Management of Bacterial Meningitis in Children

Management of Bacterial Meningitis in Children ALLEN W. MATHIES,

JR.,

M.D.

PAUL F. WEHRLE, M.D.

Despite the development of effective antibiotics, the existence of intensive care facilities in many hospitals and the better management of shock, bacterial meningitis still presents a frequent and life-threatening problem in childhood. This disease, although encountered in all age groups, is most common in young children. The pediatrician must be alert to the recognition of the problem of bacterial meningitis and provide early and accurate diagnoses for optimal therapeutic results. In addition to therapy during the acute stage, early recognition and proper management of sequelae are also necessary for the total care of the patient.

EVALUATION OF THE PATIENT

General. The neonatal period is the age of greatest risk for bacterial meningitis. Case rates of 1 per 1000 to 2000 births are to be expected, with higher rates among low-birth-weight infants.3 Unfortunately, the occurrence of bacterial central nervous system sepsis at this age presents special problems in early diagnosis. Signs of meningeal irritation (nuchal rigidity, with positive Kernig and Brudzinski signs) are often minimal or nonexistent. The infant characteristically appears fretful and often anorectic. Frequent stroking of the head or a frown are characteristic infant counterparts of headache. Vomiting often appears early, and the dehydration which ensues is likely to prevent the appearance of the characteristic "full fontanelle" until late in the course of the disease. Fever is often absent, and in fact the temperature may fall below normal levels. If recognition of the true nature of the problem does not occur, further progression of the disease leads to somnolence, convulsions and coma. Opisthotonos appears late in the course of the illness. In the older infant and the child, the illness is somewhat more easily Pediatric Clinics of North America-Vol. 15, No.1, February, 1968

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recognized and more closely resembles that seen in the adult. Headache is an early complaint at ages of 6 years and older, and the signs of meningeal irritation are usually recognizable. Fever, vomiting, convulsions and drowsiness leading to coma are often encountered, although the older infant and the child are usually brought to the physician prior to this stage of the disease. Shock. Approximately 10 per cent of children with acute bacterial central nervous system disease arrive at the hospital in definite or impending shock. Shock may be unrecognized in young infants, but poor circulatory status may be suspected in those with subnormal temperatures. Prompt recognition of this problem is essential, as is the administration of intravenous fluids for rapid expansion of intravascular volume. Administration of isoproterenol (Isuprel, 5 mg./lOOO mI., given slowly intravenously and monitored by blood pressure response) may be helpful in patients unresponsive to initial hydration or administration of colloid solutions. Pharmacologic doses of glucocorticoids (Decadron, 0.5 mg./kg. initially with repeated doses of 0.25 mg./kg. every 3 or 4 hours as indicated by patient's response) may be used, although clinical proof of their efficacy is lacking. A central venous catheter must be used for patients in shock to monitor circulatory status in order to guide therapy. It should be noted that the period of greatest risk of death is the first few hours after hospital admission for all cases of bacterial meningitis. Skin Lesions. The evaluation of the patient includes careful search for skin lesions characteristic of meningococcal disease. Although occasionally seen in acute staphylococcal endocarditis or in fulminant pneumococcal infections, the petechial lesions of meningococcal septicemia are nearly diagnostic. The skin lesions of meningococcal disease are fully described below (p. 189). Neurological Signs. In the newborn, neurological signs are frequently limited to a high-pitched cry and slight to moderate fullness of the fontanelle. Occasionally, if diagnosis is delayed, the fontanelle may be markedly bulging. In the older child, signs of meningeal irritation are easily elicited. Nuchal rigidity may be recognized early in the course of the disease if the child is seated with legs outstretched when flexion of the neck is attempted. By this means, minor degrees of neck stiffness may be emphasized, although they are easily overlooked if simple flexion of the neck is attempted with the child supine. The Kernig and Brudzinski signs are readily elicited if meningeal inflammation is moderate to marked. Tendon reflexes remain normal. If there is alteration in tendon reflexes or sensory disturbances, or if Babinski's sign is present, subdural or brain abscess, interference with the long tracts due to cord compression (epidural abscess) or other complications must be suspected. Presence of Underlying Disease. Although bacterial meningitis in infancy and childhood usually appears spontaneously and without under-

