Infections of the Central Nervous System



Infections of the Central Nervous System


Tracey A. Cho



BACTERIAL MENINGITIS


Background

Widespread use of Haemophilus influenzae type b conjugate vaccines has dramatically decreased the incidence of bacterial meningitis in children but has not affected the incidence in adults.


Pathophysiology



  • 1. Pathology is characterized by inflammation of meninges and of cortical blood vessels with varying degrees of microthrombosis.


  • 2. The likely etiology of bacterial meningitis can be predicted on the basis of the patient’s age and clinical characteristics (Table 17-1).


Prognosis



  • 1. Early and late complications of bacterial meningitis can occur.



    • a. Early: Cerebral edema, communicating hydrocephalus, infectious vasculitis with stroke or seizure, dural sinus thrombosis, brain abscess, subdural abscess or effusion, and hearing loss.


    • b. Late: Developmental delay or cognitive deficits, focal neurologic findings other than or in addition to hearing loss, and epilepsy.


  • 2. Mortality is highest in Streptococcus pneumoniae meningitis and in patients who present with depressed level of consciousness.


  • 3. Dexamethasone decreases neurologic complications in children with H. influenzae and S. pneumoniae meningitis treated in the developed, but not the developing, world. Dexamethasone improves neurologic outcome and decreases mortality in adults with S. pneumoniae meningitis. Dexamethasone should be given before or with the first dose of antibiotics (see Treatment, this section).


Diagnosis



  • 1. Clinical findings include fever, neck stiffness, and change in mental status. The very young, very old, and immunocompromised may have minimal symptoms and signs.


  • 2. Cerebrospinal fluid (CSF)



    • a. Usually it shows neutrophilic pleocytosis, low glucose level, and elevated protein concentrations (Table 17-2).


    • b. Gram stain and culture are usually positive unless the patient has been treated with antibiotics.


    • c. CSF latex agglutination tests can detect antigens of S. pneumoniae, Neisseria meningitidis serogroups A, B, C, Y, and W135, H. influenzae type b, and
      group B streptococci, but they are often negative when the CSF culture is negative.








      TABLE 17-1 Empiric Therapy for Bacterial Meningitis

































      Patient characteristic


      Likely organisms


      Antibiotics


      <1 moa


      Group B streptococci, Escherichia coli, Listeria monocytogenes, Klebsiella spp.


      Ampicillin plus cefotaxime or ampicillin plus aminoglycoside


      1-23 mo


      Streptococcus pneumoniae, Neisseria meningitidis, group B streptococci, Haemophilus influenzae, E. coli


      Vancomycinb,c plus ceftriaxoned or cefotaximee


      2-50 yr


      N. meningitidis, S. pneumoniae


      Vancomycinb,c plus ceftriaxoned or cefotaximee


      >50 yr


      S. pneumoniae, N. meningitidis, monocytogenes, aerobic gram-negatives


      Vancomycinb,c plus ampicillinf plus ceftriaxoned or cefotaximee


      Impaired cellular immunity


      L. monocytogenes, gram-negatives


      Ampicillinf plus ceftazidimeg


      Head trauma,h neurosurgery, or shunt


      Coagulase-positive or coagulasenegative staphylococci, gram-negatives, S. pneumoniae


      Vancomycinb plus cefepimei or ceftazidimeg or meropenemj


      a Doses depend on age, weight, and prematurity. Expert consultation is advised.
      b Children: 60 mg/kg/d IV divided q6h. Adults: 1 g IV q12h. Adjust dose for renal function. Follow levels: trough of 10-15 μg/mL.
      c Some experts would add rifampin if dexamethasone is used.
      d Children: 100 mg/kg/d IV or IM divided q12h. Maximum dose 2 g/d in children 45 kg or less. Adult: 2 mg IV or IM q12h. Maximum dose 4 g/d in adults.
      e Children: 200 mg/kg/d IV divided q6h. Adults: 2 g IV q4-6h. Maximum dose in children and adults is 12 g/d.
      f Children: 200-400 mg/kg/d IV divided q4h. Adults: 2 g IV q4h. Maximum dose in children and adults is 12 g/d.
      g Children: 150 mg/kg/day IV divided q8h. Adults: 2 g IV q8h. Maximum dose in children and adults is 6 g/d.
      h Except basilar skull fracture, for which vancomycin plus ceftriaxone or cefotaxime is recommended.
      i Children: 150 mg/kg/d IV divided q8h. Adults: 2 g IV q8h.
      j Children: 120 mg/kg/d IV divided q8h. Adults: 2 g IV q8h.



