BACTERIAL AND MYCOBACTERIAL INFECTIONS OF THE CNS

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BACTERIAL AND MYCOBACTERIAL INFECTIONS OF THE CNS
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Outline

• Acute bacterial meningitis
• Tb of the CNS
• Neurosyphilis

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ACUTE BACTERIAL MENINGITIS

• An acute inflammatory disease of the
  leptomeninges
• Bacteria may gain access to the
  ventriculo-subarachnoid space
• - hematogenous-in the course of
  septicemia or dissemination from infection of the
  heart, lungs, or other viscera
• - direct extension- septic focus in the
  skull, spine or parenchyma.
• - sinusitis, otitis,
  osteomyelitis, and brain abscess.
• - organisms may gain access- cpd fractures of
  the skull, fractures thru the nasal sinuses or
  mastoid, or after neurosurgical procedure.

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ctd

• Causative organisms
• Up to age 60
• - S. pneumoniae was responsible for 60
  percent of cases
• - N. meningitidis (20 percent),
• - H. influenzae (10 percent),
• - L. monocytogenes (6 percent), and
• - group B streptococcus (4 percent).
• Age 60 and above,
• - almost 70 percent of cases were due to
  S. pneumoniae,
• - approximately 20 percent to L.
  monocytogenes, and
• - 3 to 4 percent each to N. meningitidis,
  group B streptococcus, and H. influenzae.
• - An increased prevalence of L.
  monocytogenes in the elderly has been noted in
  other reports.

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• Nosocomial meningitis
• - different etiologic agents
• - In one study of 197 patients -
  gram negative- 33
• - Streptococci, Staph, and coagulase
  negative Staph- 9 each.
• - S.pneumoniae, N.meningitidis,
  L.monocytogenes- accounted for 8

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• Geographic factors
• - distribution depends on region
• - e.g. epidemics of N.meningitidis-
  uncommon in Europe and N.Amherica
• but occur thru out the developing world.
• Predisposing factors
• -Three major mechanisms for developing
  meningitis
• Invasion of the CNS following bacteremia due to a
  localized source, such as infective endocarditis
  or a urinary tract infection
• Colonization of the nasopharynx with subsequent
  bloodstream invasion and subsequent central
  nervous system (CNS) invasion
• Direct entry of organisms into the CNS from a
  contiguous infection (eg, sinuses, mastoid),
  trauma, neurosurgery, or medical devices (eg,
  shunts or intracerebral pressure monitors)

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• Host factors predisposing to meningitis
• - Asplenia
• - complement deficiency
• - corticosteroid excess
• - HIV infection
• Patients should also be questioned
• - Recent exposure to someone with
  meningitis
• - A recent infection (especially
  respiratory or otic infection)
• - Recent travel, particularly to areas with
  endemic meningococcal disease such as sub-Saharan
  Africa
• - Injection drug use
• - Recent head trauma Otorrhea or rhinorrhea

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Clinical Features

• Pts are quite ill and often present soon after
  symptom onset
• - for e.g., in a series of 301 pts- median
  duration before admission- 24hrs
• Presenting manifestations-
• - triad of fever, nuchal rigidity, and
  mental status changes
• - most pts have high fever often gt38 Oc
• - small percentage- hypothermia
• - no pt- normal temperature

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• Head ache- also common
• Chills, nausea and vomiting, pain in the back,
  and prostration- initial manifestation
• With progress- sensorium becomes clouded and
  stupor or coma supervenes
• Convulsive seizures are often- early symptoms- in
  children
• Although one or more of the classic findings are
  absent- virtually all pts have at least one of
  the findings
• - sensitivity of 99-100
• The absence of all of the classic findings-
  excludes Dx of bacterial meningitis.

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• In addition to the classic findings
• - Significant photophobia.
• - Seizures have been described in 15 to
  30 percent of patients and
• - focal neurologic deficits in 20 to 33
  percent. - - Hearing loss is a late
  complication. Dexamethasone therapy may reduce
  the rate of neurologic sequelae, particularly in
  selected patients with pneumococcal meningitis of
  intermediate severity.

