1. Bacterial Meningitis in Children
Dr Rajesh Kumar MD (PGI), DM (Neonatology) PGI, Chandigarh, India Rani Children Hospital, Ranchi

2. Inflammatory disease of the leptomeninges
three parts: the pia, arachnoid, and dura maters
Meningitis reflects inflammation of the arachnoid mater and the cerebrospinal fluid (CSF) in both the subarachnoid space and in the cerebral ventricles.
Suspected bacterial meningitis is a medical emergency,
Meningitis is an inflammatory disease of the leptomeninges, the tissues surrounding the brain and spinal cord. The meninges consist of three parts: the pia, arachnoid, and dura maters. Meningitis reflects inflammation of the arachnoid mater and the cerebrospinal fluid (CSF) in both the subarachnoid space and in the cerebral ventricles.
Suspected bacterial meningitis is a medical emergency, and immediate diagnostic steps must be taken to establish the specific cause so that appropriate antimicrobial therapy can be initiated. The mortality rate of untreated bacterial meningitis approaches 100 percent. Even with optimal therapy, morbidity and mortality may occur. Neurologic sequelae are common among survivors.

3. Organisms
1 month to 2 years — The major causes were S. pneumoniae (45 percent), Neisseria meningitidis (30 percent), and group B streptococcus (18 percent).
2 through 18 years — N. meningitidis was the most common cause, accounting for 59 percent of cases, followed by S. pneumoniae (approximately 25 percent) and Hib (approximately 8 percent).

4. Organisms H influnzae Pneumococcus N meningitidis
In <3 months: E.coli, Listeria

5. Clinical Features Two patterns
Develops progressively over one or several days and may be preceded by a febrile illness.
Acute and fulminant, with manifestations of sepsis and meningitis developing rapidly over several hours. The rapidly progressive form is frequently associated with brain edema

6. Symptoms Depends upon age Fever
Infants, 1-5 years, >5 years
Fever
Symptoms and signs of meningeal inflammation (nausea, vomiting, irritability, anorexia, headache, confusion, back pain, and nuchal rigidity)

7. Clinical features
In one review of 1064 cases of acute bacterial meningitis in children older than 1 month, 16 (1.5 percent) had no meningeal signs during their entire period of hospitalization
Kernig sign — With the hip and knee flexed at 90º, cannot extend the knee more than 135º and/or there is flexion of the opposite knee
Brudzinski sign — Brudzinski sign is present if the patient, while in the supine position, flexes the lower extremities during attempted passive flexion of the neck
Signs of meningeal irritation are present in 60 to 80 percent of children with bacterial meningitis at the time of presentation and in approximately 25 percent of children with normal CSF findings
Bulging fontanel was present in 20 percent of infants with meningitis, but also in 13 percent of infants with normal CSF and viral infections other than meningitis

8. Clinical features
Papilledema, which takes several days to become apparent, is an uncommon finding in acute bacterial meningitis. The finding of papilledema should prompt evaluation for venous sinus occlusion, subdural empyema, or brain abscess, TBM
Signs of increased intracranial pressure that may occur in bacterial meningitis include palsies of the third, fourth, and sixth cranial nerves
Seizures — Seizures, typically generalized, occur before admission to the hospital or within the first 48 hours of admission in 20 to 30 percent of patients with meningitis. Seizures later in the course are more often focal and may indicate cerebral injury

9. Focal findings — In one review of 235 children with bacterial meningitis, focal neurologic findings (hemiparesis, quadriparesis, facial palsy, visual field defects) were present at the time of admission in 16 percent of patients overall and in 34 percent of those with pneumococcal meningitis. The presence of focal neurologic signs at the time of admission correlated with persistent abnormal neurologic examination one year after discharge and with cognitive impairment.

10. History The course of illness
The presence of symptoms consistent with meningeal inflammation.
The presence of seizures, an important prognostic finding.
The presence of predisposing factors
Immunization history
Recent use of antibiotics, which may affect the yield of blood and/or CSF culture.

11. Examination
Vital signs: volume status, presence of shock, and the presence of increased intracranial pressure. The constellation of systemic hypertension, bradycardia, and respiratory depression (Cushing triad) is a late sign of increased intracranial pressure.
Head circumference should be measured at the time of admission in children younger than 18 months of age
Elicitation of meningeal signs
Cutaneous examinations are discussed above.
Other bacterial infections (eg, facial cellulitis, sinusitis, otitis media, arthritis, pneumonia).

