were not broken down. Both dura and lateral sinus were quite n o r m a l Fo]lowing this operation the t e m p e r a t u r e gradually returned to n o r m a l On Feb. 8 an x-ray of the petrous pyramid was interpreted a s showing petrositis on the left. The boy was discharged on Feb. ]3, a p p a r e n t l y completely recovered from the meningitis. As in some of the previous cases, f r e q u e n t transfusions had to be given to counteract the t e n d e n c y toward anemia, probably the result both of infection and drug administration. Considerable methylene l~ue had to be given first intravenously and ]ater orally to control methemog]ob~nemia, and at the start os treatment considerable parenteral fluid was required and a d m i n i s t r a t i o n of the drug was largely p a r e n t e r a l during the first few days. Iql40 JANUARY SPINAL FLUID: CELL COUNT S M E A ~(O~C,~NISrt S|

CULTURE

,IG.17.18 .Iq .10.l.I

,l,l .Z3,&4.LS 3 ~'4 D A Y OF M E N I N G I T I S 750 ,~008~0 440 B8 ~.7 I?.0 760 + . . . . 4- -- --

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8.8.C.(nauoNS/C.mll.) 3.7~ 5.7.9 3.80 3.~7 3.80 Ha. r e.e. 14',G I",'~ I~.l I&.O 10.rq,9 t0.O q,& M E T H 8 . GM./100 e.o. 0.0~ I.~. I"IETNEMOGLOBINEMIA PREVENTED BY ORAL AO~INISTRATION OF METN~fLENE. BLUE: EACH 5 ~ . ME.THYLENE BLUE rlG. LV.'50}0RALB90 780585 390 590 780 7807B0 7~50 7c50 ~90 590 3~)0.~q0 TABLET OF 5ULFANILAI~IIDE CONTAINED WHOLE BLOOD LV.C.0. ?.SO 150 100 s 150 175 ~O0 a00 l~r.(65mg.) I'IETHYLEIqE BLUE DEXTROSE lOg( LV.C.C. 150 500 LACTAI'E-RINGER'~ C,0. 400 400 600 800 400 ~.00 qo0 9 MG./10OO.B. AS S U L F A N I L A r l t D E

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CASE JACK H. AGE. ~ YR. PAIN iN LEFT EAR FOR 8 bAYS DRAINAGE. "~ * G HEADACHE, $'t'IPF NECK " PRECEIVE0 FIRST SULFONAMID~ ON ~nd DAY Of" I'IIrNINGITIS-1.5 Grl, 5ULFAPYRIBINE O R A L L Y

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Chart 6.

Follow-Up Examgnation.--Thls boy was again seen on Jan. 31, 194:2, two years a f t e r recovery from the meningitis. His parents stated t h a t he had been quite well since returning home, but t h a t he seemed a little " n e r v o u s ' ~ and fidgety the first year. t i e weighed 40a~ pounds, and was 461A inches tall. During tl:o physical examlnatlon~ which was otherwise entirely negativ% be seemed apprehensive and blinked his eyes frequently. ~V[ental appraisal b y one of us (B. S. K,e) was as follows: W h e n seeu on the same dat% the p a t i e u t was 7 year% 1 month old and in the second grade. ~ e co-

606

THE JOURNAL OF PEDIATRICS

operated willingly but was not at ease and b a t t e d his eyes a good deal. He worked cautiously, but answered readily and expressed himself well. The Stanford-Bluet examination (Form L) yielded a mental age of 6 years, 10 months. P e r f o r m a n c e work scored at the same level, but the Gdodenough drawing r a t e d nearly a year higher. While no serious i n t e r f e r e n c e w i t h effort was manifest, the f a c t t h a t the p a t i e n t was doing acceptable work in the second grade suggested the possibility t h a t he had failed to do himself full justice in this examination. CASE 7 (Chart 7 and Table I I ) . - - T h i s 7-year-old boy, J. IV[., developed a generalized acute upper respiratory infection on Feb. 11, 1940, which included bilateral otltis media. J u s t two days later meningeal symptoms began and admission to the hospital occurred on the t h i r d day of meningitis, Feb. 15, 1940. The initial examination revealed a very seriously and acutely ill boy with spinal fluid literally teeming w i t h streptococci, proved l a t e r on culture to be hemolytic. Cell count of this initial tap was, only 380. The Tobey-Ayer test was already positive on the r i g h t side, and the blood culture proved also to be positive on the day of admission. Treatment was started with a single dose of sodium sulfamethylthiazole followed b y sulfamethylthiazole given orally. F r o m the second through the fourt e e n t h day of sulfonamide t r e a t m e n t , both sulfamethylthiazole and sulfanilamide were administered, the total dosage averaging about 0.4 Gin. per kilogram of body weight per day. The temperature fell steadily a f t e r the beginning of treatment, and the boy showed gradual improvement. While organisms could not be seen in the spinal fluid on the second day and t h e r e a f t e r , t h e y continued to grow on culture for the first six days, a f t e r which the spinal fluid continued to be sterile. As in previous cases of a similar nature, i m m e d i a t e l y a f t e r t r e a t m e n t the spinal fluid cell count rose as the number of organisms diminished, and then f e l l On the s e v e n t h day of sulfonamlde t r e a t m e n t , a f t e r the blood culture had been sterile for five days, and on the first day of sterile spinal fluid, ]igatlon of the right internal jugular vein was made, and t h e n a right .simple mastoldectomy was performed with exposure and incision of the lateral sinus. /Kastoid cells everywhere were found involved; granulations spread over the knee of the lateral sinus, and, where exposed, the dura was found red and thickened. The tempe~.ature then slowly r e t u r n e d toward normal. The spinal fluid continued to show some increase in cell count but remained without organisms to be seen, and always sterile, findings possibly to be explained by some remaining pocket of infection. Strabismus and dilated pupils were the only neurologic findings suggestive of continued central nervous system involvement. As in the previous cases, there was need for considerable supportive t r e a t m e n t , especially early in the course of the infection, and for about t h i r t e e n days fluid was given by the continuous intravenous injection method , consisting of dextrose and l a c t a t e - R i n g e r ' s solution to which s u l f a n i l a m i d e was added for the total sulfanilamide administration during this period. For the first four days continuous spinal fluid drainage was also effected. The spinal fluid concentrations averaged about 7 rag. per 100 c.c. during the period when organisms continued to be grown on culture. Also, as in the p a t i e n t s in some of the previous cases, a t r a n s i e n t leucopenia was noted, the blood count dropping from 23,500 on Feb. 16 to 6,400 on Feb. 19. The dosage of the drug, however, was not reduced, and on Feb. 21 the count doubled. On April 6 the tonsils and adenoids were removed, and on April 17 he was t r a n s f e r r e d to Ridge F a r m , our country convalescent department, to complete his recovery. He was finally discharged from the hospital on June 19, 1940, completely recovered except for a dilated and fixed right pupil.

