Listeria monocytogenes meningitis

T h e Journal of P E D I A T R I C S

337

Listeria monocytogenes meningitis O b s e r r a t i o m " b a s e d o n 1 3 case r e p o r t s a n d

a

consideration o f recent literature

Meningitis caused by Listeria monocytogenes occurs predominantly in the neonate and the aged. It is the most common manifestation o[ listeriosis in humans. Although listeriosis is recognized as a major global problem in both human and animal health, the epidemiology of human injection is poorly understood; attention presently centers about events o[ pregnancy and the puerperium. Animals and animal products may represent reservoirs [or human injection. Thirteen instances of meningitis caused by this organism are reported; death occurred in onPy one in[ant. Antimicrobial therapy resulted in recovery without evident sequelae in the remaining 12 patients.

Wallace Nichols, Jr., M.D., and Paul V. Woolley, Jr., M.D. 's DETROIT,

MICH.

T H ~. basic description of Listeria monocytogenes was provided 35 years ago by Murray, Webb, and Swann 1 who, from an epizootic among laboratory animals, recovered a small, motile, gram-positive bacillus which, when injected into rabbits, elicited monocytosis. Since then the organism has been recognized in a variety of conditions in man and animals. It .is common among wild rodents and has been recovered from 11 species of birds, including the chicken. Circling disease, a meningoencephaIitis caused by Listeria, is a major source of economic loss to

From the Department o[ Pediatrics, Wayne State University College o[ Medicine, and The

Children's Hospital of Michigan. "X'Address, 5224 St. Antoine, Detroit 2, Mich.

raisers of sheep and cattle. Gray and others 2-~ have emphasized the peculiar predilection of the bacillus for gravid animals, especially ruminants, and its importance in the train of abortion, sepsis, stillbirth, or infection of the living newborn. A number of investigators have recovered it from the milk of naturally and experimentally infected animals, and several have demonstrated its survival after pasteurization. In man, a variety of disorders are caused by Listeria, including febrile states, pneumonitis, endocarditis, conjunctivitis, urethritis, and pyoderma; in the European literature there are reports of repeated abortions attributed to this infection, a, 6 Numerically the most important h u m a n disease is meningitis with or without visceral lesions characteristic of septicemia. In spite of the in-

History

A 14-day-old white female was admitted on Oct. 15, 1959, with fever, restlessness, and vomiting for 24 hours. The birth weight was 5 pounds, 12 ounces. The birth was at term by calculation. The pregnancy and delivery were uneventful. She was formula fed and is gaining well.

Case 3 (208656)

A 14-day-old white female was admitted Jan. 30, 1957, because of seizure. The birth weight was 8 pounds, and the pregnancy and delivery were uneventful. She was breast fed for 3 days and then started on a formula. Few loose stools occurred for 1 week, but there was no vomiting or fever. The mother has "stitch abscesses." Temperature was 98 ~ F.; fontanel, flat; neck, supple; liver, not enlarged; and umbilicus "dirty."

Case 2 (162962)

A 19-day-old white female was admitted on April 17, 1956, with irritability, fever, and vomiting of 1-day duration. The birth weight was 8 pounds, 15 ounces with an uneventful pregnancy and delivery. Formula feeding was begun at birth. No complaints were present prior to onset. There was no illness in the remainder of the family. Temperature was 103 ~ F.; fontanel, full; respiratory tract, clear; liver, not enlarged; and umbilicus, clean.

Case 1 (148350)

[ Laboratory data

Initial 1,900 white blood cell, 90% polymorphonuclear leukocytes

Cerebrospinal fluid

White blood cell count, 19,000 Polymorphonuclear leukocytes, 58% Hemoglobin, 13 Gin.%

Blood

1,325 white blood cell, no growth Blood culture, negative

After 48 hours

Initial 7,200 white blood cells Sugar reduced Protein, 113 mg.% Direct examination, no organism seen Culture, Listeria

Cerebrospinal fluid

White blood cell count, 28,000 Polymorphonuclear leukocytes, 52% Hemoglobin, 11.2 Gin.%

Blood

1,325 white blood cells Polymorphonuclear Ieukoeytes, 70% Culture, sterile Blood culture, negative Vaginal culture (mother), no Listeria

After 48 hours

Initial 2,200 White blood cells, all polymorphonuclear leukocytes Sugar reduced Protein, 120 mg.% Direct smear, negative Culture, positive in 24 hours

Cerebrospinal fluid

White blood cell count, 37,000 Polymorphonuclear leukocytes, 75% Hemoglobin, 13.8 Gin.%

