Acute bacterial meningitis seminar swastik

Acute Bacterial Meningitis

Preceptors: Prof. Rita Sood Prof. Padma M.V. Dr. Rohit Bhatia

Speaker: Swastik Agrawal

Presentation outline

Introduction Epidemiology Etiology Pathophysiology Clinical presentation Investigations Differentiating acute bacterial from non bacterial

meningitis Prognostic markers Treatment Complications and outcome Prevention Summary

Introduction Definition- Acute purulent infection within the

subarachnoid space. Meninges, subarachnoid space and brain parenchyma

frequently involved together-meningoencephalitis.

Pus covered surface - Leptomeninges

Incidence- 0.6-4/1,00,000 adults in developed nations.

Upto 10 times higher in developing nations.

Mortality 16% to 37% despite modern antibiotics.

Lancet Infect Dis 2007; 7:191–200 Lancet Neurol 2006; 5: 332–42

Epidemiology

Disease burden greatly reduced as a result of routine immunization of children with Hib vaccine.

Further reduction expected with wider usage of pneumococcal and meningococcal vaccines.

Proportion of cases in adults on the rise (≈ 56%)Lancet Infect Dis 2007; 7:191–200

Epidemiology (contd.)

In poorer countries where routine vaccination has not been implemented H. influenzae is still an important causative

organism.

Etiology

In developed world MC organism in both children and adults is S. pneumoniae ≈ 50%

N. meningitidis ≈ 25%

Group B Streptococcus ≈ 15%

Listeria monocytogenes ≈10%

H. influenzae < 10%

Staphylococcal species and gram negative bacilli in special circumstances.

Common causes of acute bacterial meningitis in resource poor settings

Lancet Neurol 2008; 7: 637–48

Tubercular and cryptococcal meningitis common in HIV

Maybe difficult to distinguish from acute bacterial meningitis.

Etiology (contd.)

Etiology (contd.)

Age wise distribution of pathogens- 10 year study from south India.

Indian Journal of Medical Microbiology, (2007) 25 (2):108-14

S. pneumoniae: pneumococcal pneumonia, sinusitis otitis media, alcoholism, diabetes mellitus, asplenia, HIV, hypogammaglobulinemia, complement deficiency, head trauma,CSF rhinorrhea.

N. meningitidis: asplenia, complement deficiency.

L. monocytogenes: neonates, elderly (>60 years),

pregnancy, immunodeficiency.

Group B streptococcus: neonates, age> 50 years.

Predisposing conditions

H. influenzae: unvaccinated children and adults.

Staphylococci: neurosurgical procedures, s.c. Ommaya reservoirs, shunts etc.

Enteric gram negative bacilli: diabetes, cirrhosis, alcoholism, chronic UTI, craniotomy

Predisposing conditions (contd.)

Pathophysiology Pneumococci colonize the nasopharynx and compete

with resident flora. Balance effected by recent antibiotic usage, host

immunity, smoking, over crowding. Invade intravascular space via the nasal epithelium. Avoid phagocytosis and complement mediated

destruction mainly by virtue of polysaccharide capsule. Invade choroid plexus cells and gain access to CSF via

transcytosis. Low levels of complements, antibodies and leukocytes in

CSF allow rapid bacterial multiplication.

Invasion of SAS by pathogenic bacteria

Multiplication and lysis of organisms

Release of bacterial cell wall components (endotoxin, techoic acid)

Production of inflammatory cytokines like TNFα, IL-1β, and IL-6

Altered BBB permeability

Adherence of leukocytes to

endothelial cells

Alterations in cerebral blood

flow

Production of excitatory AA,reactive O and

N species

↑Permeability of vesselsLeakage of plasmaproteins into CSF

Leukocytes enter CSF,degranulate and release

cytokines

Cell injury and death

Exudate obstructs outflow& resorption of CSF and

Infiltrates vasculatureCerebral ischemia ↓ Blood flow ↑ Blood flow

vasogenic edema

Obstructive and communicating hydrocephalus

Interstitial edema cytotoxic edema, stroke

seizures

↑ ICP

Coma

DEATHDEATH

Hence neuronal injury can progress even after CSF sterilization.

Clinical Presentation


Common signs and symptoms of acute bacterial meningitis

Right 3rd nerve palsy and severe herpes labialis in a patient of acute bacterial meningitis

Classic triad of fever, neck stiffness, and altered sensorium seen in only 2/3rd of adults.

More common in pneumococcal than other bacterial meningitis.

1 of the 3 elements present in almost all patients.

Absence of all 3 rules out acute meningitis with sensitivity of 99-100%.

Usually history is of 24 to 48 hours.

Clinical Presentation (contd.)