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lying disease, the evaluation of the patient should include a careful search for otitis media, pneumonia and signs of other septic foci. Sickle cell disease appears to predispose to pneumococcal meningitis,9 as does previous skull fracture or mastoiditis. Endocarditis is often associated with unusual causes of bacterial meningitis, as are immunological defects or prior treatment with immunosuppressive agents. Congenital defects, such as meningoceles and dermal sinuses, and recent neurosurgical procedures with installation of tubes or valves, are frequently associated with unusual organisms should infection occur.

SPECIFIC IDENTIFICATION OF THE TYPE OF BACTERIAL MENINGITIS

Examination of the spinal fluid is the only method for immediate confirmation of the diagnosis. At the time spinal fluid is obtained, at least one and preferably two blood cultures should also be collected, prior to instituting therapy. Other methods of identifying the organism include gram stain of petechial smears in patients with cutaneous lesions. An examination of the eye grounds should precede lumbar puncture. If choked disks are seen, small-diameter needles should be used and minimal quantities of fluid removed slowly. Mter adequate skin preparation, the patient should be restrained firmly. The bevel of the needle should be parallel to the trunk in order to minimize dural tear. A dry tap should alert the physician to the possibility of epidural abscess or other obstruction. Gelatinous fluid with a few elliptical cells is occasionally seen in young infants when spinal fluid is obtained by relatively inexperienced physicians. This represents the fluid from the nucleus pulposus rather than spinal fluid. It is imperative that spinal fluid pressures be recorded and flow carefully controlled during the collection of fluid. Immediate examination of the spinal fluid in the clinical and bacteriological laboratories should indicate whether infection exists, and if so, whether it represents a chronic meningitis due to acid-fast organisms or fungi, or whether it is an acute bacterial or viral disease. Bacterial infections characteristically have a marked cellular response, with cell counts in the thousands, depressed sugar and elevated protein. The predominant cell is the polymorphonuclear leukocyte, and in approximately two thirds of patients organisms may be seen in the gram-stained sediment on direct examination. Fluorescent microscopy, if available, may occasionally be helpful in specific identification of a single organism, or in providing etiologic confirmation for those infections in which the patient has received antimicrobial therapy before spinal fluid is obtained. A complete examination of the spinal fluid should always be carried out, since fulminant pneumococcal meningitis at the extremes of life as well

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as acute meningococcemia may not have cellular response. Particularly in the former, gram stains of the sediment will yield large numbers of organisms, although white cells may be absent.

CHARACTERISTICS OF COMMON CAUSATIVE ORGANISMS

Neisseria Meningitidis. During epidemic periods of meningococcal disease, meningococcal meningitis is the most frequent type seen. Approximately 5 per cent of the patients have a fulminant course resembling the classical Waterhouse-Friderichsen syndrome. In the latter, the disease may progress to death prior to cellular response or the appearance of organisms in spinal fluid. The distribution of patients by age group with outcome is noted in Table 1. As noted, the first year of life is the age of greatest frequency of disease. Table 1. Meningitis in Children by Age Group and Outcome* AGE GROUP

OUTCOME OF ILLNESS

Lived Died Total Case Fatality

<2

MO.

1 0

-

2-5

MO.

2 -0 2

Lived Died Total Case Fatality

2 0 -2

Lived Died Total Case Fatality

0 0 0

MO.

1

YR.

2-4

YR.

Meningococcal Disease 22 32 55 1 2 0 23 32 57

17 4 21 19.0%

Lived Died Total Case Fatality

6-11

4.3%

3.5%

Hemophilus influenzae Meningitis 33 80 71 76 4 5 5 7 80 38 85 78 13.2%

12 3 15

5.9%

8.9%

5.0%

Pneumococcal Meningitis 11 13 19 1 1 1 20 12 14

20.0%

5.0%

8.3%

7.1%

Purulent Meningitis of Unknown Etiology 29 8 16 16 0 0 0 0 29 16 16 8

5-14

YR.