Blood

Treatment

Penicillin, sulfadiazine, and chloromycetln

Penicillin, sulfadiazine, streptomycin; later chloromyetln

Penicillin, sulfadiazine, streptomycin; later chloromycetin

Table I. Case summaries from the Children's Hospital of Michigan from 1953 to 1961 ] CouYse

Temperature normal in 48 hours No sequelae on follow-up visits

Never febrile but 3 seizures during the first 48 hours Recovery thereafter uneventful Follow-up, no sequelae

Afebrile in 48 hours No symptom on discharge or following visits

F~

g~

Blood White blood cell count 9,450 Polymorphonuclear leukocytes, 70% Hemoglobin, 14.2 Gin.% Cerebrospinal fluid Initial 4,800 cells, 70% polymorphonuclear leukocytes Sugar reduced Protein, 135 mg.% Direct smear, Gram-positive coccobacilli Culture, positive for Listeria After 48 hours 200 white blood cells Culture, sterile

Blood culture Positive initially Blood White blood cell count, 37,000 Polymorphonuclear leukocytes, 53% Hemoglobin, 14.2 Gin.% Cerebrospinal fluid Initial 2,670 cells, 93% polymorphonuclear leukocytes Sugar, absent Protein, 441 mg.% Direct smear, no organisms seen Culture, positive for Listeria After 48 hours 437 white blood ceils, 30% polymorphonuclear leukocytes Culture, sterile

Blood White blood cell count, 11,800 Polymorphonuclear leukocytes, 47%

Case 5 (184317) 11-day-old white male was admitted on April 11, 1958, after 36 hours of fever and irritability which terminated in a "choking spell." Birth weight was 7 pounds, 11 ounces after an uneventful pregnancy. He was fed an evaporated milk formula from beginning. Temperature was 103 ~ F.; neck, supple; fontanel, full without bulging and conscious and irritable periodically; liver, not palpable ; umbilicus, not inflamed hut granuloma present; and circumcision wound clean.

Case 6 (198093) 15-day-old Negro male was admitted Jan. 17, 1959, after 24 hours of fever and

Sugar reduced Protein, 100 rag.% Direct smear, negative Culture, Listeria After 48 hours Traumatic puncture Culture, negative

Case 4 (229015) A 15-day-old female was admited on Jan. 19, 1961, with high-pitched cry, irritability, and fever for 36 hours. The birth weight was 10 pounds, 10 ounces after an uneventful pregnancy. A proprietary milk formula was given from birth. Temperature was 102 ~ F.; fontanel, flat; neck, supple; umbilicus, inflamed, and liver, not palpable. She was extremely irritable.

Temperature was 103 ~ F.; fontanel, tense and alert; liver, not enlarged; and umbilicus, clean.

Penicillin, sulfadiazine, and chloromycetin

Penicillin, sulfadiazine, and chloromycetin

Penicillin, sulfadiazine, and chloromycetin

Temperature, normal in 48 hours No further seizures

Temperature, normal after 24 hours Free from symptoms and discharged on tenth day No sequelae detected at recent visit

Child went home on the eighth day No sequelae on continuing follow-up Extensive efforts to isolate Listeria from mother were unsuccessful

hours

Temperature normal in 48

2.

X %

~~

v,.

History

[

Laboratory data

Case 8 (St. Joseph Mercy Hospital) A 28-day-old white female was readmitted May 14, 1960, because of vomiting, irritability, and fever. Birth weight was 8 pounds, 2 ounces. First 2 weeks were uneventful, then purulent omphalitis from which S. aureus was obtained, as well as from blood. Treated with penicillin and tetracyclines and home on fifth day. T h e n there was a 10-day period of well being.

9-day-old white male was admitted Nov. 23, 1955, after 48 hours of irritability, fever, and anorexia. Birth weight was 5 pounds, 14 ounces, t i e was fed a proprietary milk formula from birth. Umbilical inflammation noted the day prior to admission. Temperature was 102 ~ F.; fontanel, flat; definite omphalitis. He was lethargic.