Rash most commonly seen with meningococcal disease (92% of meningitis cases with rash).

Presence of shock, rash or clustering of cases should raise suspicion of meningococcemia.


Petechial skin rash that accompanies meningitis due to Neisseria meningitidis.

Fine petechial rash in disseminated infection and meningitis due to Staphylococcus aureus

Kernig’s and Brudzinski’s sign have poor sensitivity (5%) with high specificity (95%)

Nuchal rigidity has low sensitivity (30%) and specificity (68%).


Jolt accentuation test - exacerbation of existing

headache on having the patient rotate his head horizontally

@2-3 times/ sec.

Sensitivity of 97%, specificity of 60% in a small study, never

been further evaluated extensively.


Lancet Infect Dis 2007; 7:191–200 N Engl J Med 2004;351:1849-59.

Investigations

↑ TLC (mean 10,600/cc vs 8900/cc).

↓Platelet counts- systemic infection, sepsis.

**Hyponatremia (serum Na < 135mEq/l) seen in 30% cases.

- Severe (Na <130) in 6%. (resolves spontaneously)

- More common with L. monocytogenes and in patients with symptoms > 24 hours.

Blood culture- should be taken immediately, before

starting antibiotics. Positive in 74% cases. **QJ Med 2007;100:37-

Acute inflammatory markers - ESR, CRP and Procalcitonin elevated : distinguish acute bacterial from non bacterial meningitis.

Diagnostic lumbar puncture - performed in all cases unless specific contraindications present-

i) local infection at puncture site ii) subdural abscess iii) bleeding diathesis iv) septic shock- diastolic BP < 60 mm of Hg v) mass lesion/ ventricular obstruction/ brain shift on

cranial imaging

Investigations (contd.)

Indications for cranial imaging before L.P.

Non contrast CT scan of the head before L.P. is indicated if one of the following is present:

i. New onset seizure (within one week of presentation)ii. Immunocompromised stateiii. Papilledemaiv. Focal neurological signs (excluding hearing loss)v. Moderate to severe impairment of consciousness

(GCS <10)

Absence of all these features has 97% negative predictive value for an intra cranial abnormality that would preclude a lumbar puncture

N Engl J Med 2004;351:1849-59. Lancet Neurol 2006; 5: 332–42

Meningeal enhancement in Bacterial meningitis.

Analysis of CSF- typical findings in bacterial meningitis Opening

pressure>180 mm water in 90% cases

WBC 10-10,000/cc, predominantly neutrophils (>100cells/cc in 90% cases)

RBC Absent in non traumatic tap

Glucose <40 mg/dl in 60% cases

CSF/blood glucose

<0.4 in 60% cases

Protein >45mg/dl (in 90% cases)

Gram’s stain Positive in > 60%

Culture Positive in > 80%

Latex agglutination

+ in pneumococcal, meningococcal, H. influenza, E.coli, Gr B streptococcus

Limulus lysates + in gram negative meningitis

PCR for bacterial DNA

Research test

Harrison's Principles of

Internal Medicine, 17th ed

Cell type Cell count Glucose Protein

Normal Lymphocytes 0-4 >60% of blood glucose

< 0.45 mg/dl

Viral Lymphocytes 10-2000 Normal Normal

Bacterial Polymorphs 1000-5000 Decreased Increased

Tubercular Lymphocytes/polymorphs

50-5000 Decreased Increased

Fungal Lymphocytes 50-500 Decreased Increased

CSF findings in infectious meningitis


Examine CSF before or shortly after antibiotics started.

Submit large volume of CSF ( >5 ml) for microbiology.

Gram stain and inoculation for culture as soon as possible.

Centrifuge at high force ( 3000g) for 20 min and stain and culture the deposit.

Subculture after 24 hr inoculation in brain heart infusion broth at 37°C with 5% CO2.

Storage/ transport of CSF – incubate at 37°C if available or at room temperature.

Do not refrigerate.


Methods to improve diagnostic yield of microbiology

Turbid CSF with fibrous spider clot after 1 hour in pyogenic meningitis

Gram positive diplococci of S. pneumoniae in CSF. Neutrophils and gram negative bacilli in

CSF of an elderly patient of E. coli meningitis

Gram negative rods- H. influenzaGram negative diplococci of meningococci in CSF

CSF latex agglutination for pneumococcal and meningococcal antigen - specificity of 95-100%.

Sensitivity 70-100% for pneumococci, 30-70% for meningococcci.

Pneumolysin in CSF - detected by Cowan 1 Staphylococccal protein A co-agglutination method.

Sensitivity and specificity of 91 and 92% respectively. Indian J Med Res 119, February 2004, pp 75-78


CSF C reactive protein (CRP)- rapid test by latex slide agglutination method, available as a kit.