Follow-bVp l~xamination.--This boy was again examined on Jan. 31, 1942, app r o x i m a t e l y t~vo years a f t e r recovery from the meningitis. His parents stated

HARTMANN ]~T AL. :

SEVEI~E INFECTIONS I N INI~'ANTS AND CHILDREN

607

t h a t he had b e e n q u i t e n o r m a l since r e t u r n i n g home. H i s w e i g h t w a s 5 0 ~ p o u n d s , and his h e i g h t , 5 0 ~ inches. The r i g h t p u p i l w a s d i l a t e d a n d fixed, b u t no o t h e r p h y s i c a l a b n o r r a a ] i t i e s w e r e noted.

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M e n t a l a p p r a i s a l b y one of us ( B . S . K . ) w a s as f o l l o w s : W h e n seen on Feb. 11, 1942~ t h e p a t i e n t w a s 9 y e a r s , 10 m o n t h s old a n d in the l a s t q u a r t e r of the second grade. E f f o r t and a t t e n t i o n w e r e f a i r , Sad he g o t some p l e a s u r e f r o m the t a s k s , b u t to some e x t e n t r e s t l e s s n e s s i n t e r f e r e d w i t h a t t e n t i o n . P a t i e n t w a s unable to say the sound of sh, and had to s u b s t i t u t e the sound of s. T h e S t a n f o r d - B i n e t e x a m i n a t i o n ( F o r m L ) yielded ~ m e n t a l age of 7 years, 2 months, and an I.Q. of 73, with a r a n g e of f o u r years. W h e n asked fez'

608

THE

JOURNAL

OF PEDIATIgICS

s i m i l a r i t i e s , p a t i e n t s e e m e d able to g i v e o n l y color d i f f e r e n c e s ; he f a i l e d i n det e c t i n g p i c t u r e d a b s u r d i t i e s a n d in c o m p r e h e n s i o n . I~est w o r k w a s in c o n s t r u c t i v e visual imagination and in making change. Performance work was variable; the f o r m b o a r d w o r k w a s g e n e r a l l y h i g h a v e r a g e , b u t t h e m a n i k i n scored a t 5 y e a r s , and the cube imitation and Healy Picture Completion I at the Bluet level T h e p a t i e n t is r e p o r t e d to be g e t t i n g a l o n g well in a g r a d e a b o u t two y e a r s b e l o w e x p e c t e d p l a c e m e n t . T h e l a c k of u n i f o r m i t y in scores in d i f f e r e n t t y p e s of a b i l i t y m a y be g r e a t e r t h a n w o u l d be a c c o u n t e d f o r b y r e s t l e s s n e s s a n d s u p e r ficial a t t e n t i o n , a n d it is p o s s i b l e t h a t t h e r a t i n g s a r e n o t r e p r e s e n t a t i v e of original intellectual endowment. I ~40 MARCH SPINAL FLUID: CELL COUNT SMEAR (ORGAN~MS)

112113114115116117 l l S [ l ~ t 2 0 I ~ 1 2 2 t 2 3 1 2 4 1 2 5 ~ 2 6 1 2 7 1 2 8 ~ 2 ~ 130~ 4 ~ DAY E~lO03600 ~ 1240 8~0 450 580 150 200 I~,0 I00 70

'

CULTURE BLOOD:

CULTUt~E LEUCOCY'T ES

~1600 HSCO " 185(}0 170aOi2900 74~ CONT. I.V, DRiP ~ IOY.GLUCOSE & LACTATE-RINGER'S + I~'.SULF~N%LAMIDE r COMTINUOU$SPINAL FLUIDD~AINA6E "~ ~" X- RAY. BtLATERA L BOTH EAR DRUMS MAS"T01DITI$-,~(?) P[RI'3INU5 AB$CE$5 THICK ANb D U L L I It NEG.QUEC K'T X-RAY. (f~ LT. PE TROS|TI,5

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RI~. (MILLIONS) Hll. G N S . / % 0 ~ c-,..

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6.2:

II.0

METHB. GM$./IOOc.c._ V/HOLE BLOOD I.V. cc. ~ 5 0 Z~O METHYLENE BLUE t.V. MGS. ~ 20 LACTATE -RINGER'S ,~0 600 810 800 10ZS 750 595 DEXTROSE %0X r162 2~0 700 ~0 800 IO25 750 595

M6S •

CASE ROBERT H. HEMO.STREP. MENINGITIS AGe" GYR..

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HUMPS 4U 89 PREVIOUSLY HEADACHE 3~,/K. MENINGEAL SYM PTOrl5 ~V0rlITiNG FE'~',/ER STWF NECK) ~E,GAN 3-r

6 3 4 3 2 I

N Chart 8.