Case 7

CerebrospinaI fluid Initial 4,400 white blood cells, 90% polymorphonuclear leukocytes Protein, 224 mg.% Direct smear, no organisms Culture, positive for Listeria Alter 24 hours Still many cells and culture again positive Alter 4B hours Marked clearing Culture, negative Serum protein, normal Transaminase ( S G O T and S G P T ) , normal

Blood culture Sterile Bilirubin, 5.6 rag. Cerebrospinal fluid Contained 1,700 white blood cells, predominantly polymorphonuclear leukocytes Direct smear, Gram-positive coccobacilli Culture, positive for Listeria

Monocytes, 16% anorexia. Birth weight was 6 pounds, 11| Hemoglobin, 14.4 G m . % ounces; an evaporated milk formula was] given from birth. fluid I Gerebrospinal Initial Temperature was 99.6 ~ F. with irritable, 2,300 White blood cells, 60% polymorstaring, periodic apnea, jaundice, and conphonuclear leukocytes vulsion during examination. Liver was not Sugar reduced palpable; umbilicus was clean. Protein, 163 rag.% Direct smear, Gram-positive coccobacilli Culture, positive for Listeria After 48 hours 3,700 white blood cells Sugar, 46 mg.% Culture, negative

Table I. Cont'd

A variety of drugs including penicillin, sulfadiazine, and chloromycetin One blood culture contained S. aureas (eoagulase post.) which led to further treatment with bacitracin and achromycin

Penicillin, sulfadiazine, and chloromycetin Blood and adrenal cortical extract

Treatment

Home after 17 days, free from symptoms Six months later, developing w e l l - - n o sequelae Intensive culturing of mother failed to reveal either Listeria or S. aureus

Died in 12 hours

Discharged asymptomatlc on seventh day Follow-up visits show no sequelae

Course

#,

A 6-month-old Negro female was admitted April 23, 1954, with fever, restlessness, and vomiting for 1 day. She had been well previously, with development adequate and no environmental illness. Birth was by elective cesarean at term. Temperature was 102 ~ F. T h e child was extremely irritable. The fontanel was full and the neck stiff, tympani injected. Nasal discharge showed throat clean.

Case 11 (101798)

A 4-month-old Negro male was admitted Sept. 3, 1953, because of fever and diarrhea for 4 days and irritability for 48 hours. He was previously well with no household illness. Birth weight had been 8 pounds, 12 ounces and postnatal period had been uneventful. Temperature was 104 ~ F.; fontanel, full but baby alert; tympani, full and throat injected.

Case 10 (99499)

A 15-day-old white female was admitted on July 5, 1961, because of diarrhea for 48 hours, fever, and irritability. Birth weight was 7 pounds, 15 ounces. Maternal health was good except for leukorrhea off and on throughout pregnancy.

Case 9 (237848)

9

j,

Initial 5,000 white blood cell, 90% polymorphonuclear leukocytes Direct smear, negative Protein, 50 rag.% Culture, L~stena

Cerebrospinal fluid

White blood cell count, 29,000 Polymorphonuclear leukocytes, 63% Hemoglobin, 5.7 Gin.% with markedly hypochromic smear

Blood

Initial 1,138 white blood cells, 50% polymorphonuclear leukocytes Protein, 209 rag.% Direct smear, no organisms seen Culture, Listeria

Cerebrospinal fluid

White blood cell count, 7,700 Polymorphonuclear leukocytes, 67% Monocytes, 8 % Hemoglobin, 10.7 Gm. %

Blood

Clear, no white blood ceils and no growth

The seventh day

Traumatic fluid Culture, negative

After 72 hours

Initial 3,150 white blood cells, predominantly polymorphonuclear leukocytes Sugar reduced Protein, 80 mg.% Smear, gram-positive short rods Culture, L. monocytogenes

Cerebrospinal fluid

White blood cell count, 25,000 Polymorphonuclear leukocytes, 67% Monocytes, 3 %

Blood

Penicillin, sulfadiazine, streptomycin, and blood

Penicillin, sulfadiazine, and streptomycin

Sulfadiazine, penicillin, and chloromycetin Sulfadiazine discontinued after 24 hours

Temperature remained unstable for 6 days and then normal until discharge on the thirteenth day Follow-up years later shows no sequelae

Afebrile in 72 hours Free from symptoms when discharged on seventh day

Temperature, normal after 48 hours Home on twelfth day Two-month follow-up shows no present sequelae

%

o~

History

Temperature was 103 ~ F. The neck was stiff. She was lethargic and acutely ill. Neurologically she was intact.

A 5-year-old Negro female was admitted July 24, 1955, following 24 hours of fever, irritability, and lethargy. Growth was adequate and there were no environmental exposures. Perinatal period had been uneventful.

Case 13 (61373)

Temperature was 102 ~ F. He was disoriented and quite i11. The neck and back were stiff but neurologically intact.

A 15-month-old Negro male was admitted April 21, 1954, following 24 hours of fever and extreme irritability. Growth was adequate. There was no illness in the family, and perinatal experience was uneventful. been uneventful.

