Central Nervous System Infection

Lingyun Shao Department of Infectious Diseases

Huashan Hospital, Fudan University

Definition Meningitis: an inflammation of

the arachnoid membrane, the pia mater, and the intervening cerebrospinal fluid (CSF).

The inflammatory process extends throughout the subarachnoid space around the brain and spinal cord and involves the ventricles.

Anatomy

Meningies

1. Bacterial Meningitis (Purulent Meningitis)

化脓性脑膜炎

Definition

• Bacterial meningitis is usually an acute bacterial infection that evokes a polymorphonuclear response in CSF

Epidemiology & Etiology

Causes of bacterial meningitis in adults

<1 month Streptococcus agalactiae, Escherichia coli, Listeria monocytogenes, Klebsiella species

1 - 23 mos Streptococcus pneumoniae, Neisseria meningitidis, S. agalactiae, Haemophilus influenzae, E. coli

2 - 50 yrs N . meningitidis, S. pneumoniae

>50 yrs S.pneumoniae, N. meningitidis, L. monocytogenes, gram-negative bacilli

ETIOLOGY OF BACTERIAL MENINGITIS BY AGE

ETIOLOGY OF BACTERIAL MENINGITIS BY PREDISPOSING CONDITION

Immunocompromised state: S. pneumoniae, N. meningitidis, Listeria, aerobic GNR

Basilar skull fracture: S. pneumoniae, H. influenzae, beta-hemolytic strep group A

Head trauma or post-neurosurgery: S. aureus, S. epidermidis, aerobic GNR

CSF shunt: S. epidermidis, S. aureus, aerobic GNR, Propionibacterium acnes

Pathogenesis

Routes for bacterial invasion of the meninges

Neisseria meningitidis Nasopharynx

Streptococcus pneumoniae Nasopharynx or direct extension across skull fracture (cerebrospinal rhinorrhea)

Listeria monocytogenes GI tract, placenta

Haemophilus influenzae Nasopharynx

Staphylococcus aureus Bacteremia, skin, or foreign body

Staphylococcus epidermidis Skin or foreign body

Organism Site of entry

Pathogenesis

Brain with inflammatory exudate covering the cortical hemispheres in purulent meningitis.

Pathology

• Bacterial Meningitis: – Infection of the pia mater and arachnoid, the subarachnoid

space, the ventricular system, and the CSF – Infectious agents:

• Meningococcus (Neisseria meningitidis) • pneumococcus (streptococcus pneumoniae)

– URI---blood borne---CNS entry – Inflammatory response by meninges, CSF, ventricles – Neutrophils migrate producing exudate that plugs off CSF

flow around the brain and spinal cord

Clinical manifestations

Symptoms

• Acute-onset fever • Generalized headache • Vomiting • An antecedent or accompanying upper

respiratory tract infection or nonspecific febrile illness, acute otitis, or pneumonia

• The illness usually progresses rapidly, with the development of confusion, obtundation, and loss of consciousness

Physical signs

• Stiff neck • Kernig’s sign • Brudzinski’s sign

• a combination of two of four symptoms is found in 95% of patients – Headache – Fever – stiff neck – altered mental status

Initial symptoms and signs

Symptoms or signs Relative frequency Headache ≥90% Fever ≥90% Meningismus ≥85% Altered sensorium >80% Kernig’s or Brudzinski signs ≥50% Focal findings 10-20%

Neurologic Findings

• Cranial nerve abnormalities

– the third, fourth, sixth, or seventh nerve

• Increased CSF pressure is associated with seizures, vomiting, sixth and third nerve dysfunction, abnormal reflexes

Diagnosis

CONFIRMATION OF SUSPECTED BACTERIAL MENINGITIS

• Lumbar puncture ASAP • If LP has to be delayed for any reason, send

blood culture and start empiric antibiotics

• Who should undergo CT prior to lumbar puncture?

Who should undergo CT prior to lumbar puncture?

Criterion Comment Immunocompromised state

HIV infection or AIDS, receiving immunosuppressive therapy, or after transplantation

History of CNS disease Mass lesion, stroke, or focal infection New onset seizure Within 1 week of presentation; some

authorities would not perform a lumbar puncture on patients with prolonged seizures or would delay lumbar puncture for 30 min in patients with short, convulsive seizures

Papilledema Presence of venous pulsations suggests absence of increased intracranial pressure

Abnormal level of consciousness

...

Focal neurologic deficit Including dilated nonreactive pupil, abnormalities of ocular motility, abnormal visual fields, gaze palsy, arm or leg drift

DIAGNOSIS - CSF Examination Typical CSF in Patients with Bacterial Meningitis

• Opening pressure 200-500 mmH2O • White blood cell count 1000-5000/μL • Neutrophils >80% • Protein >1000 mg/L • Glucose <400mg/L • CSF/serum glu ratio <0.4 • Gram stain Positive in 50-80% • Culture Positive in ～85%

CSF Profiles in Central Nervous System Infections

Special Testing Procedures

• PCR: Broad-range PCR with CSF in patients: – antimicrobial therapy was begun before lumbar puncture

– when cultures are negative and a bacterial origin is still suspected

• Specific real-time PCR

• Latex agglutination test

Differential Diagnosis

• Viral meningitis, tuberculous meningitis • Acute subarachnoid hemorrhage

Treatment

PRINCIPLES OF TREATMENT

• Prompt initiation of treatment. • Bactericidal agents, with adequate CSF levels. • Empiric Rx (based on age and predisposing factors)

• Specific Rx (based on Gram-stain or antigen).