CASE 8 ( C h a r t $ a n d T a b l e I Z ) . - - - T h i s 6-year-o[d frequent attacks of otitis media with spontaneous 15~ 1939. Some four weeks prior to admission, on mumps~ c o m p l a i n e d of h e a d a c h e s a w e e k l a t e r , a n d

boy, R.H., rupture of ]Vlareh ]2, developed

h~ul t h e histo.ry of the drums on Dec. 1940~ he developed clear-cut meningeal

HARTMANN ET AL. :

SEVERE INFECTIONS IN INFANTS AND CI~ILDREN 609

symptoms w i t h vomiting, high fever~ and stiff neck on ~iarch 9. On admission he was in his fourth day of meningitis, thought at first possibly to be due to mumps. The initial examination, however, revealed purulent spinal fluid with organisms seen and grown as hemolytic streptococci. T r e a t m e n t was s t a r t e d as sodium sulfamethy]thiazole intravenously, followed by su]famethylthiazo]e orally and sulfanilamide orally and intravenously. Spinal fluid smears and cultures persisted positive on the second day, but t h e r e a f t e r were negative. Spinal fluid cell counts first rose and then diminished rapidly:# The t e m p e r a t u r e fell sharply initially, and t h e n continued to decline at a less rapid rate. On a d m i s s i o n both eardrums were i n t a c t but somewhat thick and dull, and a little later x-ray examination was i n t e r p r e t e d as revealing bilateral mastoiditis with a questionable perisinus abscess on the l e f t side. The Tobey-Ayer test, however, was f r a n k l y negative. L a t e r another x-ray examination was interpreted as revealing questionable petrositis on the l e f t side. Early in the course of the infection continued spinal fluid drainage by the needle method was employed, and fluid was given by a cbntinued intravenous injection method, which included a d m i n i s t r a t i o n of sulfanilamlde. Also, a number of transfusions were given, and on two occasions methylene blue had to be given to control methemoglobinemia. Spinal fluid concentrations of sulfonamide averaged about 10 to 12 nag. per 100 c.c. while both drugs were administered and t h e n fell sharply to very low levels when only sulfathiazole was given. By this time, however, the infection seemed well under control. Because of the minimal involvement of the ears, it was the opinion of members of the d e p a r t m e n t of otolaryngo]ogy, and we agreed, t h a t m a s t o i d e c t o m y was not necessary unless f u r t h e r trouble developed which could be a t t r i b u t e d to middle ear a n d mastoid infection. REPORT OF FATAL CASES CASE 9 (Chart 9 and Table I I ) . - - T h i s boy, C. C., 6 months old when admitted, developed an acute upper respiratory i n f e c t i o n about one month prior to admission with drainage from one ear, exactly which side was not remembered. About one month later, on Dec. 17, 1939, signs of acute upper r e s p i r a t o r y infection were again noted, and the next day, Dec. 18, meningeal symptoms developed. He was a d m i t t e d to the hospital on Dec. 21, the f o u r t h day of meningitis. The initial examination revealed purulent spinal fluid containing a great many organisms seen on smear and on culture, proving to be the hemolytic streptococci. Throughout the whole course of this disease the spinal fluid continued to be grossly purulent, finally becoming so thick t h a t an accurate cell count could not be made; it continued also to teem with viable organisms. A f t e r approximately twenty-four hours of t r e a t m e n t w i t h sulfapyridine alone, given both intravenously as the sodium salt and orally, t r e a t m e n t was continued as sulfapyridine administered intravenously and sulfanilamide orally and intraspinously. Despite an early promising t e m p e r a t u r e fall to normal with a subnormal t e m p e r a t u r e persisting for approximately four days, no other signs of improvement were noted, and a f t e r the fifth day of t r e a t m e n t f e v e r was continuous until shortly before death on Jan. 17, 1940. During the first fifteen days of treatment, spinal fluid concentrations never exceeded 8 rag. per 100 c.c. Later, w i t h increased drug dosage, somewhat higher levels were obtained but never higher than 15 rag. per 100 c.c. At autopsy extensive brain involvement was noted as described in the following pathologic report by Dr. W. O. Russell, of the Department of Pathology: The dura was adherent to the underlying ]eptomenlnges in several places, and when it was sectioned, a large amoun~ of purulent fluid containing fibrin was revealed. Both cerebral hemispheres were of softer consistency t h a n normal, and there was p u r u l e n t material ia the ventricles. The meningitis was quite marked also at the base of the brain, but here the nervous tissue was of normal con-

610

THE JOURNAL OF PEDIATRICS

sistency. There w a s t h i c k e x u d a t e over the whole of the b r a i n surface. Grossly~ the a i r cells of b o t h m a s t o i d s were observed to c o n t a i n p u r u l e n t exudate, a n d there Was e x u d a t e i n the middle ears. Post-mortem otorhinologic report by D. Wolff: Severe bilateral chronic purulent otitis med~a~ mastoiditis~ a n d ] a b y r i n t h i t i s were p r e s e n t (Figs. 2 a n d 3). g I .LIO 10~ 3Hcl g~g I .L|gO~.L3d ' ; l i f o lOig~W ' V l O 3 U ~ ; l l l i 0 3^l.LVWflddn~;

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Direct e x t e n s i o n of pus into b o t h l a b y r i n t h s occurred t h r o u g h t h e f o o t p l a t e s ~f the s t a p e s (Fig. 6), t h r o u g h the r o u n d window m e m b r a n e s (Fig. 4), and b y ero,sion of the b o n y wails into b o t h horizontal canals, as i l l u s t r a t e d for t h e left: i m F i g , ~ . There w a s erosion of t h e posterior canal l e a d i n g f r o m the pus-filled l a b y r i n t h on

HARTMANN ET AL. :

SEVERE INFECTIONS I N INFANTS AND CHILDREN

6]]

t h e r i g h t to t h e d u r a ( F i g . 5). The d u c t u s e n d o l y m p h a t i c u s on e a c h s i d e w a s l a d e n w i t h pus. M a r r o w i n t h e p e t r o u s a p e x w a s h y p e r a c t i v e a n d t h e cells dist o r t e d i n s h a p e . A m i n u t e p a t h o l o g i c d e h i s c e n c e w a s also seen f r o m t h e nose, ext e n d i n g ~ n t r a e r a n i a l w a r d n e a r t h e c r i b r i f o r m p l a t e ( F i g . 8).

Fig. 2 (Case 9 - - 8 4 9 5 ) . - - H o r i z o n t a l section of r i g h t ear, s h o w i n g pus in m a s t o i d a n t r u m , middle ear, l a b y r i n t h , and i n t e r n a l a u d i t o r y meatus. The a r r o w in the vestibule p o i n t s to the oval w i n d o w t h r o u g h which direct e x t e n s i o n from the middle ear occurred. See h i g h p o w e r (Fig. 6).