Positive when value > 6μg/ml. Sensitivity of 84% and specificity of 100% in

distinguishing acute bacterial from aseptic meningitis. Indian Pediatrics, Vol. 32-June 1995

Semi quantitative measurement of glucose and protein using urinary dipsticks may be acceptable if lab. facilities unavailable.

It is able to differentiate abnormal from normal CSF in 97% and viral from bacterial meningitis in 98% cases.



American Journal of Emergency Medicine (2007) 25, 179–184

Study of 151 adults with acute meningitis-

Comparison between ABM and NBM on biological variables

Differentiating acute bacterial from non bacterial meningitis


Comparison of the efficiency of the emergency physician and various biological results

Differentiating acute bacterial from non bacterial meningitis (contd.)


Threshold values for each variable determined by the AUC


Bacterial meningitis score (BMS)

Predictor

Points

Present Absent

CSF Gram stain 2 0

CSF protein > 80mg/dl 1 0

CSF ANC>1000/cc 1 0

Peripheral blood ANC > 10,000/cc

1 0

Seizures at or before presentation

1 0

JAMA. 2007;297:52-60


Risk of bacterial meningitis is very low (0.1%) with BMS 0 and it increases as the score increases:-

– 3% with score 1– 27% with score 2– 70% with score 3– 95% with score ≥ 4

It has a negative predictive value of 99.9% for acute bacterial meningitis.

Validated only in age group of 29 days to19 years. Not applicable to adults and neonates.

JAMA. 2007;297:52-60


Prognostic markers Indicators of poor prognosis in a case of bacterial

meningitis are:-

1. Evidence of systemic compromise – tachycardia (HR>120 bpm), low blood pressure, positive blood culture, raised ESR, low platelet count.

2. Low CSF leukocyte count (<100/cc).

3. Low score on GCS

4. Advanced age

5. Predisposing conditions like immunocompromised state, pneumonia, otitis, sinusitis.

6. Cranial nerve palsy

7. Pneumococcal meningitis- 6 times higher chance of unfavorable outcome compared to meningococcal meningitis.

Lancet Infect Dis 2007; 7:191–200 N Engl J Med 2004;351:1849-59.

Prognostic markers (contd.)

A bedside risk score to identify individuals with high risk of adverse outcome that can be used within 1 hour of presentation has been developed using both a derivation cohort (696 cases) and a validation cohort (301 cases).

22 variables were studied and 6 were found to have a significant bearing on outcome.

Prognostic markers (contd.)

Ann Neurol 2008;63:90–97

This score helps to decide level of care required and for informing the patient and his/her relatives about the prognosis.

Treatment

Antibiotics are the mainstay of treatment. Should be given as early as possible. Delay >3 hours independently associated with mortality

Q J Med 2005; 98:291–298

Lancet Infect Dis 2007; 7:191–200

Initial empirical antibiotics

Clinical Infectious Diseases 2004; 39:1267–84

Dosage


These recommendations are based on the US microbiological antibiotic susceptibility patterns.

The Netherlands national guidelines recommend monotherapy with penicillin in patients 16-60 years based on low incidence of penicillin resistance locally.

No India/ SE Asia specific guidelines available.

Treatment (contd.)

Organism specific antibiotics




Duration of antibiotic therapy

WHO recommendation – 5 day antibiotic therapy To be extended if-– Immunocompromise– Persistent fever– Persistent seizures– Coma

Role of corticosteroids

Mortality and rate of neurological sequelae remain high despite appropriate antimicrobial therapy.

Due to adverse effects of inflammatory cytokines.

Corticosteroids act by– inhibiting synthesis of IL-1 and TNF at m-RNA level– decreasing CSF outflow resistance and – stabilizing the BBB.

Once macrophages and microglia activated and TNF production induced, steroids have less effect.

Hence steroids to be given early, with or before 1st dose of antibiotics to have maximum effect.

Duration of this window of opportunity not described.

Dose- Dexamethasone 0.15 mg/kg I.V. 6th hourly for 4 days is the most widely recommended dose.

2 day regimen with 0.4 mg/kg 12th hourly shown to be equally efficacious in one study(Syrogiannopoulos,1994)

Role of corticosteroids (contd.)

Cochrane review- beneficial effect of steroids in adults from both high and low income countries and children from high income countries.

Children from low income countries had neither benefit nor harm.

Overall case fatality decreased (RR 0.83), specially in pneumococcal group (RR 0.42).

10 adult patients need to be treated with steroids to prevent one mortality.

Lower rate of long term neurological sequelae (RR 0.67) Lower rate of short term neurological sequelae in high

income countries ( RR 0.56).