Case 12 (110953)

Table I. Cont'd

I

1,000 white blood cells Smear, negative Culture, negative

After 24 hours

Initial 8,000 white blood cells, 99% polymorphonuclear leukocytes Protein, 83 rag.% Smear, gram-positive bacilli Culture, Listerla

Cerebrospinal fluid

White blood cell count, 16,000 Polymorphonuclear leukocytes, 81% Hemoglobin, 9.9 G m . %

Blood

68 white blood cells Protein, 88 rag.% Culture, sterile

After 48 hours

Initial 1,100 white blood cells, 64% polymorphonuclear leukocytes Protein, 174 mg.% Sugar reduced Direct smear, not diagnostic Culture, Listeria

Cerebrospinal fluid

White blood cell count, 13,000 Polymorphonuclear leukocytes, 70% Hemoglobin, 6.9 Gm. % (hypochromic smear)

Blood

Marked clearing C~ilture, sterile

After 4 days

Laboratory data

I

Penicillin, sulfadiazine, and streptomycin

Penicillin, sulfadiazine, streptomycin, and blood transfusion and sedation

Treatment

Follow-up visits showed return of vi nerve function and intact nervous system

Transitory vi nerve pMsy noted on the fifth day

Extremely stormy course for 2 days following rapid clinical improvement

No sequelae on subsequent visits

Quite restless and febrile for 3 days; followed by rapid improvement and discharged on eleventh day

Course

ga,

Volume 61 Number 3

tensified interest in human listeriosis, many fundamental questions remain unanswered; more data on geographic distribution, incidence, the nature of the effective reservoir, and the modes of dissemination are especially desirable. A truly comprehensive review of the entire Listeria problem is available in the recent translation of Seeliger's definitive book. 7 This presentation describes 13 instances of listerial meningitis seen in children and reemphasizes the importance of the organism in the over-all problem of meningitis during early infancy. BACTERIOLOGY

In direct smears Listeria appears as a small (less than 2 ft) Gram-positive rod which undoubtedly is often called a "diphtheroid." It grows readily b o t h o n the conventional media used for the culture of cerebrospinal fluid and in the broths usually employed for blood cultures. Subculture on blood agar produces vigorous growth of smooth colonies surrounded by clear bands of hemolysis. When colonies formed on tryptose phosphate agar are examined through a dissecting scope by reflected light, they characteristically present a bluish, almost fluorescent sheen? This attribute, in our experience, is lost to a large degree when incubation is accomplished under reduced oxygen tension. A "tumbling" motility sets the species apart from other small aerobic gram-positive rods commonly encountered in the clinical laboratory. This frequently can be observed directly in hanging drop preparations made from actively growing strains--especially if they have been held at roughly 25 ~ C---but confirmation should be obtained through growth in semisolid media containing glucose. Also rather specific for Listeria is its ability to produce a fulminating conjunctivitis or panophthalmitis upon introduction into the conjunctival sac of the rabbit. A serologic classification of the species is well established but is of limited value in the routine laboratory.

Listeria monocytogenes meningitis

343

A variety of methods have been suggested to facilitate isolation of Listeria from mixed flora or contaminated specimens--such as lochia or tissue from animal sources. Gray s has popularized a technique involving refrigeration at 4 ~ G for several months with periodic and terminal subculturing. We have had no experience with fluorescing antibodies against this species, but others have reported success with the technique. R E P O R T OF C L I N I C A L M A T E R I A L At the Children's Hospital of Michigan, during the period from 1953 to 1961, L. monocytogenes was recovered from the cerebrospinal fluid of 12 children and the clinical data relating to these patients ar% summarized in Table I. T o them is added a thirteenth protocol (Case 8) of a patient studied by our staff at a neighboring hospital In order to obtain a profile of listerial meningitis as a wider problem we have examined reports made from this country and Canada since 1954, when the last review of listerial meningitis was published; ~~ these have been summarized in Table II. Nine of the patients in our group were under 1 month of age, 2 were less than 6 months, 1 was 15 months, and the oldest was 5 years. When the 9 neonates are considered alone we find that the mothers invariably enjoyed good health during pregnancy. None had experienced repeated abortion nor did any report premature rupture of the membranes, febrile illnesses, or early labor. All were residents of the metropolitan Detroit area and none had unusual occupational or avocational exposure to animals. Postpartum complications were limited to a single instance of stitch abscesses at the site of an episiotomy. Intensive efforts to obtain Listeria from the lochia of 4 by both immediate and delayed cultures were unsuccessful Of the newborn infants, 2 weighed slightly under 6 pounds while the remainder were of good size and free from neonatal distress prior to the onset of acute illness. One baby died; at autopsy, there were severe meningitis, leukocytic infiltration of the brain,

3 44

Nichols and Woolley

Table II. Summary

September 1962

of l i s t e r i a l m e n i n g i t i s r e p o r t e d f r o m N o r t h A m e r i c a s i n c e the

r e v i e w of F i n e g o l d 1~

Location

Date

Author

Age

Sex

Comments and outcome

Alabama

1952

Winkler (South. M. J. 45: 1181, 1952)

55 years

M

Pre-existing heart disease Died in 8 days

Texas

1953

Schulze et al. (Am. J. Clin. Path. 23: 1028, 1953)

19 years

F

Pre-existing lupus Died in 48 hours

Washington, D.C.