    • d. CSF polymerase chain reaction (PCR) tests that amplify highly conserved regions of the bacterial 16S RNA gene provide a potentially rapid diagnostic test but are not yet clinically available.


  • 3. Blood cultures are positive in 30% to 80% of cases and may be positive when CSF culture is negative.


  • 4. Neuroimaging should be considered before lumbar puncture in the following settings:



    • a. Sixty years of age or older


    • b. Depressed level of consciousness


    • c. Focal neurologic signs


    • d. Papilledema


    • e. Immunocompromised patient








    TABLE 17-2 Cerebrospinal Fluid Findings in Bacterial and Viral Meningitis







































    Type of meningitis


    CSF parameter


    Bacterial


    Partially treated bacterial


    Viral


    WBC count


    >2,000/μL, >60% PMNs


    >2,000/μL, 60% PMNs


    <1,000/μL, PMNs in 10%


    Glucose


    <40 mg/dL


    <40 mg/dL


    >40 mg/dL


    Protein


    >200 mg/dL


    >200 mg/dL


    <100 mg/dL


    Gram stain-positive


    80%


    60%


    No


    Culture-positive


    >90%


    65%


    No


    CSF, cerebrospinal fluid; WBC, white blood cell; PMNs, polymorphonuclear cells (neutrophils).



  • 5. Diagnostic approach for bacterial meningitis



    • a. Perform rapid, directed general physical and neurologic examination looking for sources of infection, underlying illness, and contraindications to lumbar puncture.


    • b. Draw blood cultures.


    • c. Perform neuroimaging if indicated. Empiric antibiotics should be given prior to neuroimaging. If indicated, dexamethasone should be given before or with the first dose of antibiotics.


    • d. Lumbar puncture: If the patient is clinically worsening or if a delay in lumbar puncture anticipated, give empiric antibiotics. If indicated, dexamethasone should be given before or with the first dose of antibiotics. Every effort should be made to obtain CSF within 2 to 3 hours of giving antibiotics.


    • e. Treatment: Base regimen on CSF gram stain findings if patient is neurologically normal, clinically stable, and has not been given oral or parenteral antibiotics. Otherwise, give empiric regimen as soon as lumbar puncture is complete (see Treatment, this section).


Treatment



  • 1. Empiric regimens are based on age, clinical setting, and local patterns of antibiotic susceptibility (Table 17-1). In the United States, about 25% of pneumococcal isolates are not susceptible to penicillin.


  • 2. Once culture information is available from CSF or blood, tailor antibiotic regimens to cover specific organisms (Table 17-3).


  • 3. When possible etiologies for meningitis include H. influenzae or S. pneumoniae in children, or S. pneumoniae in adults, give dexamethasone 0.15 mg/kg intravenous (IV) every 6 hours for 2 to 4 days in children and 10 mg IV every 6 hours for 4 days in adults. Dexamethasone should be given before or with the first dose of antibiotics.


  • 4. Patients with H. influenzae and N. meningitidis meningitis should be placed in respiratory isolation for the first 24 hours of antibiotic therapy.



  • 5. Prophylaxis



    • a. According to the American Academy of Pediatrics, 2000 Red Book: Report of the Committee on Infectious Diseases, prophylaxis for H. influenzae is indicated in



      • 1) All household members (except pregnant women) if there is a child in the household who is a contact to an index case, and



        • a) The contact child is younger than 48 months and has not been completely immunized against H. influenzae.









          TABLE 17-3 Specific Therapy for Bacterial Meningitis

























          Organism


          Duration of therapy (days)


          Comments


          Haemophilus influenzae


          7


          Ampicillin resistance is common.