Fig. 3 (Case 9 - - 8 4 9 5 ) . - - I - I o r ~ z o n t a l section of left ear. The m a s t o i d a n t r u m and a d i t u s on this side e x h i b i t a more chronic s t a t e as evidenced by the web of fibrous tissue b i n d i n g s u b m u c o s a of the a n t r u m w i t h m a l l e o - i n c u d a l joint. CASE 10 ( C h a r t J u l y 2, 1938~ i n a mission and after taneously. There

9 a n d T a b l e I I ) . - - T h l s 6 - y e a r - o l d girl~ P . B . , w a s a d m i t t e d on m o r i b u n d eondition~ d y i n g a p p r o x i m a t e l y f o u r h o u r s a f t e r adb u t a s i n g l e dose of s u l f a n i l a m i d e c o u l d be a d m i n i s t e r e d subcuw a s a h i s t o r y of a d r a i n i n g ] e f t e a r f o r one m o n t h , d r o w s i n e s s

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f o r one w e e k , and c o n v u l s i o n s f o r t w e l v e h o u r s p r i o r to admission. A s p i n a l t a p m a d e i m m e d i a t e l y a f t e r admission r e v e a l e d e x t r e m e l y cloudy fluid w i t h too m a n y l e u c o c y t e s to be c o u n t e d a c c u r a t e l y a n d w i t h m u c h fibrin. The blood leucocyte c o u n t w a s e x t r e m e l y high, b e i n g 48,500. A t a u t o p s y it w a s f o u n d t h a t a b r a i n a b s c e s s h a d r u p t u r e d into t h e v e n t r i c l e , and t h i s a b s c e s s h a d a p p a r e n t l y developed

l~ig. 4 (Case 9--8495).--Horizontal section of left ear at the level of round window which is completely eroded and offers a route of direct extension from middle ear to labyrinth.

Fig. 5 (Case 9--8495).--Horizontal section of the left ear, showing the unclosed bony

facial canal

at the level of the oval window

and

the marked

pathologic

erosion

of the nonampullated limb of the horizontal canal as it r e t u r n s to the vestibule. fistula from posterior canal to dura.

Note

as a r e s u l t of erosion of t h e g r e a t e r w i n g of the sphenoid. T h e r e w a s also f o u n d a chronic l e f t otitis media and mastoi,ditis. A r e p o r t of the general pathologic findings b y Dr. J. tt. Wedig, D e p a r t m e n t of Pathology, is as follows: A filmy exudate was present about the base of the brain. The posterior t i p of the g r e a t e r

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w i n g of the l e f t s p h e n o i d bone showed an erosion a b o u t 1 era. in d i a m e t e r . The b r a i n o v e r t h i s a r e a s h o w e d a r o u n d s o f t d e m a r c a t e d a r e a w h i c h on c u t seetlon revealed a left cerebral abscess moderately encapsulated and extending into the ventricle. Abscess and ventricle contained purulent exudate.

Fig. 6 (Case 9 - - 8 4 9 5 ) . - - D e t a i l of Fig. 2, s h o w i n g a mere f r a g m e n t of f o o t p l a t e of s t a p e s r e m a i n i n g in the oval window.

Fig. 7 (Case 9 - - 8 4 9 5 ) . - - D e t a i l of Fig. 5, s h o w i n g the unclosed f a c i a l c a n a l (a norm a l s t a t e for t h i s 6-month-old i n f a n t ) and the m a r k e d p a t h o l o g i c erosion of the bony w a l l of the h o r i z o n t a l canal. P o s t - m o r t e m otologic r e p o r t by D. W o l f f :

Gross e x a m i n a t i o n of the p e t r o s a e at

a u t o p s y r e v e a l e d t h e p r e s e n c e of u n u s u a l l y l a r g e s u p e r i o r p e t r o s a l s i n u s e s on e a c h side, a n d e a c h of t h e s e t o o k a m o r e e x p o s e d a n d l a t e r a l c o u r s e t h a n u s u a I b e f o r e e n t e r i n g t h e c a v e r n o u s sinus. T h e r e w a s f r e e flow of b l o o d f r o m t h e s i n u s e s . On t h e l e f t a d a r k s p o t w a s seen on t h e s u r f a c e of t h e d u r a o v e r t h e l e f t m a s t o i d p o r t i o n of t h e t e m p o r a l bone, p o s t e r i o r to t h e a r c u a t e e m i n e n c e . 3/iicroscopie e x a m i n a t i o n r e v e a l e d a h e a v i l y i n f e c t e d m a s t o i d , m i d d l e e a r ( F i g . 10), a n d eust a c h i a n tube. T h e d r u m m e m b r a n e was n o t r e m a r k a b l y thickened~ b u t b o t h mucosal

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a n d e p i d e r m a l l a y e r s w e r e s l o u g h e d off in pus. D i r e c t e x t e n s i o n of i n f e c t i o n f r o m t h r o u g h p a t h o l o g i c dehiscenees of bone c r a n i a l a n d the p o s t e r i o r c r a n i a l f o s s a e

areas. P r u s s a k ' s p o u c h w a s laden w i t h a pus-filled angle cell in t h e m a s t o i d could be t r a c e d into b o t h t h e middle (Fig. 9). The dehiscence t h r o u g h the

Fig. 8 (Case 9--8495).--Pathologic dehiscences f r o m the nasal cavity t h r o u g h the eribriform plate intraeranialward.