12. Lab evaluation
Blood cultures: positive in at 50 % of patients. Among children who were not pretreated with antibiotics.
Contraindications to LP:
cardiopulmonary compromise,
increased intracranial pressure,
papilledema,
altered respiratory effort,
focal neurologic signs,
skin infection over the site for LP
CSF culture may be positive in the absence of pleocytosis

13. CSF
TLC:typically >1000 WBC/microL, with a predominance of neutrophils .A CSF WBC count >6/microL is considered abnormal in children older than 3 months of age
Traumatic LP: should be treated presumptively for meningitis pending results of CSF culture.
The presence of a single neutrophil in the CSF is considered abnormal
Glucose: <40 mg/dL in > 50% cases. ratio of the CSF to blood glucose concentration is usually depressed (<0.66)
Protein:100 to 500 mg/dL

14. CSF CRP 100 % sensitive and 96-100 % specific
-ve CRP rules out bacterial meningitis

15. Role of urine culture
Urine cultures should be obtained in infants (<12 months of age) who present with fever and nonspecific symptoms and signs of meningitis since urinary tract infection may be the primary source of the meningitis pathogen in such patients

16. Neuroimaging
Indications for imaging before LP in children with suspected bacterial meningitis include
Coma
The presence of a CSF shunt
History of hydrocephalus
Recent history of CNS trauma or neurosurgery
Papilledema
Focal neurologic deficit (with the exception of palsy of cranial nerve VI [abducens nerve] or VII [facial nerve])

17. Bacterial Meningitis Score
Positive CSF Gram stain
CSF absolute neutrophil count of <1000 cells/microL
CSF protein of at least 80 mg/dL
Peripheral blood ANC of at least 10,000 cells/microL
History of seizure before or at the time of presentation
The Bacterial Meningitis Score is a clinical prediction rule for children with CSF pleocytosis that classifies children at very low risk of bacterial meningitis if they lack all of the following [48]:
Positive CSF Gram stain
CSF absolute neutrophil count of <1000 cells/microL
CSF protein of at least 80 mg/dL
Peripheral blood ANC of at least 10,000 cells/microL
History of seizure before or at the time of presentation
The Bacterial Meningitis Score was validated in a retrospective cohort of 3295 children (29 days to 19 years) with CSF pleocytosis who presented to 20 academic emergency departments in the United States between January 2001 and June 2004 [48]. Approximately 4 percent had bacterial meningitis. Among the 1714 patients characterized as very low risk, only two (0.1 percent) had bacterial meningitis; both were younger than two months of age. The sensitivity and specificity of the Bacterial Meningitis Score were 98.3 and 61.5 percent, respectively. With additional study, the Bacterial Meningitis Score may prove to be helpful in clinical decision making for children with CSF pleocytosis.
In a review of 650 children (0 to 12 years) who underwent LP for evaluation of possible meningitis, CSF findings were normal in 57 percent of patients [18]. Indications for LP included fever; headache; vomiting; nuchal rigidity; first episode of convulsion with fever; and encephalopathic, toxic, or septic appearance. The incidence of normal CSF varied according to age, occurring in 83 percent of infants 0 to 8 weeks, 65 percent of children 8 weeks to 24 months, 53 percent of children 2 to 5 years, and 37 percent of children 5 to 12 years.
Absence of all these excludes bacterial meningitis

18. Treatment: General Principle
Avoidance of delay
Emperical antibiotic

19. Drug entry into CSF —Most drugs reach peak concentrations in the CSF that are only 10 to 20 percent of peak concentrations in the serum. This is because the blood-brain barrier blocks macromolecule entry into the CSF, with small, lipophilic molecules penetrating most easily.
The peak concentration of drugs in CSF increases with inflammation of the blood-brain barrier. The mean CSF/serum ratio two hours after administration of the same intravenous dose of penicillin was 42 percent on the first day of therapy but fell to less than 10 percent on the tenth day, when the inflammatory changes had subsided

20. Immediate management
Assurance of adequate ventilation and cardiac perfusion.
Initiation of hemodynamic monitoring
Establishment of venous access.
Administration of fluids as necessary to treat septic shock, if present.
Administration of dexamethasone if warranted. before or immediately after the first dose of antimicrobial therapy.
Administration of the first dose of empiric antibiotics
Administration of glucose (0.25 g/kg) for documented hypoglycemia (serum glucose concentration less than 40 mg/dL
Treatment of acidosis and coagulopathy