          Neisseria meningitidis


          7


          If the organism is sensitive, high-dose IV penicillin is appropriate. Penicillin resistance is increasing; clinical significance is uncertain


          Streptococcus pneumoniae


          10-14


          Penicillin nonsusceptibility is increasing. If sensitive to penicillin, ceftriaxone, or cefotaxime, discontinue empiric vancomycin. With cephalosporin resistance, use ceftriaxone or cefotaxime plus vancomycin and examine CSF at 36-48 hr. If sensitive to rifampin, add rifampin if clinical deterioration, persistent CSF infection, or unusually high MIC to ceftriaxone or cefotaxime. Consider adding rifampin to empiric regimen if dexamethasone is used, because regimen dexamethasone may decrease CSF penetration of antibiotics


          Listeria monocytogenes


          ≥21


          Use ampicillin or penicillin plus gentamicin for severe infections. Use trimethoprim-sulfamethoxazole if allergic to penicillin


          IV, intravenous; CSF, cerebrospinal fluid; MIC, minimum inhibition concentration.



        • b) If the contact child is immunocompromised, regardless of immunization status.


        • c) The contact child is younger than 12 months. A contact is defined as a person living with an index case or who spent 4 or more hours with an index case for 5 or more of the 7 days before hospitalization of the index case.


      • 2) The index case if he or she did not receive cefotaxime or ceftriaxone.


      • 3) Children at nurseries and child care centers who are contacts to an index case, regardless of age, when two or more cases of invasive disease have occurred within 60 days.


    • b. Prophylaxis for H. influenzae with rifampin should ideally be given within 7 days of contact. In infants younger than 1 month, the dose is 10 mg/kg by mouth (p.o.) daily for 4 days. In those older than 1 month, the dose is 20 mg/kg (maximum, 600 mg) p.o. daily for 4 days.


    • c. According to the American Academy of Pediatrics 2000 Red Book, prophylaxis against N. meningitidis is indicated in



      • 1) Household contacts.


      • 2) People who eat or sleep in the same place as the index patient.


      • 3) People who have had close contact with the index patient such as through sharing toothbrushes or eating with the same utensils or kissing in the 7 days before onset of illness.









        TABLE 17-4 Prophylactic Regimens for N. meningitidis






















        Agent


        Dosage according to age


        Rifampina


        ≤1 mo: 5 mg/kg p.o. q12h for 2 d


        >1 mo: 10 mg/kg (max., 600 mg) p.o. q12h for 2 d


        Ceftriaxone


        ≤12 yr: 125 mg IM, 1 dose


        >12 yr: 250 mg IM, 1 dose


        Ciprofloxacinb


        ≤18 yr: not recommended


        ≥18 yr: 500 mg p.o., 1 dose


        a Do not use during pregnancy; use with caution in women taking birth control pills.
        b Do not use during pregnancy or for lactating women.


        p.o., by mouth; IM, intramuscular.



      • 4) Nursery or childcare center contact in the 7 days before onset of illness.


      • 5) Health care personnel with direct contact to index patient’s oral secretions such as through unprotected mouth-to-mouth resuscitation, tracheal intubation, or suctioning in the 7 days before onset of illness.


      • 6) Passengers seated next to index patient on a flight lasting more than 8 hours.


      • 7) The index case if he or she did not receive cefotaxime or ceftriaxone.


    • d. Prophylaxis for N. meningitidis should be administered within 24 hours of diagnosis of the index case (Table 17-4).


TUBERCULOUS MENINGITIS


Background

Tuberculous meningitis is the most common form of nervous system infection by Mycobacterium tuberculosis.


Pathophysiology



  • 1. Tuberculous meningitis may accompany primary infection. This is often the case in children.


  • 2. It may also result from reactivation of previous infection. During primary infection, the brain and meninges may be seeded with low numbers of organisms. These foci of infection can develop into larger caseous lesions or “rich foci.” When a meningeal lesion ruptures into the CSF space, meningitis ensues.


  • 3. Fibrosis of basal meningeal exudate can lead to communicating hydrocephalus. Involvement of the ventricular system can lead to occlusion of the cerebral aqueduct and noncommunicating hydrocephalus. Hydrocephalus is more common in children than in adults.


  • 4. Vasculitis may develop in blood vessels traversing the meningeal exudate leading to occlusion and stroke. Stroke is most common in the middle cerebral artery distribution.


Prognosis



  • 1. Overall mortality in tuberculous meningitis is about 30%.



    • a. Mortality rate is highest in those with low Glasgow Coma Scale score or higher Medical Research Council (MRC) stage at presentation (Table 17-5).