Fig. 9 (Case 10--7516).--Vertical section t h r o u g h left mastoid, showing direct extension superiorly into the middle fossa and postero-inferiorly into the posterior fossa. t e g m e n a n t r i into the middle f o s s a w a s 2 n~m. in l e n g t h a n d f r o m 2 to 5 ram. in w i d t h . O v e r t h i s lay h e a v i l y i n f e c t e d dura. T h e i n t e r n a l c a r o t i d a r t e r y in this p e t r o s a c o n t a i n e d a blue s t a i n i n g e x u d a t % a n d c l u m p e d in the u p p e r b o r d e r w e r e

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w h a t a p p e a r e d to be b a d l y d i s t o r t e d r e d b l o o d c e l l s . T h i s c o n d i t i o n s u g g e s t e d a v a s c u l a r b l o c k i n s o m e portio~! of t h i s a r t e r y . M a r r o w c e l l s i n t h e a p e x of t h e p e t r o s a a p p e a r e d S h r u n k e n a n d c r e n a t e d . Tho e n d o r g a n s of t h e i n n e r e a r s h e w e d

:Fig. 10 (Case 1 0 - - 7 5 1 6 ) . - - V e r t i c a l section t h r o u g h the middle e a r and v~stibule. Note t h e t h i c k e n e d m u c o s a over the p r o m o n t o r y a n d the s t r a n d s of e i e a t r i c i a l tissue extending' across the middle ear.

:Fig. 11 (Case l l - - 7 9 2 1 ) . - - H o r i z o n t a l section of the r i g h t ear, s h o w i n g long flmbria p r o j e c t i n g into the e u s t a c h i a n tube. a t r o p h i c d e g e n e r a t i o n . A f e w f r e e b l o o d cells w e r e s e e n i n t h e s c a l a t y m p a n i . T h e r i g h t e a r w a s e s s e n t i a l l y n o r m a l a t t h e t i m e oK d e a t h b u t w i t h e v i d e n c e of a past infection:

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In summary, there seem to have been two avenues of entry of infection to the meninges in this case. There was a route from the nasopharynx eroding through t h e s p h e n o i d bone, c a u s i n g a b r a i n a b s c e s s w h i c h h a d r u p t u r e d i n t o t h e v e n t r i c l e , a n d t h e r e w a s also a r o u t e of d i r e c t e x t e n s i o n f r o m t h e i n f e c t e d l e f t m a s t o i d a n d m i d d l e ear.

Fig. 12 (Case ll--7921).--Horizontal section bf the left ear, showing mastoid, aditus, a n d r e t r o l a b y r i n t h i n e cells filled w i t h pus. A n t e r i o r l y a p a t h o l o g i c dehiscence into the i n t e r n a l c a r o t i d c a n a l is seen.

Fig. 13 ( 3 1 ) . - - N o t b e l o n g i n g to this series of cases b u t i l l u s t r a t i n g p e r i c a r o t i d venous sinus t h r o m b o s i s and i n v o l v e m e n t of the p e r i e a r o t l d s h e a t h in Strep. hemolyticus infection in a 4-year-old boy. Specimen received p r i o r to the d a y s of c h e m o t h e r a p y . CASE 11 ( C h a r t 9 a n d T a b l e I I ) . - - T h i s g i r l of 8 y e a r s , R. S., w a s also a d m i t t e d i n a m o r i b u n d Condition, d y i n g t h i r t e e n h o u r s a f t e r a d m i s s i o n . T h e r e w a s a hist o r y of o t i t i s m e d i a one y e a r p r i o r to a d m i s s i o n w i t h a r e c u r r e n c e on J a n . 24, 1939. S h e w a s a d m i t t e d to t h e h o s p i t a l o n J a n . 29, 1939, a p p a r e n t l y on t h e f o u r t h

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day of meningitis. The spinal fluid was very cloudy, containing 22,300 cells; organisms could be seen on smear and grown on culture. Tyro doses of sulfanilamide were given subcutaneously and one intraspinous]y before death occurred. The general findings at autopsy were reported b y D r . F. Woolsey, D e p a r t m e n t of Pathology, as follows: In addition to generalized leptomeningitis more marked in the r i g h t temporoparietal and basi]ar regions, there existed bilateral chronic supp u r a t i v e otitis media, mastoiditis, and sphenoiditis. Post-mortem otorhinologic report by D. Wolff: Bilateral chronic otitis media petrosltis and mastoiditis were present (Figs. 11 and 12), t h a t on the right being more active at the time of death. Both mastoids showed empyemic membrane p a r t i a l l y filling many of the pneumatic spaces, in the center of which were pockets of pus. Numerous long tlmbria, which were infiltrated w i t h cells, protruded into the lumen of the eustachian tubes (Fig. 11). ~Iultip]e minute pathologic dehiscences of the bony wall of the carotid canM were seen on the ]eft. On the right a minute dehiscence was observed leading into the posterior fossa. In this instance the c o n t e n t s of the carotid canal were not secured at autopsy. Consequently, we cannot state whether the single dehiscence seen on the right was the origin of the meningitis or w h e t h e r the carotid sheath on the left played a role. Such an origin for meningitis has been well established, and Fig. 13 demons t r a t e s an abscess arising from perlcarotid venous phlebitis in a 4-year-old child. CASE 12 (Table I ) . - - T h i s 5-week-old boy, J. J., was said to have had a draining ear for a week previous to e n t r y to the hospital. / T r e a t m e n t may have included some su]fonamide drug. E i g h t e e n hours prior to admission he had a generalized convulsion and became suddenly much more acutely ill w i t h m a r k e d pallor, difficult respiration, and rapidly increasing stupor. On admission on Feb. 12, 1942, the initial examination revealed a markedly dehydrated infant, semistuporous and showing Cheyne-Stokes respiration, with marked slowing of the h e a r t rate during the upneic periods. The h e a r t sounds were v e r y poor and the general picture was t h a t of circulatory collapse. The left ear appeared normal, but the right ear showed purulent drainage. The f o n t a n e l was soft and the spine flexible, but the deep reflexes were absent and there was a positive B r u d z i n s k i ' s sign, inequality of the pupils and strabismus. The temperature was only 37 ~ C. L u m b a r puncture revealed grossly purulent spinal fluid loaded with streptococci which on culture proved to be hemolytic. The Tobey-Ayer test was negative. Blood culture and culture from the right ear were also posltlve for hemolytic streptococci. F i f t e e n cubic centimeters of 1 per cent sulfanilamide solution were injected into the spinM canal during the lumbar puncture, and intravenous chemotherapy was begun with sodium sulfadiazlne, 2 c.c. per kilogram of a 5 per cent solution. P a r e n t e r a l fluid was given with the i n f a n t in an oxygen tent. No i m p r o v e m e n t occurred, and the child expired about two and one-half hours a f t e r entry. No sulfanilamide was found in the spinal fluid drawn prior to drug a d m i n i s t r a t i o n in the hospital. Post-mortem examination by Dr. W. I(enney revealed a generalized purulent leptomeningitis, an acute inflammatory process in the l e f t mastoid antrum, and bronchopneumonia of the right lower lobe. Temporal bone studies have not as yet been completed. DISCUSSION