1954

Portero and Despirito (Clin. Proc. Child. Hosp., D. C. 10: 56, 1954)

M

Colllection of fluid Subdural and relapse

Michigan

1954

Williams and H o r n u n g (Am. J. Clin. Path. 24: 962, 1954)

55 years 75 years

M F

Died in 15 days Died in 10 days

Ontario

1954

Allin and Kemper (Canad. J. Pub. Health 45: 27, 1954)

Adult

M

Died in 12 hours

Ontario

1954

Stoot (Canad. J. Med. Tech. 16: 142, 1954)

36 hours

New York

1955

Selinger and Becker (Pediatrics 16: 500, 1955)

13 days

F

Normal

Nova Scotia

1955

Reed et al. (Canad. M. A. J. 73: 402, 1955)

14 years 7 months

M M

Normal Normal

Ontario

1955

Johnston, et al. (Canad. M. A. J. 73: 402, 1955)

2 days

F

Died at 7 hours (granulomatosis)

California

1955

Norman (California Med. 82: 124, 1955)

18 days

F

Sacral dermoid Normal

Virginia

1956

75 years

F

Died in 3 days

Rhode Island

1956

Carroll, et al. (Virginia M. Month. 83: 343, 1956) Mathieu, et al. (J. PEDIAT. 48: 349, 1956)

M -

Normal Hydrocephalus

Illinois

1957

Korn et al. (A. M. A. Arch. Int. Med. 99: 573, 1957)

61 years

M

Normal after 2 relapses

California

1957

Dedrick (Am. J. M. Se. 233: 617, 1957)

2 years

M

Healed tuberculosis Normal Died, less than 24 hours Died, less than 24 hours Died in 72 hours Normal Normal Normal Died in 3 days

2 weeks Wash.,

7 weeks 3 weeks

11 49 75 62 62 44 14 Nova Scotia

Louisiana

1957

1957

Girard and Gavin (J. Path. & Bact. 74: 93, 1957)

Hood (Am. J. Clin. Path. 28: 18, 1957)

days years years years years years days

Premature Died in 12 hours

M F M F M M F

5 days

F

3 weeks

M

8 days

M

14 days

M

16 months 55 years

F F

17 years

M

Premature Normal Premature Died in 48 hours Premature Died in 24 hours Died in 24 hours Normal Advanced tuberculosis Died in 3 days Pre-existing cirrhosis Died in 3 weeks

Volume 61 Number 3

Lisleria monocytogenes meningitis

345

Table II. Cont'd Location

Date

Author

Age 7 weeks

Louisiana

1961

Hood (Pediatrics 27: 390, 1961)

Sex

Comments and outcome

10 days 6 years 15 days

F F F M M

Normal Normal Normal Normal Died in 5 days Premature (granulomatosis)

15 days 67 years

M M

68 yea~

M

Normal Alcoholic Died Alcoholic Died

16 14 12 9 9 4

M F M F F F

Died Normal Died Normal Died Died Premature

days days days days days days

Oklahoma

1957

Charlotte and Powell (Hosp. Prog. 38: 134, 1957)

11 days

F

Died in 10 days

Kansas

1957

Wiener (J. PEDIAT. 51: 392, 1957)

NB

M

Premature Died at 36 hours ( granulomatosls )

Georgia

1958

Allen and Murphy (South. M. J. 51: 1454, 1958)

9 days

M

Premature Died in 24 hours (granulomatosis)

24 years

F

Died in 16 hours

Newfoundland

1958

7 days

F'

Died in 15 hours (granulomatosis)

Kepler (Arch. pediat. 75: 413, 1958)

12 days 7 days

M

F

Died less than 24 hours Membranes ruptured 60 hours before delivery Died in 3 days (granulomatosis)

Davies et al. (Canad. J. Pub. 1958)

Health

49:

203,

Josephson (Canad. M. A. J. 78: 262, 1958) California

1958

New York

1958

Howe and Southworth (Ann. Int. Med. 48: 1384, 1958)

62 years

F

Recurred at 21 days

South Dakota

1958

Bowers and Elston (Am. J. Clin. Path. 30: 447, 1958)