      TABLE 17-5 Outcome of Tuberculous Meningitis Based on MRC Stage at Presentation

























      Stage


      Clinical features


      Mortality


      Neurologic sequelae


      I


      Meningeal signs but normal mental status and no focal neurologic findings


      <10%


      Minimal


      II


      Confusion or focal neurologic findings


      20%-30%


      40%


      III


      Stupor or coma with hemiplegia or paraplegia


      60%-70%


      Frequent


      MRC, Medical Research Council.



    • b. Mortality rate is also greater in those in whom therapy is delayed or interrupted.


  • 2. Neurologic sequelae include hemiparesis or hemiplegia, paraplegia, visual or hearing loss, and cognitive changes.



    • a. Neurologic sequelae are also highest in those with low Glasgow Coma Scale score or higher MRC stage at presentation.


    • b. Neurologic sequelae are also highest in those who present with focal neurological findings (Table 17-5).


  • 3. Hydrocephalus may require external ventricular drainage or a permanent shunt.


Diagnosis



  • 1. Symptoms and signs



    • a. Early: Low-grade fever, headache, malaise, nausea.


    • b. Later: Severe headache, neck stiffness, cranial nerve palsies (most commonly VI), vomiting, drowsiness, seizures, change in mental status.


    • c. Late: Coma, brain stem dysfunction.


  • 2. Compared to patients with bacterial meningitis, patients with tuberculous meningitis typically have been sick longer, are more likely to have cranial nerve palsies, and are less likely to have highly elevated peripheral blood white blood cell (WBC) counts.


  • 3. Neuroimaging abnormalities are common: Hydrocephalus, meningeal enhancement, mass lesions (tuberculomas, tuberculous abscesses), and infarcts. All patients with suspected tuberculous meningitis should undergo neuroimaging, ideally before lumbar puncture.


  • 4. CSF



    • a. Conventional analysis



      • 1) WBC count is 100 to 500 μL, usually with lymphocytic predominance. If present, polymorphonuclear cells are fewer than 50%.


      • 2) Protein is 100 to 500 mg/dL.


      • 3) Glucose is less than 45 mg/dL.


    • b. CSF acid-fast bacillus (AFB) smear is positive in about a quarter of cases.


    • c. CSF culture is positive in about one-third. Large-volume CSF and multiple cultures (up to four) increase yield.


    • d. CSF PCR is specific and much faster, but has poor sensitivity comparable to culture.


  • 5. Abnormal chest radiograph findings (infiltrate or Gohn complex) are seen in most children and about one-half of adults.


  • 6. Purified protein derivative (PPD) test is positive in 50% to 80%. If initial PPD is negative, repeat the test in 5 to 7 days (two-step test).


  • 7. Hyponatremia due to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) or to cerebral salt wasting is common.



  • 8. Human immunodeficiency virus (HIV)-infected patients are at greater risk of tuberculosis. However, clinical and laboratory findings of tuberculous meningitis generally do not differ among patients with and without concomitant HIV, although PPD is less likely to be positive. Interferon-γ release assay may be positive in some patients with latent tuberculosis and negative PPD due to anergy.


  • 9. Because CSF smear and culture are insensitive, diagnosis is often presumptive and based on compatible clinical findings, CSF profile, risks for tuberculosis, or identification of tuberculous infection at another site, including chest or ileum.


Treatment



  • 1. Every effort should be made to isolate the organism to allow for determination of drug sensitivities (Table 17-6). This may entail multiple CSF cultures and cultures from non—central nervous system (CNS) sites.


  • 2. Early treatment is important.


  • 3. Drug-resistant tuberculous meningitis is uncommon. Resistance is most likely in individuals noncompliant with previous antituberculous therapy or those from geographic areas with high prevalence of resistance. In this case, add two additional drugs to which the organism is likely to be sensitive to the regimen, which is given in Table 17-6. Consultation with an infectious diseases specialist is recommended.


  • 4. Steroids improve outcome in children and adults. A reasonable dose in children is prednisone 2 to 4 mg/kg/d p.o. for 1 month, followed by a slow taper.
    Recommended dose in adults is dexamethasone 0.4 mg/kg/d IV for 1 week, tapered by 0.1 mg/kg/d each week down to 0.1 mg/kg/d, and then dexamethasone 4 mg p.o. daily for 1 week tapered by 1 mg daily each week.

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May 28, 2016 | Posted by in NEUROLOGY | Comments Off on Infections of the Central Nervous System
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