Etiology.--In the twelve cases of hemolytic streptococcal meningitis just described, this condition seemed definitely to have been related to acute or neglected infection in the upper respiratory tract in all but two patients, Cases 2 and 5. In Case 2 such a relationship probably

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also existed, in that this boy had a p p a r e n t l y satisfactorily recovered from otitis media and mastoiditis without the aid of adequate chemot h e r a p y but with bilateral mastoidectomy, only to develop meningitis some two months later without obvious cause. I t seems to us that it is more than possible that the meningitis developed as a result of residual infection in the temporal bone (petrous p y r a m i d ?), which surgical intervention failed to reach and drain and which remained dormant possibly because of chemotherapy too much delayed, of inadequate dosage, and of too short dliration. We feel justified in this assumption because chemotherapy l a t e r apparently proved adequate in effecting a permanent cure without :further surgery. Some hesitancy should also be felt in considering Case 5 an exception. This child was but 6 weeks of age, and it is easily possible for temporal bone infection to have existed without eardrum changes of significance. Such cases have been observed by one of us (D. W.}. Of the ten eases with u p p e r respiratory tract relationship, nine definitely had otitis media and three had mastoiditis eonfirmed by operation (Cases 3, 6, and 7), and four more had temporal bone infection proved by autopsy, which in three instances at least seems to have been the probable cause of the fatal meningitis (Cases 9, 10, and 11). In another instance, Case 8, mastoid involvement was indicated by x-ray. This child recovered without mastoideetomy. The close relationship in infants and children of hemolytic streptococcal infections, temporal bone pathology, and fatal meningitis is well established by the temporal bone studies from a variety of sources by one of us (D. W.), a brief r~sum~ of which follows: Temporal bones have been studied from twenty-six eases of otitis media in which the Streptococcus hemolylicus was recovered from some region of the body. The identification of this organism was made before death in seventeen eases. I t was recovered from the ear in seven of the seventeen patients. The aural diagnosis was reinforced by finding the organism also in the blood in two of these patients, in the spinal fluid in one, and in an aspirated brain abscess in another. In a fourth ease streptococcus not identified as hemolytieus was found in the spinal fluid. In this ease streptococcus was also found in the blood. In a fifth case streptococcus not identified as hemolyticus was found in the blood, reinforcing the finding of Strep. hemolyticus in the ear. In the remaining twelve patients the organism was recovered either from the blood or spinal fluid or both, or from a localized abscess. I n the nine remaining eases it was f o u n d only at the post-mortem examination. The twenty-six patients include only three adults. Seven of the patients were under 1 year of age. It was evident from the histories that all individuals old enough to explain their difficulty, and not moribund, had at some time complained of severe earaehe. Mastoid tenderness on the other hand was not a characteristic symptom, h a v i n g been elicited only eight t i m e s as compared with fifteen complaints of earache. There is evidently a distinct tendency for spontaneous r u p t u r e

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619

of the drum membrane to occur in these patients, .as it was f o u n d in fifteen i n s t a n c e s . Myringotomy was performed in sixteen eases, two of these being in the opposite ear from that in which the spontaneous r u p t u r e occurred. On the whole, these eases terminated very swiftly, o n l y two having long-standing otitis media, one of these for one and one-half years, the other having had chronic sinusitis for seven years. Three eases had had their symptoms less than five days, and eleven ethers had }oeen sick just three weeks or less. Fourteen of the children appeared well developed and' Well nourished at autopsy. V o m i t i n g occurred in fifteen cases. One of these was in an infant with pyloric stenosis, and one in an infant with bacillary dysenterY. I n six cases vomiting occurred only once or twice. In the nine remaining eases it occurred several times. I n this group was a twenty-fouryear-old p r e g n a n t woman who also had purulent labyrinthitis, and a twelve-year old (described as having continuous vomiting) who had purulent labyrinthitis, as shown in the microscopic sections. Nystagmus was not a common observation, being found definitely in only four eases. A fifth case Was described as t u r n i n g the eyes upward. Mastoid operations were done on ten of these eases, three of these being bilateral operations. Two radical operations were done. One simple operation was repeated. Septicemia, as p r o v e d by blood culture, was present in nine cases. Sinus thrombosis was present in eight eases. Meningitis occurred in seventeen eases, brain abscess in five, the remaining patients dying chiefly from pneumonia and one of endoearditis. Post-mortem kidney changes were recorded in nine patients, bacterial emboli being found once. Cloudy swelling was reported in the others. A study of the microscopic sections of the temporal bones revealed bilateral otitis media in six eases in which only one ear had been treated clinically. Direct extension by pathologic erosion of bone could be demonstrated in eighteen eases. E v i d e n t l y this disease is characterized by rapid dissolution of delicate bone trabeculae. It a p p a r e n t l y attacks bone even more readily than connective tissue, for p u r u l e n t labyrinthitis with extension through the round or oval window occurred in only four eases. Most eases showed a clear inner ear, sometimes with relatively normal organs of Corti. Vascular routes could be demonstrated in two, and in a t h i r d both the vascular and direct routes of extension were noted. Apieitis occurred in twelve eases. I n four of these the infection was within the bony carotid canal. Diagnosis.--Since ttie seriousness of the condition makes the immediate diagnosis and treatment of meningitis urgent, prompt measures to establish the diagnosis and institute t h e r a p y should always be taken when there is any suggestion that the meninges might be infected. In the presence of history, physical findings, of x-ray evidence of otitis media and mastoiditis, or of serious u p p e r respiratory tract infection, it is well to be on the alert for meningeal signs and symptoms. When-