• Include steroids where indicated

EMPIRIC THERAPY Patient’s Age Common pathogens Antimicrobial therapy

<1 month Streptococcus agalactiae, Escherichia coli, Listeria monocytogenes, Klebsiella species

Ampicillin plus cefotaxime

1 - 23 mos Streptococcus pneumoniae, Neisseria meningitidis, S. agalactiae, Haemophilus influenzae, E. coli

Vancomycin plus a third-generation cephalosporin

2 - 50 yrs N . meningitidis, S. pneumoniae

Vancomycin plus a third-generation cephalosporin

>50 yrs S.pneumoniae, N. meningitidis L. monocytogenes, aerobic gram-negative bacilli

Vancomycin plus ampicillin plus a third-generation cephalosporin

EMPIRIC THERAPY Predisposing factor

Common pathogens Antimicrobial therapy

Basilar skull fracture

S. pneumoniae, H. influenzae, group A -hemolytic streptococci

Vancomycin plus a third-generation cephalosporin

Penetrating trauma

Staphylococcus aureus, coagulase-negative staphylococci (especially Staphylococcus epidermidis), aerobic gram-negative bacilli (including Pseudomonas aeruginosa)

Vancomycin plus cefepime, vancomycin plus ceftazidime, or vancomycin plus meropenem

Post- neurosurgery

Aerobic gram-negative bacilli (including P. aeruginosa), S . aureus, coagulase-negative staphylococci (especially S. epidermidis)

Vancomycin plus cefepime, vancomycin plus ceftazidime, or vancomycin plus meropenem

CSF shunt Coagulase-negative staphylococci (especially S. epidermidis), S. aureus, aerobic gram-negative bacilli (including P. aeruginosa), Propionibacterium acnes

Vancomycin plus cefepime, vancomycin plus ceftazidime, or vancomycin plus meropenem

SPEC

IFIC

-RX

Microorganism Duration of

therapy (days)

Neisseria meningitidis

7

Haemophilus influenzae

7

Streptococcus pneumoniae

10-14

Streptococcus agalactiae

14-21

Gram-negative bacilli

>21

Listeria monocytogenes

21

ROLE OF STEROIDS

• Decrease subarachnoid space inflammatory response to abx-induced bacterial lysis

• Significant reduction in deafness in pediatric H. influenzae & pneumococcal meningitis

• In adults, reasonable to use steroids: – for pts with evidence of cerebral edema. – for adult with pneumococcal meningitis

Use of Adjunctive Dexamethasone Therapy in Adults with Bacterial Meningitis

In suspected or proven pneumococcal meningitis cases.

• Dexamethasone should only be continued if the CSF Gram stain reveals gram-positive diplococci, or if blood or CSF cultures are positive for S. pneumoniae.

• Adjunctive dexamethasone should not be given to adult patients who have already received antimicrobial therapy, because administration of dexamethasone in this circumstance is unlikely to improve patient outcome.

• Addition of rifampin to the empirical combination of vancomycin plus a third-generation cephalosporin may be reasonable pending culture results and in vitro susceptibility testing , in patients with suspected pneumococcal meningitis who receive adjunctive dexamethasone.

Infants and Children •Use in H. influenzae type b meningitis . •For pneumococcal meningitis, controversial.

Neonates Insufficient data to make a recommendation on the use of adjunctive dexamethasone.

Use of Adjunctive Dexamethasone Therapy in Pediatric Patients with Bacterial Meningitis

CID 2004;39:1267-1284

Prognosis

• Prompt treatment of bacterial meningitis usually results in rapid recovery of neurologic function

• The mortality rate for community-acquired bacterial meningitis in adults varies

• With current antimicrobial therapy, the mortality rate for – H. influenzae meningitis is less than 5% – meningococcal meningitis is approximately 10% – pneumococcal meningitis is approximately 20% – L. monocytogenes meningitis 20 to 30%

Prevention

Vaccination • Hib vaccine.

– Has had major impact in incidence of pediatric Hib meningitis • Pneumococcal vaccine.

– For chronically ill and elderly, & now universal use in children. – PCV-7. Use of PCV-7 for children has been an effective means of

preventing disease in older adults (JAMA. Vol. 294 No. 16, October 26, 2005 )

• Meningococcal vaccine – Effective vs serotype A, C, Y, W135 – Major reduction of disease in military recruits – Recommended for travelers to endemic areas. – Offered to college students, specially those residing in dormitory – A new quadrivalent vaccine (Menactra) was recently approved.

Summary

• Headache, fever, stiff neck, confusion, vomiting are typical clinical manifestations of purulent meningitis

• Findings on CSF analysis are strikingly abnormal

• Antimicrobial therapy should be initiated promptly in this life-threatening emergency

2. Viral Meningitis 病毒性脑膜炎

Definition

• Viral meningitis is caused primarily by the non-polio enteroviruses, echoviruses, and coxsackieviruses – In temperate climates, infections occur mainly in

the warmer months of the year, usually during the summer and early fall

– In tropical climates, the infection occurs year round

Primary clinical manifestations

• Fever, headache and photophobia, stiff neck

• No loss of consciousness

• Conjunctivitis, maculopapular rash, and occasionally with echovirus, petechial rash

• Epstein–Barr virus and cytomegalovirus

CSF Profiles in Central Nervous System Infections

Special Testing Procedures

• Polymerase chain reaction (PCR) for HSV-1 and HSV-2 in

• Enterovirus PCR

Treatment

• Mainly observation

• Symptomatic treatment: e.g. 20% mannitol

• Administer antibiotics if CSF contains PMNs

• Self-limiting disease, lasts 7 to 10 days

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