Cochrane Database of Systematic Reviews2007, Issue 1. Art. No.: CD004405.

Cochrane Database of Systematic Reviews

2007, Issue 1. Art. No.: CD004405.

Cochrane Database of Systematic Reviews2007, Issue 1. Art. No.: CD004405.

Randomized controlled trial of 301 adult patients from the Netherlands -

N Engl J Med, Vol. 347, N o. 20

Distribution of scores on Glasgow outcome scale at eight weeks


N Engl J Med, Vol. 347, N o. 20

Outcome at eight weeks according to culture results

RCT from Vietnam of 435 cases - no benefit in mortality at 1 month or mortality and disability at 6 months.

Significant increase in mortality in probable bacterial meningitis cases probably due to a number of TBM cases in this subgroup

N Engl J Med 2007;357:2431-40.


RCT of 465 adult cases in Malawi - no difference in mortality or disability, even in proven pneumococcal meningitis patients.

N Engl J Med 2007;357:2441-50.


90% of study population were HIV positive.

Since these patients already have an attenuated host response, corticosteroids may not confer any advantage.

As per these studies routine use of steroids in developing countries with high incidence of HIV and tuberculosis is questionable.

N Engl J Med 2007;357:2441-50


Potential adverse effects of corticosteroids were not found to be higher in dexamethasone treated patients.

N Engl J M ed, Vol. 347, N o. 20


No evidence to indicate that short term steroid use worsens neurocognitive consequences of meningitis by hippocampal neuron apoptosis.

Dexamethasone reduces vancomycin levels in CSF and delays CSF sterilization. Careful observation of such patients is needed.


Supportive treatment

Treatment of raised ICP – - Head end elevation (30°-45°)- IV mannitol (25-100 g 4th hourly) - Intubation and hyperventilation (PaCO2 25-30

mm of Hg). Maintain ICP below 20 mm of Hg.

Maintain blood pressure and urine output. Aggressive fluid resuscitation to be avoided for

fear of hyponatremia.

Potential treatment strategies Drugs aimed at down regulating inflammatory mediators

and pathways responsible for neuronal injury in bacterial meningitis are at the experimental level .


Effects of adjuvant therapies on experimental bacterial meningitis

Suspicion of bacterial meningitis

Immunocompromised, H/O CNS disease, new onset seizures, focal deficits, papilledema, altered sensorium , delay in performing lumbar puncture.

Blood culture STAT

Dexamethasone + empirical antibiotic therapy

CT scan head

Perform lumbar puncture

No C/I to lumbar puncture

YesNo

Blood culture and lumbar puncture STAT


CSF c/w pyogenic meningitis?Consider alternate diagnosis

No

Yes

CSF gram stain positive?


Dexamethasone + targeted antibiotic therapy

No Yes

Algorithm for management of suspected bacterial meningitis

Complications and Outcome


Cerebral abscess

Cerebral abscessGross:

Enlarged lateral ventricles in a patient with hydrocephalus - treated by placing two shunts.

Dilation of the cerebral ventricles (Hydrocephalus).


19%21%

5%

14%13%12%

10%

4%

Complications and Outcome (contd.)


Complications and Outcome (contd.)

Prevention

Vaccination and chemoprophylaxis useful for prevention.

Chemoprophylaxis reserved for meningococcal disease.

Only for close contacts, to be given as early as possible.


Meningococcal vaccine – quadrivalent polysaccharide vaccine against serotypes A,C,Y and W 135.

Indications- - Control type C outbreaks- Travelers to endemic regions - Asplenia and terminal complement deficiency Single dose, repeated in 3-5 years after age of 2 years.

Prevention (contd.)

Meningo-coccal vaccine introduced

Prevention (contd.) Pneumococcal vaccine - 23 valent polysaccharide

vaccine. Indications- asplenia, immunodeficiency, DM, CRF,

nephrotic syndrome, CLD, malignancies etc. 2 doses 1-2 months apart after age of 2 years One time revaccination after 5 years if age < 65 years.

H. influenzae type b vaccine - conjugate vaccine. Indication- Routine immunization of all children. 3 doses 2 months apart starting at 2 months age. Booster at 15 months age.

Summary Most common organisms are S. pneumoniae and N.

meningitidis. Absence of clinical triad, Kerning's and Brudzinski's sign

do not rule out acute bacterial meningitis. Start antibiotics early, before lumbar puncture if need be. Empirical antibiotics based on age, predisposing

condition and geographical resistance patterns. Give dexamethasone with or before 1st dose of antibiotic. Imaging not needed before lumbar puncture in all cases. Absence of typical CSF findings do not rule out acute

bacterial meningitis.

Thank You

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