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ever physical findings indicative of meningeal irritation are present, immediate lumbar puncture with examination of the spinal fluid is indicated. Main reliance for the diagnosis of meningitis must always be placed on this test. I t has been argued that performance of lumbar puncture in the presence of serious infection elsewhere in the body and especially in the presence of baeteremia is a dangerous procedure. The point should be emphasized, however, that wide clinical experience has proved that danger of contamination of uninfected meninges by lumbar puncture seems much more theoretical than real, 2 and the advantage to be gained from the avoidance of loss of time in starting treatment by far Outweighs any such danger. Advantage should be taken at the time of such a diagnostic puncture of performing also the Tobey-Ayer modification of the Queckensted t test, especially if there exists otitis media and the picture of sepsis with, therefore, the possibility of lateral sinus phlebitis and thrombosis. The fluid once obtained should be examined by stained smears and by culture. In the examination of the smears certain pitfalls must be avoided. As may be seen from consulting Table II, in eight of the cases incorrect eoneIusions as to the identity of the infecting organism were drawn from examination of the original smears, and the first impressions later proved to be incorrect by the culture resuIts. The use of the Gram stain technique is often misleading if one is not thoroughly familiar with the method and the appearance of organisms when so stained. Deeolorization to too great a degree on the one hand and failure to decolorize sufficiently on the other may lead to a wrong decision as to the nature of the organism; for example, meingocoeei may be mistaken for pneumoeoeci or vice versa. Decisions based on stained smears, therefore, should be made only by those skilled in interpreting their significance. Culture results will usually correct any errors thus made but may take twenty-four to forty-eight hours in returning. The finding of purulent spinal fluid with or without organisms visible on smear must be taken as an indication for the immediate institution of p r o p e r therapy. In this connection, it may be noted that in Case 10 no organisms were seen on smear and that growth was obtained only from the autopsy culture. We have included in another group to be discussed in a later paper those cases in which confirmation of the nature of the organisms was not obtained by culture, although in some of them organisms were visible on the stained smear. This group of so-called " s t e r i l e " meningitides show some striking differences from those in which there were positive cultures. I t may also be seen from examination of Table I I that in one case in which organisms were not visible in the stained smear they nevertheless grew out in culture. F r o m these facts the conclusion may be drawn that it is always important to obtain cultural confirmation of the diagnosis of type of meningitis, but that institution of chemotherapy because of the broadness of coverage of the newer drugs should not wait upon accurate cultural data. Serum

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therapy, however, we believe should not be used without accurate bacteriologic diagnosis because of its specificity, greater risk of danger of administration, and its much greater expense. Treatment and Results.--If the mortality of the twelve cases presented be corrected by the exclusion of the three cases which were moribund on admission, the resulting mortality is one of nine, or 11 per cent, which compares favorably with results of sulfonamide therapy of hemolytic streptococcal meningitis already reported in the literature2 This is in striking contrast to the results obtained at the St. Louis Children's Hospital before the advent of chemotherapy, there being not a single recovery among those cases in which organisms were actually obtained on culture from the spinal fluid. I f we turn our. attention first to the recovered cases, we are immediately impressed by the speed with which infection in the meninges was brought under control by all three of the drugs used (Table II). In three instances (Cases ], 4, and 6) positive spinal fluid cultures were obtained on only the first day, in three more (Cases 2, 7, and 8) on only the first two days, in Case 5 for the first three days, and in Case 7 for the first six days. What seems also important is the fact that in not one instance was there a return to positive cultures after the first negative had been secured. This is in marked contrast to what so frequently is noted in influenzal, and to a somewhat less degree, in pneumocoecal meningitis, where relapse, which includes a return to positive cultures, is quite common. Complete eradication of the infection does not occur so quickly, however, if we are to judge from the frequent tendency toward persistence of fever, increased cell count* in the spinal fluid, blood leucocytosis, and the occasional recurrence of acute meningeal sigmas and symptoms (Cases 2, 4, 5, and 6) with return to purulent, though sterile, fluid. Because of such a tendency, and because of the apparently greater difficulty in eradicating infection completely from the temporal bone, continuation of drug administration, sometimes for long periods, seems unavoidable. The question of when to discontinue chemotherapy is one of the most difficult to answer, and, it seems to us, must always be decided for each individual case. I f a coalescent type of mastoiditis exists and can be diagzmsed with certainty, surgical intervention will be necessary for complete eradication of the infection in the mastoid process of the temporal bone. There is no advantage of delaying such an operation beyond the time required for control of the infection in the meninges, and it would seem wiser to perform such an operation when the subject is still receiving full doses of the drug. Unnecessary operative delay and long continuation of sulfonamide therapy on the other hand might lead to the development * L a t e r i n c r e a s e in t h e cell c o u n t is n o t to b e c o n f u s e d w i t h t h e f a v o r a b l e a n d alm o s t i n v a r i a b l e r i s e w h i c h o c c u r s o n t h e s e c o n d d a n of t r e a t m e n t a n d is a s s o c i a t e d w i t h d i m i n u t i o n of t h e n u m b e r of o r g a n i s m s .