38 5 43 11.6%

16 1 17 5.9%

15 2 17 11.8%

23 0 23

TOTAL INCLUDED

165 12 177

-

6.8%

278 22 300 7.3%

72 8 80 10.0%

92 0 92

* Communicable Disease Service, Los Angeles County General Hospital, July 1963 to July 1966 (pneumococcal meningitis, to April 1967).

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Two thirds of patients with meningococcal disease have one or more types of rash. Five different types of rashes have been seen with the bacteremic stage of meningococcal disease. Early in the illness a morbilliform rash may appear, particularly on the trunk and lower extremities. This rash is often evanescent and usually is replaced by classical petechial lesions within a few hours. These lesions range from minute petechiae to relatively large extravasations of blood directly into the skin. Large ecchymotic or purpuric lesions may be seen in severe or fulminant disease and occur most frequently on the face and extremities. Occasionally, lesions similar to erythema nodosum may be seen on the forehead or in the skin covering the anterior surface of the tibia. Very rarely, large bullae may appear adjacent to the large ecchymotic or purpuric areas. These bullae characteristically make their appearance during convalescence. Hemophilus lnfl,uenzae Type B. This organism represents the most common type of bacterial meningitis in children, and is the type responsible for the greatest number of total cases with the exception of peak meningococcal epidemic years. The age of greatest risk is again the first year of life, with cases rare prior to 2 months of age. 6 Only 10 per cent of patients with Hemophilus inHuenzae meningitis develop their illness after the fourth year of life. 2 Nearly all infections are due to type B, a common inhabitant of the nasopharynx in children. Although most disease appears to occur either spontaneously or following a mild respiratory infection, episodes apparently secondary to acute otitis media, pneumonia or cellulitis are seen. Table 1 indicates the age distribution and outcome of children with Hemophilus inHuenzae meningitis by age group and outcome through age 14 years. Diplococcus Pneumoniae. The third most common type of bacterial meningitis is that due to various types of pneumococci. Young infants appear to have pneumococcal meningitis de novo, but in the older child, meningitis frequently has its origin in otitis media, mastoiditis or pneumonia, and the child with sickle cell disease appears unduly susceptible. Indeed, nearly half of the Negro children admitted to our service with pneumococcal meningitis have been found to have associated sickle cell disease. Table 1 indicates the age distribution and outcome of pneumococcal meningitis occurring in children under age 15 admitted to our service recently. Other Organisms. Streptococcal meningitis, rarely seen, may result from extension of group A streptococcal infections of the upper respiratory tract, particularly following middle ear disease. Non-group A streptococcal meningitis is most frequently seen during the neonatal period; in older patients, the infection may be secondary to endocarditis. Staphylococcal meningitis, Axtremely rare, may be secondary to acute staphylococcal endocarditis or a neurosurgical procedure, or a direct extension from an abscess.

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Meningitis rarely is caused by more than a single organism. 10 When mixed infections are encountered, the patient usually has an obvious mechanical, immunological or congenital defect. Infants with meningoceles and those with prior neurosurgical procedures are particularly likely to have unusual or multiple organisms and require particular care in evaluation and in identification of the organism and its antibiotic susceptibilities. Purulent Meningitis of Unknown Etiology. In approximately 16 per cent of patients with frankly purulent meningitis, no organism is recovered. The age distribution parallels most closely that of meningococcal disease. Prior antibiotic therapy is the most common reason for failure to recover organisms, and may thus be important in favorably influencing the outcome, as noted in Table 1. Neonatal Meningitis. Meningitis of the newborn infant presents special problems in management. The organisms associated with meningitis in older children are infrequently found in this age group. In contrast, enteric and unusual organisms presenting special requirements for antimicrobial therapy are seen, as recorded in Table 2. This, together with the difficulty in recognition of the disease and in determining the circulatory status of the newborn, accounts, at least in part, for the high case fatality rate.