21. Supportive care Fluid and electrolyte management —
Isotonic fluid to maintain blood pressure and cerebral perfusion.
Children who are hypovolemic, but not in shock, should be rehydrated with careful and frequent attention to fluid status.
For children who are neither in shock nor hypovolemic, moderate fluid restriction (1200 mL/m2 per day) initially, especially if the serum sodium is less than 130 meq/L. Fluid administration can be liberalized gradually as the serum sodium reaches 135 meq/L. Most children can receive maintenance fluid intake within 24 hours of hospitalization.
Monitoring —
increased intracranial pressure, seizure activity, development of infected subdural effusions, particularly during the first two to three days of treatment,
Heart rate, blood pressure, and respiratory rate should be monitored regularly with a frequency appropriate to the care setting.
A complete neurologic examination should be performed daily; rapid assessment of neurologic function should be performed several times per day for the first several days of treatment.
Head circumference should be measured daily in children younger than 18 months

22. In US (nelson) In INDIA ? 25-50% S.pneumoniae resistant to penicillin
25 % S Pneumoniae resistant to cefotax or ceftraixone
30-40 % Hib resistant to ampicillin
In INDIA ?
Spinal fluid levels in normal infants are approximately 10-20% of the serum concentrations and may reach 50% when the meninges are inflamed. Amikin has been demonstrated to cross the placental barrier and yield significant concentrations in amniotic fluid
It penetrates into the cerebrospinal fluid in the presence of inflamed meninges. Because piperacillin sodium is excreted by the biliary route as well as by the renal route, it can be used safely in appropriate dosage

23. JIPMER Study
Organisms were isolated from the cerebrospinal fluid (CSF) in 35% of cases. Among infants and children, the two major pathogens were H. influenzae (17%) and S. pneumoniae (12%). RESULTS: The illness at presentation was mild in 13% and severe in 36% of cases. The

24. Emperic Therapy
empiric regimen should include coverage for Hib, penicillin resistant S. pneumoniae and N. meningitidis. E.coli in young infants
High dose of 3rd generation cephalosporin + Vancomycin

25. Dexamethasone
Animal studies:hearing loss is associated with the severe inflammatory changes
RCT and meta-analyses indicate that dexamethasone therapy provides no survival advantage in children, but reduces the incidence of deafness and severe neurologic complications in selected children, predominantly those with meningitis caused by Hib. The data are insufficient to demonstrate a clear benefit in children with pneumococcal meningitis
before or within one hour of the first dose of antibiotic therapy
concern that the CSF concentration of vancomycin may be diminished when administered with dexamethasone
> 6 weeks of age
0.15 mg/kg per dose) every 6 hours for 2 to 4 days

26. Duration of treament S. pneumoniae: 10-14 days
N. meningitidis: 5-7 days
Hib: 7-10 days
Gram –ve: 3 weeks
CSF analysis near the end of therapy, particularly in young infants, needs longer therapy if
Percentage of neutrophils >30 percent,
or CSF glucose concentration <20 mg/dL

27. Out patient therapy Completion of at least 6 days of inpatient therapy
Afebrile for at least 24 to 48 hours before initiation of outpatient therapy.
No significant neurologic dysfunction or focal findings.
No seizure activity.
Clinical stability.

28. Response to therapy
duration of fever is typically four to six days after the initiation of adequate therapy
Persistence of fever beyond 8 days and secondary fever have a number of causes, including:
Inadequate treatment
Development of nosocomial infection
Discontinuation of dexamethasone
Development of a suppurative complication (pericarditis, pneumonia, arthritis, subdural empyema)
Drug fever (a diagnosis of exclusion)

29. Repeat CSF Poor clinical response after 24-36 hours of antibiotics
Persistence or recurrence of fever
Gram –ve meningitis

30. Neuroimaging
Focal neurologic signs, increasing head circumference, or prolonged obtundation, irritability, or seizures (>72 hours after the start of treatment);
Persistently positive CSF cultures despite appropriate antibiotic therapy
Persistent elevation of CSF neutrophils at the completion of standard duration of therapy (more than 30 to 40 percent)
Recurrent meningitis

31. Prognosis
Mortality:meta-analysis: children 4.8 %in developed countries and 8.1 % in developing countries
Hib:3.8 %, N. meningitidis: 7.5 %, S. pneumoniae: 15.3 %
Neurological sequele:16% in developed and 26 % in developing countries
Deafness — 11 percent, including bilateral severe or profound deafness in 5 percent
Mental retardation — 4 percent
Spasticity and/or paresis — 4 percent
Seizures — 4 percent