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of serious toxic manifestations from drug administration, which in turn may make necessary discontinuation of chemotherapy and operative intervention without its protection. Subsequent spreading of the infection may thereby result. Ifl on the other hand, the nature and the extent of the involvement of the temporal bone are doubtful, and either bone destruction is thought not present or infection is thought to be in some inaccessible part of the bone, as, for instance, the bony carotid canal, long-continued chemotherapy would seem indicated. In some instances it may be difficult to diagnose accurately conditions within tl~e temporal bone by any method short of operative inspection. Exploratory mastoidectomy we feel is often justified and may be safely performed after meningitis is under control and while the patient is still receiving full doses of sulfonamide drag. Such a procedure should not, however, be undertaken too early in the course of infection or before the drug and the patient have been ,given ample opportunity to overcome the infection completely. Such principles as those stated above were followed in most of our successfully treated cases. In Cases 1, 4, and 5, no evidence of temporal bone involvement existed, and there was no surgical intervention seriously contemplated. In Case 8 the subsidence of infection in the middle ears and the improvement of the drum membranes during treatment of the meningitis, together with the x-ray finding of just cloudiness of the mastoid region on both sides without clean-cut evidence of cell breakdown, prompted us to refrain from surgical exploration. In Case 2 bilateral simple mastoidectomy had already been performed and occurrence of meningitis was without associated localizing evidence of infecti0n in the temporal bone. There was, therefore, no choice but to rely entirely on chemotherapy. In Case 7 six days of chemotherapy were allowed to elapse during which time the meningitis was brought under control and the septicemia abolished before operative intervention was thought safe. In reviewing Case 6, we are inclined to believe that decrease in drug dosage was made too soon and surgical exploration postponed too long, permitting exacerbation of meningeal signs and symptoms, which required a second period of intensive chemotherapy. It should be noted that when mastoidectomy was performed on the fourteenth day of treatment, no breaking down of cells was present which was in keeping with the x-ray finding of simple cloudiness of the mastoid. It is unfortunate that a culture was not made of the bone, the cells of which were found lined with pyogenic membrane, to determine whether or not viable organisms were still present. In Case 3, surgical intervention was performed perhaps earlier than desirable with, however, only some rise in fever as a postoperative reaction. If we turn next to the fatal cases, we note that in two of them (Cases 10 and 11), despite long-standing infection in the temporal and sphenoid bones, no chemotherapy had been employed until they were admitted to the hospital in moribund condition. Much the same could be said of

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the other case (Case 9). In this instance, we question seriously, in light of our more recent experiences with intensive chemotherapy, whether sufficient drug was ever administered, since spinal fluid concentrations never exceeded 15 mg. per 100 c.c. and for the first two weeks were well under IO rag. per 100 c.c. Such levels were probably too low for the heaviness of the infection, the spinal fluid at all times teeming' with organisms. It is from this experience and other experiences such as this

(especially in pneumococcal and Hemophilus influenzae infections) that we have come to feel that while low concentrations of sulfonamide drugs may suffice to sterilize the spinal fluid in some ins~tances, in others quite high concentrations are needed. It seems best to start with large enough doses to cover the latter cases and to reduce the amount of drug administered if the larger doses are later found unnecessary. In our earliest cases the dosage rarely exceeded 0.3 Gin. per kilogram body weight per day; now our initial dosage for the first few days averages 0.6 Gin. per kilogram per day. Sulfadiazine seems to be the best drug at present, with sulfapyridine second choice. The poor diffusion of sulfathiazole into the spinal fluid, regardless of the explanation, 4 must be given due consideration and prompts us to give sulfathiazole an inferior ranking for the treatment of most acute pediatric infections. We have witnessed the development of pneumococeal meningitis (to be reported in a later paper) during su]fathiazole treatment of otitis media., the meningitis responding later quite promptly to sulfadiazine. Instances of pneumococeal meningitis following immediately upon the successful treatment of pneumonia with sulfathiazole have also been reported2 Sulfanilamide, despite its lower order of effectiveness and its greater tendency to produce objectionable central nervous system symptoms, methemoglobinemia, and anemia, possesses some advantage. When parenteral administration is necessary and intravenous administration of sodium salts difficult, it can quite safely and easily be administered subcutaneously or intraperitoneally. It is also compatible with all solutions likely to be given intravenously, such as dextrose, lactateRinger's and amigen solutions, whole blood or plasma; and, finally, when dissolved in "artificial" spinal fluid,6 may be given intrathecally without irritation and with the desirable effect of producing very high, if but temporary, spinal fluid concentrations. The value of spinal drainage is considerably in doubt. Laminectomy we have always felt undesirable because of the subsequent difficulty of securing specimens of spinal fluid fit for bacteriologic examination. Invariably, staphylococci gain entrance, and confuse the picture. Ureteral catheter drainage seems open to the same objection. Continuous needle drainage, which was employed in four of our cases, may occasionally be of some value, particularly in late cases with very thick spinal fluid, and requiring much supportive parenteral fluid therapy.

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Not only can the danger of too greatly increased spinal fluid pressure in such cases be easily avoided, but bacteriologic sampling of the spinal fluid is also made easy and with little danger of contamination. While we agree with Hoyne ~ that frequent lumbar punctures are usually unnecessary for treatment, information so gMned lends much to the understanding of the clinical picture and may sometimes be the only reliable means of determining whether to increase drug dosage in the presence of continued fever or to discontinue such administration entirely. Subsequent studies may also prove that such frequent punctures are of assistance in controlIing internal hydrocephalus, which, we are now beginning to believe, frequently develops and may persist for some time after infection has disappeared. SUM:IV~ARY AND CONCLUSIONS

Careful study has been made of twelve patients with hemolytic streptococcal meningitis admitted to the St. Louis Children's Hospital since treatment with su]fonamide drugs has been possible. It may be concluded that this infection almost invariably is a complication of acute or neglected infection in the upper respiratory tract and usually in the temporM bone. In three fatal cases of this series, and in twenty-six others, the involvement of the meninges was shown usually to have been the result of direct extension of the infection from the middle or inner ear, the mastoid or petrous portion of the temporal bone, or from the pericarotid veins in the carotid sheath. Complete recovery with little or no residua in eight of the twelve patients is to be attributed to both early and accurate diagnosis, adequate administration of sulfonamide chemotherapy, adequate supportive treatment of all types, and to surgical drainage of accessible suppuration within the temporal bone. We wish to express our appreciation of the valuable service rendered b y Dr. lVL M. Cook in photographing the illustrations which are reproduced ]n this paper. REFERENCES 1. ttartmann, A. F., Wolff, D., and Love, F.: J. PE~IAT. 21: 435, 1942. 2. Pray, L. G.: Am. J. Dis. Child. 62: 295, 1941. 3. Loug~ P. tI., and Bliss, E. A.: The Clinical and Experimental Use of Sulfanilamide, Sulfapyridine, and Allied Compounds, New York, 1939, The Macmillan Co. 4. Davis, Bernard D.: Science 95: 78, 1942. 5. Wooley, P. V.: J. PEDIAT. 20: 185, 1942. 6. Hartmann, A . F . : J . A . M . A . 103: 1349, 1934. 7. ttoyne, A. J.: J. PEDIAT. 19: 778, 1941.