Table 2. Purulent Meningitis in Infants Less than 1 Month oj Age by Etiology and Outcome* CLINICAL RESULT TYPE OF ORGANISM LIVED

DIED

TOTAL CASES

CASE FATALITY

%

Gram-negative

E. coli Paracolon K.A. group Proteus Salmonella H. influenzae Pseudomonas Mimae

7 8 4 3 1 0 1 1

12 5 7 1 2 2 0 0

19 13 11 4 3 2 1 1

63.2 38.5 63.7 25.0 66.6 100.0 0.0 0.0

2 1 1 2 2 1

3 3 0 0 1 2

5 4 1 2 3 3

60.0 75.0 0.0 0.0 33.3 66.6

Unknown Etiology

17

5

51

43

22 94

22.7

Total

Gram-positive

Listeria Beta hemo. strep. Alpha hemo. strep. Gamma hemo. strep. S. albus Pneumo.

-

45.7

*Communicable Disease Service, Los Angeles County General Hospital, 1961 to 1966.

MANAGEMENT OF BACTERIAL MENINGITIS IN CHILDREN

Table 3. AGE OF PATIENT

<2 months 2 months and older

191

Recommended Therapy

INITIAL THERAPY

DEFINITIVE THERAPY

Ampicillin, 75-150 mg./kg./day and kanamycin 15 mg./kg./day Ampicillin 150 mg./kg./day

Dependent upon specific sensitivities of organisms Meningococci = Penicillin G or ampicillin Pneumococci = Penicillin G or ampicillin H. influenzae = Ampicillin Purulent, unknown = Ampicillin

SELECTION OF SPECIFIC THERAPY

As noted in Table 3, the preferred antimicrobial management for initial therapy for the newborn infant differs from that recommended for the older infant and the child. In the neonatal period no single antimicrobial agent is optimally effective against more than two thirds of the organisms likely to be encountered. Therefore a combination of either penicillin or ampicillin with kanamycin must be used, and can be expected to be effective against more than 95 per cent of organisms found in this age group. After the organism has been isolated and appropriate antibiotic susceptibility has been determined, continued treatment with a single antimicrobial agent is preferred, provided one with bactericidal activity can be identified. An important consideration in therapy at this age is that the duration of treatment should be at least 3 weeks, and spinal fluid should be examined at intervals to ensure that the appropriate response is obtained and that cultures are sterile during therapy. Occasionally intrathecal therapy is necessary in this age group, and it is usually required with polymyxin treatment for pseudomonas infection. For patients 2 months of age and older, and without evidence suggesting that an unusual organism may be present (prior neurosurgical procedure, endocarditis, immunological defect, leukemia, etc.), ampicillin is the preferred initial therapy. This drug is at least as effective against H. influenzae type B as is chloramphenicol, on the basis of both in vitro and in vivo data. 4 It shares with penicillin G bactericidal activity against both the meningococcus and the pneumococcus, as well as other penicillin-sensitive organisms. This activity, together with its lack of toxicity, makes ampicillin a logical choice for initial therapy in the patient older than 2 months of age. 7 The addition of other antibiotics has not proved benefical in controlled evaluation. l l After specific identification of the organism is assured, penicillin G may be used for pneumococcal and meningococcal infections in doses

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equivalent to 150 mg. per kg. per day of ampicillin. These doses approximate 3 million units in patients under the age of 2 years, 6 million units from age 3 through 6 and 15 million units per day in patients older than 6 years. All drugs should be given intravenously with the exception of kanamycin. Although sulfonamides were considered the drugs of choice in the past for meningococcal disease, recent experience indicates that they no longer have a place in therapy. During recent years approximately two thirds of meningococcal infections in our hospital have been due to type B organisms. Approximately one third of meningococci have been resistant to sulfonamide in vitro in concentrations of 10 mg. per 100 m!. or greater. 5 Therefore, since sulfonamides can no longer be depended upon for a satisfactory therapeutic result, and since they add appreciably to drug toxicity (fever, rash), there seems little reason to continue theIr use in the therapy of meningitis. Assessment of the patient's response to therapy is based on his general condition and repeated evaluation of the spinal fluid. A repeat lumbar tap should be done 24 to 36 hours after initiation of therapy. The cell count is frequently higher than the initial count, but viable organisms will be absent if the appropriate drug has been administered. (An exception is neonatal meningitis caused by enteric bacilli, which may persist and be viable for several days.) Therapy should be continued until the patient is afebrile for 5 days, the cerebrospinal fluid cell count is 30 cells or less and the sugar and protein have returned to normal. If these somewhat rigid criteria are followed, relapse will not occur (no relapses in over 900 patients meeting these criteria).