52 years

M

Normal

New York

1959

Rosengarten (Neurology 9: 704, 1959)

48 years

F

Pre-existing lupus taking steroids Died in 6 days

Wisconsin

1959

Houghton (Wisconsin M. J. 58: 245, 1959)

58 years 74 years

M M

Normal Pre-existing Parkinson Normal

Ontario

1958

Luttor (Am. J. Obst. & Gynec. 75: 759,

1958)

1 day

Premature Died in 48 hours

3 46

Nichols and W o o l l e y

September 1962

T a b l e II. C o n t ' d Location Virginia

Quebec

Date 1959

1959

Author Welshimer and Wigglewash (J. A. M. A. 171: 1319, 1959)

Martineau (Union m~d. Canada 88: 679, 1959)

Age 47 years 57 years 57 years

Sex M M M

9 10 2 64

F M M M

days months weeks years

16 days 22 days I0 days 20 months

Dead on arrival (granulomatosis) Normal Normal Hydrocephalus

36 cases

18 died

New York

1960

Miller (Proc. New York State A. Pub. Health Lab. 40: 5, 1960) (Personal communication)

Minnesota

1960

Claypool et al. 68 years (Proc. Staff Meet., Mayo Clin. 35: 609, 1960)

M

Comments and outcome Normal Normal Residual central nervous system damage Died in 2 days Normal Died in 5 days Normal

M

Normal

T a b l e I I I . S u m m a r y of the cases of listerial meningitis since 1954 Under 1 to 1 to12 1 tolO 10 to 40 Over 40 1 month months years years years Total mortality Source Total I Died Total] Died Total] Died I Totall Died Total I Died i Total[ Died [ % Present review~ 43 25 8 2 11 4 11 6 36 16 110 54 49 Present report 9 1 2 0 2 0 __ 1 7.7 Total ~ 52 26 10 2 13 4 11 6 36 16 13 55 44.8 Mortality rate (%) 50 20 30.8 54.5 44.4 123 44.8 ~Excluding 7 eases of unknown age or outcome.

a n d microscopic areas of g r a n u l o m a t o u s necrosis t h r o u g h o u t the liver a n d adrenals. Small g r a m - p o s i t i v e organisms could be seen in p r e p a r a t i o n s f r o m all lesions. This infant was the youngest of the g r o u p at the onset of symptoms. Of interest a m o n g the survivors was the presence of definite omphalitis in 3 a t a n age when it w o u l d not be expected, of u n e x p l a i n e d icterus in one, a n d of h e p a t o m e g a l y in still another. N o clinical features set these children a p a r t from those who a t the s a m e age experience " p r i m a r y " p u r u l e n t meningitis due to other pathogens. Since recognition of the o r g a n i s m i n ' d i r e c t smears of cerebrospinal fluid was seldom accomplished, all patients

were t r e a t e d e m p i r i c a l l y w i t h t h e r a p e u t i c amounts of penicillin, sulfadiazine, chlora m p h e n i c o l a n d / o r streptomycin. This p r a c tice has long been routine at our institution whenever d o u b t has existed as to the identity of the p a t h o g e n in p u r u l e n t meningitis. I n vitro sensitivity studies on the various strains recovered from these infants suggest t h a t penicillin, chloramphenicol, or streptom y c i n alone would have been quite sufficient. Response to c o m b i n e d t h e r a p y was p r o m p t a n d cerebrospinal fluid collected after its institution u p o n r e p e a t l u m b a r puncture, usually within 48 hours of beginning treatment, was i n v a r i a b l y sterile a n d reflected a decrease in i n f l a m m a t o r y elements. N o sur-

Volume 61

Number 3

Listeria monocytogenes meningitis

vivor in this group suffered detectable neurologic sequelae, and none evinced symptoms referable to areas apart from the nervous system. The 4 children who acquired the disease after the neonatal period provided no epidemiologic clues. Each was well and progressing satisfactorily while concomitant disease was not present in the several households. Injection of ears and pharynges was noted, but this frequently, in our experience, is a subjective finding and the specific organism was not recovered from nose or throat cultures. Again, there was nothing to set these children a p a r t clinically from other cases of purulent meningitis, and response was prompt to the combined therapy mentioned earlier. No sequelae were noted for this group either.