32. Poor prognostic factors
Etiology: more with pneumocaccal
Seizure after 72 hours
CSF sugar < 20 mg per dl at admission
Delayed sterlization of CSF : > 24 hours

33. Untreated meningitis as hydrocephalus
infantile hydrocephalus due to clinically unsuspected meningitis.
8 year study period 54.2% (39/72) of hydrocephalus were found to be due to infection, far higher than what is reported from developed nations
it may be a good practice to sample the CSF in every infant with hydrocephalus before a shunting
Hydrocephalus in infancy is either due to prenatal etiologies like aqueductal stenosis, and meningomyelocele or due to peri-postnatal etiologies like infection and hemorrhage(1-3) Epidemiological studies in the West indicate that approximately two-thirds of infantile hydrocephalus is prenatal(1).
Hydrocephalus usually presents with a progressive macrocrania, irritability and vomiting. In post-meningitic hydrocephalus there is usually an apparent history of symptomatic neonatal meningitis and the hydrocephalus is not unexpected. Over the last few years we have identified several infants with progressive macrocrania in early infancy, without a past history of overt neonatal or early infantile meningitis and who on subsequent investigation had confirmed active meningitis/ventriculitis (MV). We believe that these cases were due to unrecognized meningitis in the neonatal period where clinical symptoms were masked by the use of inadequate antibiotics.
Subjects and Methods
The relevant medical records between 1991 and 1998 were reviewed by searching under the ICD coding of hydrocephalus for infants. Etiology was determined using clinical, imaging and other relevant data. MV was diagnosed when lumbar and ventricular CSF showed pleocytosis with or without positive cultures. The study group includes only those patients with hydrocephalus where the diagnosis of MV was not clinically suspected and where there was no obvious history of prior meningitis. This group was then analyzed for presence or absence of risk factors for meningitis(4) i.e., pre-maturity, low-birth weight, multiple births, signs of sepsis in the neonatal period, prolonged neonatal hospitalization, and empirical antibiotic use in the neonatal period. We also analyzed the clinical details of the current illness, the CSF biochemistry and culture, duration of antibiotic use and the use of neurosurgical procedures such as external ventricular drainage (EVD) and VP shunt. Outcome was analyzed after follow-up of at least 6 months. Patients were classified as normal/near normal, mildly disabled and severely disabled. The evaluation was based on both routine neurological examination and the Denver Developmental Scale.
Results
Analysis of records revealed that 39 out of 72 cases of hydrocephalus (54.2%) were the result of meningitis. 13/72 infants had confirmed prior neonatal meningitis and a further 13/72 had tuberculous meningitis. In 13/72, the patients had no obvious clinical MV and were diagnosed only by CSF examination and culture results. These 13 are reported here. The average age of the patients in the study group was 3 months with a range from 2 to 6 months of age. There were 12 males and 1 female.
All the patients in the study group had risk factors for meningitis(4) in the neonatal period. 8/13 were premature or low birth-weight, 3/13 were one of twins or triplets, 8/13 had clinical evidence of sepsis in the neonatal period. At least 5/13 had a history of prolonged hospital stay ranging from 11 days to 1.5 months. 1/13 had an invasive procedure (exchange transfusion). 10/13 had been given a course of antibiotics course in the neonatal period. In 6 of these 10, where details were available the duration of antibiotics was less than 2 weeks. Only one CSF study was performed in the neonatal period, and was abnormal (‘60 cells’).
Between the time of discharge from the newborn nursery to the time of presentation to us, 6/13 were perceived as "sick", and 6/13 were thought to be "well" by parents and the doctors following the children. 10/13 patients presented in early infancy with increasing head circumference (HC). All patients had macrocrania at presentation. Fever was present in only 5/13, seizures in 4/13, and vomiting in 3/13. Only 1/13 blood culture was positive, while all lumbar and ventricular CSF results were abnormal. 10/13 CSF cultures were positive and the samples grew a variety of organisms including Candida albicans, Staphylococcus aureus, Pseudomonas, Acinetobacter, Enterococcus, Steptococcus pneumoniae and Moxarella catarrhalis. Contrast CT scans revealed hydrocephalus in all 13 infants, 9 of whom were thought to be due to acqueductal obstruction. Ventriculitis was obvious in 2/13 and abscesses were seen in 1 case. Average total length of antibiotics given was 32.8 days. 4/13 patients required EVD and all were shunted between 1-5 weeks after admission. At follow-up, 7 patients were severely disabled, 2 mildly disabled, 2 were normal/near normal, and 2 were lost to follow-up.