GENERAL THERAPEUTIC CONSIDERATIONS

The monitoring of the patient's condition during the course of the infection is essential if instability of blood pressure is noted. An indwelling central venous catheter should be inserted, and frequent blood pressure determinations must be made. Fluid volume should be restored until reflected in increased central venous pressure, digitalization may be necessary, and isoproterenol may be used. Although pharmacologic doses of hydrocortisone or other glucocorticoids have been advocated, and seem to have a sound physiologic basis, no control data are available which would support their use. Enzymes of various types have been advocated for intrathecal use in patients with unusually purulent spinal fluid. We believe that there are insufficient experimental data to justify their general use, even with grossly purulent spinal fluid. Routine intrathecal administration of antibiotics also has been advocated, although there are no data that would suggest that either mortality or morbidity is decreased by this practice. The sole exception is the intrathecal use of polymyxin in pseudomonas

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infections, since this drug is sufficiently toxic that high serum levels cannot be obtained without renal damage. Acute cerebral edema presents a serious problem. While urea (0.5 gm. per kg. intravenously every 12 hours) or mannitol (2.0 gm. per kg. intravenously given in 30 minutes) has been advocated for its control, these are not as effective in inflammatory central nervous system disease as in patients suffering acute brain trauma. If either of these agents is used, both electrolytes and blood urea nitrogen should be followed carefully. Persistent fever is usually due to continued sepsis in a subdural effusion, the formation and persistence of a brain abscess, lateral sinus thrombosis, tissue necrosis, ecchymotic cutaneous lesions, sinusitis or mastoiditis, a urinary tract infection, pneumonia or drug fever. In our experience, the latter is the most deceptive and most frequently overlooked of these possible sources for continued pyrexia. Diffuse intravascular clotting has been described in meningococcal disease. 1 This phenomenon is generally associated with a poor prognosis, and although heparinization may control the defect, the outcome is frequently fatal. 8

PROBLEMS REQUIRING SURGICAL CORRECTION

Approximately 10 per cent of infants with bacterial meningitis have associated symptomatic subdural effusions, although nearly 50 per cent may have small amounts of subdural fluid if explored. While removal of subdural fluid may not be essential for recovery, we prefer to remove any such accumulation by daily subdural taps. A maximum volume of 15 ml. is removed daily from each side of the fontanelle. Fluid should be permitted to drip freely, and if fluid reaccumulates without obvious diminution after 2 weeks, the patient should be reviewed with the neurosurgeon. Surgical removal of the membrane is infrequently required. If indicated, it should be performed approximately 3 weeks after recognition of the effusion. Antimicrobial therapy should be continued until after the surgical correction of the lesion, since overwhelming sepsis may ensue if therapy is discontinued prior to the surgical procedure. If brain abscess is suspected, cerebral angiograms and a bran scan are indicated, provided the patient's condition permits. Occasionally an echo encephalogram is helpful in lateralizing the lesion. Surgical treatment should be delayed, if possible, until the subacute stage of the disease and the abscess has been well localized. Abscess with meningitis secondary to acute mastoiditis should be managed in a similar fashion, with a simple or total mastoidectomy during the convalescent stage or scheduled several months after recovery if indicated due to chronic mastoid disease. Occasionally, mastoiditis is associated with lateral sinus thrombosis. If so, prompt intervention may be necessary. Repeated episodes of meningitis are usually of pneumococcal etiology. They suggest a prior skull fracture with spinal fluid leakage. Surgical correction is possible if the sinus tract can be identified. In those with satisfactory identification and repair, experience suggests that recurrences are not likely. Occasionally plastic surgical procedures and skin grafts are necessary in the patient with severe meningococcal disease. By the time the skin lesions are ready for surgery, the generalized infection has been eradicated.