due to Listeria is shown by Fig. 1 which has been constructed from the data summarized in Table I I I . No explanation has been offered for the prevalence of the disease late in life. Several workers mention the role of "pre-existing disease" in the older age group but no absolute relationship between debility and this specific infection can be derived from the literature--certainly at least, to no greater extent than for purulent meningitis in general. Much has also been written on the relationship between meningitis and occupational exposure to susceptible animals but, here again, this is difficult to equate with the over-all picture. For instance, Gray 17 surveyed the distribution of listeriosis among animals in Michigan and pointed out several regions of maximal density, yet no h u m a n infections have been reported from these areas in recent years. T h a t the high incidence of infection during the first month of life is connected with events of the gravid state and the puerperium can hardly be denied, and evidence has accumulated to suggest clearly a direct contamination of the fetus or newborn by the mother? s Hood has been especially successful in recovering the same bacterial strains from both mothers and their offspring. It is her concept that clinical manifestations in the mother may be mild and transient with no correlation to the-severity of the disease in the child. This fits well with what

DISCUSSION

H u m a n listeriosis manifested especially as meningitis is widely distributed throughout Canada and the United States. Wherever intensive search has been made--Virginia, 1~ New York, 12, 16 California,14 Louisiana,15, 16 or M i c h i g a n - - a surprising number of cases are found. This same prevalence would appear to apply also through much of Europe; Seeliger has written that 114 strains from human sources were received in his laboratory alone during the first 9 months of 1960. The unique age distribution of meningitis

to

~o

~o

4Q

~o

I

i

i

,'o. Ir

RIi

"~

4o ,-~o-

G o ~ ov~/~

Fig. 1. Age distribution and mortality for series summarized in Table III.

347

= i'~'~OWN

EXPI,~ED

3 48

Nichols and Woolley

September 1962

to collate perinatal infections with maternal illness, premature rupture of fetal membranes, premature birth, congenital anomalies, and various forms of "distress syndromes." In Table I V we have shown overall experience with meningitis in infants under 1 month of age at this hospital for the period covered in the current study. From this we see that predisposing conditions characterize predominantly patients from which gram-negative bacilli, usually enteric, or various strains of the staphylococcus are recovered. On the other hand, those from whom streptococci, pneumococci, or Listeria were isolated have been free from other handicaps. That this is not invariably true, at least for Listeria, is obvious from others' series in which prematurity has been a common feature. From the epidemiologic viewpoint cases due to the hemolytic streptococcus and the pneumococcus usually should be considered apart from Listeria since they represent possibilities for environmental contamination beyond those provided by the specific relationship of intrauterine channels and events of the puerperium. The extremely low case fatality rate observed in our cases, only one death among 13 patients, is in contrast with experience reflected by the literature. In fact, this survival rate, coupled with the absence of sequelae, makes listerial meningitis the most benign of the common bacterial forms seen in this hospital during early life. No single factor would appear to explain wide discrepancies in prognosis between various

comparable data are available through epidemiologic and experimental studies in animals. Our experiences would certainly support her hypothesis, but we would point out that in the majority of instances our patients were large healthy babies born at term and that there were relatively long and uneventful periods of incubation prior to the onset of meningeal symptoms. Only in the infant who died was there distinct evidence of severe visceral involvement. This must mean that pathways do exist apart from transplacental septicemia, in the usual sense, but still intimately related to the perinatal processes. Because of the shedding of bacteria into milk of infected ruminants, we have rechecked the feeding histories of our younger patients; only 1 of the 9 infants had been p u t to breast and he for only a few hours. Still unanswered are such questions as where and how the mothers come in contact with the organism initially and what exactly predisposes the gravid female to invasion and localization of organisms within the genital structures. We throw no light on the problem of sporadic listerial meningitis in later infancy or childhood, and here also the natural reservoir from which organisms are acquired is not defined nor is the portal for body invasion evident. The position of meningitis due to L. rnonocytogenes in relation to other purulent meningitis during the neonatal period is of interest especially with the current tendency

Table IV. Neonatal meningitis at Children's Hospital from 1954 to 1961

Organism Gram-negatlve bacilli (Paracolon, Proteus, Pseudomonas, and Eschericia coli) Streptococci Staphylococci Gonococcus Pneumococcus Mixed Etiology undetermined Listeria