Discussion
The aim of this study was to highlight the fairly common occurrence of infantile hydrocephalus due to clinically unsuspected meningitis. This is probably a unique problem in our country because of non-standardized practices of neonatal care. In this 8 year study period 54.2% (39/72) of hydrocephalus were found to be due to infection, far higher than what is reported from developed nations. An ongoing Swedish study from 1967 to 1994, found a prenatal etiology to be the most common cause in full term infants(l) and IVH to be the most common cause in pre-term infants(2,3). Infection was seen in only about 5% of term(l) and 7% of pre-term infants(3). Infection seems to be a more common etiology in India not unexpectedly. In 3/13 study patients CSF culture was negative despite a CSF picture typical of MV. Two of these infants were premature, raising the possibility of a persistent chemical (from IVH) rather than infective MV. In our study, of the 26/72 patients with neonatal meningitis, only 13 were diagnosed in the neonatal period. The other 13, despite risk factors for meningitis, were empirically treated for "sepsis" with an inadequate course of antibiotics. Only one child had a neonatal CSF examination. As a result, probably no newborn was treated for the recommended period of 3 weeks(4). This possibly resulted in a partially treated MV manifesting later as hydrocephalus. Partially treated meningitis often results in communi-cating hydrocephalus due to a block at the level of the convexity subarachnoid space. Ventriculitis, however results typically in inflammatory acqueductal obstruction(5,6) resulting in obstructive tri-ventricular hydrocephalus that can be easily confused on imaging with congenital acqueductal stenosis. To confound matters further 8/13 infants in our series did not have the usual symptoms of infection and could have been thus misdiagnosed as being due to prenatal acqueductal stenosis. However in our patients the ventricular CSF was clearly abnormal and grew microorganisms in the majority confirming the etiology of this obstructive hydrocephalus. If the CSF had not been sampled it could have led to a shunting procedure in infected CSF (as was the case in our initial patients) with disastrous results.
There is controversy in the literature about the need for a CSF examination in newborns with clinical or microbiologically proven sepsis(7-10). Though 8/13 in our series had clinical evidence of sepsis, 5/13 were asymptomatic and were treated with routine antibiotics only because they were ‘high-risk’. This suggests that CSF examination should be done in any high-risk newborn given antibiotics regardless of symptomatology, as ventriculitis maybe completely masked(10).
Even with early recognition and prompt treatment, there are long-term consequences of neonatal bacterial meningitis(2). Fernell and Hagberg(3) reported a 42% rate of CP in the survivors in 1967 a rate that improved to 22% by We believe that the poor outcome in 50% of our study group was the result of delayed diagnosis and inadequate treatment. It seems likely that had the diagnosis of meningitis been made in the neonatal period with a CSF examination and had adequate therapy been given then, long-term morbidity could have been reduced to a minimum.
Finally, it may be a good practice to sample the CSF in every infant with hydrocephalus before a shunting procedure is performed especially in those who had risk factors for meningitis in the neonatal period. This might prevent shunting infected ventricles with potential disastrous consequences.

34. Long-term Disability Following Neonatal and Infantile Meningitis -results at 5 years of age
Disability Neonates Infants Controls
n=274(%) n=1304(%) n=1391(%)
Severe (7.3)* 72 (5.5) 1 (0.1) – p<0.0001
Moderate (18.2)** 103 (7.9) 20 (1.4) – p<0.0001
Mild (24.1) (30.1) (19.8)
None (50.4) 737 (56.5) (78.7)
 * not significant. ** p<0.001

36. Meningococcal Vaccination
Currently licensed vaccine is composed of elements of polysaccharide coat of the bacteria
Serogroups A, C, W-135, and Y
Recommended for control of serogroup C meningococcal disease outbreaks although its not guaranteed to control them
Recommended for use among certain high risk-groups

37. Vaccine may benefit travelers to countries in which disease is hyperendemic or epidemic
A poor vaccine in children <18-24 months
Immunity of limited duration, especially in young children. Only 2-3 years at best.
Vaccine confers effective protection
Protective levels of antibody are usually achieved within 7-10 days