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REHABILITATION

The most frequently overlooked portion of the therapy for acute bacterial central nervous system disease is the careful evaluation for motor or sensory defect during convalescence. Proper rehabilitative measures should be planned during and after convalescence from the acute disease. It is important to remember that motor, intellectual or hearing impairments are seen in an appreciable proportion of patients surviving the acute illness. These defects occur with much greater frequency among yeung infants than among older children or adults. Fully 50 per cent of neonates recovering from bacterial meningitis may be expected to exhibit either motor or intellectual impairment. While many of the defects observed may not be severe, and may be overlooked in the hospital prior to discharge, it is apparent that the patient must be evaluated carefully during convalescence and must have repeated evaluations every 3 or 4 months during the year following the acute disease. In young infants repeated evaluations must be continued over a longer period, since intellectual impairment may not be apparent or recognized until school entry unless particular care is taken with the complete evaluation. Proper counseling and attention to defects, when noted, will do much to diminish the impact of these defects upon the development of the individual in his adult life. CONCLUSION

Despite the advances in antimicrobial and supportive therapy, acute bacterial infections of the central nervous system remain an important and serious disease in childhood. Prompt clinical recognition, specific identification of the infectious agent and the administration of bactericidal drugs by the intravenous route, with proper monitoring of the acute disease, are essential for optimal results. Spinal fluid examination must be repeated 24 hours after institution of therapy in order to be certain that the proper in vivo response has been obtained, and therapy must be continued until specific criteria for response have been fulfilled. Clinical monitoring of the patient for control of shock and for early recognition of complications is essential. Due to the frequency of residual defects, particularly among young infants, the patient should be carefully reevaluated at intervals during convalescence. The early recognition of defects will permit the planning of rehabilitative measures and will diminish the impact of these defects upon both patient and family. REFERENCES 1. Abildgaard, C. F., Corrigan, J. J., Seeler, R. A., et al.: Meningococcemia associated with intravascular coagulation. Pediat., 40:78-83, 1967.

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2. Fothergill, L. D., and Wright, W. R.: Influenzal meningitis. The relation of age incidence to bactericidal power of blood against the causative organism. J. Immunol., 24:273, 1933. 3. Groover, R. V., Sutherland, J. M., and Landing, B. H.: Purulent meningitis of newborn infants. New Eng. J. Med., 264:1115, 1961. 4. Ivler, D., Thrupp, L. D., Leedom, J. M., et al.: Ampicillin in the treatment of acute bacterial meningitis. Antimicrobial Agents and Chemotherapy 1963, p.335. 5. Leedom, J. M., Ivler, D., Mathies, A. W., et al.: Importance of sulfadiazine resistance in meningococcal disease in civilians. New Eng. J. Med., 278:1395,1965. 6. Mathies, A. W., Jr., Hodgman, J., and Ivler, D.: Hemophilus influenzae meningitis in a premature infant. Pediat., 85:791, 1965. 7. Mathies, A. W., Leedom, J. M., Thrupp, L. D., et al.: Experience with ampicillin in bacterial meningitis. Antimicrobial Agents and Chemotherapy, 1965, p. 610. 8. McGehee, W. G., Rapaport, S. I., and Hjort, P. F.: Intravascular coagulation in fulminant meningococcemia. Am. Int. Med., 67:250, 1967. 9. Robinson, M. G., and Watson, R. J.: Pneumococcal meningitis in sickle cell disease. New Eng. J. Med., 274:1006,1966. 10. Vaden, E. B., Rice, E. C., and Stadnichenko, V.: Meningitis due to simultaneous double infections in children. J.A.M.A., 143:1402, 1950. 11. Wehrle, P. F., Mathies, A. W., Jr., Leedom, J. M., and Ivler, D.: Bacterial meningitis. Ann. N.Y. Acad. Sci., 145:488, 1967. 1200 N. State Street Los Angeles, Calif. 90033