Total

Predisposing condition

Sequelae

15 6 4 1 3 1 8 8 46

12 1 4 1 3 21

3 1 1 5

Died 9 1 1

Mortality (% ) 60 16.6 25

I

33

2

25

1

12.5

15

32.6

Volume 61 Number 3

series but 2 elements undoubtedly contribute. First is the obvious selection o f material in our group as indicated by the absence of premature infants; the paucity of maternal complications, and the presence of only one example of severe septicemia. Services with direct responsibility for large nurseries of newborn infants would inevitably record more of the poor risk patients and have a higher loss. Second is the extreme sensitivity a m o n g the housestaffs of children's hospitals to the possibility of purulent meningitis in any infant whenever the clinical course and behavior cannot be otherwise explained, so that lumbar puncture is apt to be performed earlier in the course of an infant with meningitis. S U M M A R Y AND C O N C L U S I O N S D a t a from 13 patients with meningitis due to L. monocytogenes have been presented. This information has been supplemented by a selective review of recent publications and the following conclusions have been reached. 1. T h e age distribution of patients with this f o r m of meningitis is unique in that the highest incidence is during the neonatal period. T h e r e are only sporadic cases during childhood and early adult life, but there is a marked increase in the incidence during the later years. 2. Evidence suggests that the high incidence during the first m o n t h of life reflects a direct contamination of the infant by an infected mother but the mode of transfer is not clear. 3. Little is known of the reservoir responsible for the sporadic cases during childhood, and there is no clear explanation for the frequency of infection in the later years. 4. I n our experience the very young patients have been full-term, healthy infants free from handicaps usually associated with pyogenic infections of the newborn period. The mothers have experienced a paucity of complications related either to pregnancy or to the puerperium. 5. A n over-all consideration of meningitis in infants under 1 m o n t h of age would

Listeria monocytogenes meningitis

349

separate Listeria from the gram-negative bacilli and staphylococci, which are largely secondary to debilitating factors or congenital anomalies, at one extreme, and from the hemolytic streptococci and pneumococcus at the other, where environmental spread is of prime import. 6. T h e prognosis for listerial meningitis, based on our experience alone is excellent - - o n l y 1 of the 13 patients succumbed and no sequelae were recognized a m o n g the survivors. 7. T h e importance of early l u m b a r puncture whenever symptoms in a y o u n g infant are not adequately explained by physical findings is stressed. REFERENCES

l. Murray, E. G. D., Webb, R. A., and Swarm, M. B. R.: A disease of rabbits characterized by large mononuclear monocytosis caused by a hitherto undescribed bacillus, bacterium monocytogenes, J. Path. & Bact. 29" 407, 1926. 2. Gray, M. L., Singh, C., and Thorp, F., Jr.: Abortion and prior-postnatal death of young due to Listeria monocytogenes. III. Studies in ruminants, Am. J. Vet. Research 17: 510, 1956. 3. Osebold, J. W., and Inouye, T.: Pathogenesls of Listeria monocytogenes infections in natural hosts. II. Sheep studies, J. Infect. Dis. 95: 67, 1954. 4. Graham, R., Hester, H. R., and Levine, N. D.: Listerella from a premature bovine fetus, Science 90: 336, 1939. 5. Rappaport, F., Rabinovitz, M., Toaff, R., and Krochik, N.: Genital listeriosis as a cause of repeated abortion, Lancet 1: 1273, 1960. 6. Rost, H. F., Paul, H., and Seeliger, H. P. R.: Habitueller Abort und Listeriose, Deutsche reed. Wchnschr. 83: 1893, 1958. 7. Seeliger, H. P. R.: Listeriosis, New York, 1961, S. Karger. 8. Gray, M. L., Stafseth, H. J., Thorp, F., Jr.: Sholl, L. B, and Riley, W. R., Jr.: A new technique for isolating listerella from the bovine brain, J. Baet. 55: 471, 1948. 9. Gray, M. L.: A rapid method for the detection of colonies of listeria monocytogenes, Zentralbl. Bakt. I., Orig. 169: 373, 1957. 10. Finegold, S. M., Bradley, J. (3., Gampbell, M. K., and Greenberg, A. J.: Listeria monocytogenes meningitis, summation of literature and report of two new cases, A. M. A. Arch. Int. Med. 93: 515, 1954. 11. Welshimer, H. J., and Winglewish, N. G.: Listeriosis--summary of seven cases of llsteria meningitis, J. A. M. A. 171: 1319, 1959.

350

Nichols and Woolley

12. Miller, J. K.: Personal communication, 1961. 13. Miller, J. K.: Human listeriosis in New York State, Proc. New York State A. Pub. Health Lab. 40: 5, 1960. 14. Dedrick, J. W.: Listeria meningitis, a report of eight cases, Am. J. M. Sc. 233- 617, 1957. 15. Hood, M.: Listeriosis as an infection of preg-

September 1962

nancy manifested in the newborn, Pediatrics 27: 390, 1961. 16. Hood, M.: Listeriosis, report of 10 cases, Am. J. Clin. Path. 28: 18, 1957. 17. Gray, M. L., Stafseth, H. J., and Thorp, F., Jr.: A four year study of listeriosis in Michigan, J. Am. Vet. M. A. 118: 242, 1951.