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• Certain bacteria, particularly N. meningitidis,
  can cause characteristic skin manifestations,
  such as petechiae and palpable purpura. In two
  large series of patients
• - rash was present in 11 and 26 percent-
• - 75 and 92 percent were
  associated with meningococcal meningitis.
• - A petechial rash is not
  specific for meningococcal infection -some
  patients have a maculopapular rash

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• Bacterial meningitis tends to spare other organs
  unless severe sepsis ensues.
• However, if meningitis is the sequela of an
  infection elsewhere in the body, there may be
  features of that infection still present at the
  time of diagnosis of meningitis (e.g., otitis or
  sinusitis).
• Examination for nuchal rigidity
• - neck stiffness
• - Kerning and Brudzininski signs

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• Laboratory features
• - routine hematology- often unrevealing
• - WBC- elevated,
• - leukopenia with severe infection
• - platelet- may be reduced if there is DIC or in
  meningococcal meningitis
• - blood culture- often positive
• - useful in the event
  that LP cant be performed due
  contraindications
• - 70-75 - positive
• - lowest yield- with
  meningococcal

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• CSF analysis- xic findings
• - cell count gt 1000, with neutrophil
  predominance
• - protein gt 500mg/dl
• - glucose lt 45mg/dl
• - spectrum of values differs
• - review of 296 episodes of
  meningitis
• - 50- glucose gt 40mg/dl
• - 44- protein lt 200mg/dl
• - 13- WBC lt 100cells

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ctd

• Grams stain and culture
• - Grams stain- advantage of suggesting
  bacterial etiology one day prior to culture
• - findings
• - Gram-positive diplococci suggest
  pneumococcal infection
• - Gram-negative diplococci suggest
  meningococcal infection
• - Small pleomorphic gram-negative
  coccobacilli suggest Haemophilus influenzae
• - Gram positive rods and coccobacilli
  suggest listerial infection

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ctd

• In a trial of 301 adults- Gram stain was
  positive in 74 and culture in 78
• - Grams stain- positive in 10-15 of
  culture negatives
• Latex agglutination test for the detection of -
  S. pneumoniae
• - N. meningitidis
• - H. influenzae type b
• - group B streptococci and E. coli
• - very useful for making rapid DX- especially
  in pts who have been pretreated with antibiotics
• - specificity of 95-100 for the detection of
  S. pneumoniae and N. meningitidis
• - A positive test is diagnostic of
  bacterial meningitis
• - sensitivity- 70-100 for S.pneumoniae and
  33-70 for N.meningitidis
• - negative test doesnt r/o bacterial
  meningitis

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ctd

• Limulus amebocyte lysate assay- rapid diagnostic
  test for the detection of Gram negative endotoxin
• - high sensitivity and specificity
• - positive in all pts with Gram negative
  meningitis
• Petechial skin lesions should be biopsied- may
  reveal meningococci

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General Principles of Therapy

• The most important initial issues
• - avoidance of delay
• - choice of drug regimen
• Avoidance of delay antibiotics should be started
  immediately after the results of LP if the
  clinical suspicion is high or if CT is to be
  performed before LP
• - retrospective study of 119 pts
• - The adjusted OR for mortality was 8.4
  for those with a door to antibiotic time gt6hrs
  when pt presented afebrile
• - OR of 12.6 for those with impaired
  mental status
• Components of delay
• - time from triage to contact with a
  physician
• - time from LP until administration of
  antibiotics
• - performance of CT to exclude mass lesion
• - screening CT before LP is not necessary
  in the majority

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ctd

• Indications for CT before LP
• - Immunocompromised state (eg, HIV infection,
  immunosuppressive therapy, after transplantation)
  
• - History of CNS disease (mass lesion, stroke,
  or focal infection)
• - New onset seizure (within one week of
  presentation)
• - Papilledema
• - Abnormal level of consciousness
• - Focal neurologic deficit
• Should LP be delayed for cranial imaging-
  antibiotics should be started empirically before
  the imaging

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ctd

• Antibiotic regimen
• - two general principles
• - use of bactericidal drugs effective for
  the infecting organism
• - use of drugs that enter the CSF
• Empiric drug regimen
• - selected third generation cephalosporins
• - ceftriaxone and cefotaxime- beta-lactams
  of choice in the empiric treatment
• - have potent activity against most
  pathogens
• - exception- L. monocytogenes
• - with the world wide emergence of
  penicillin resistant pneumococci addition of
  vancomycin is recommended

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ctd

• Rather than empiric therapy- IV antibiotics
  should be directed against the presumed pathogen
  if the Grams stain is diagnostic
• Then, modify treatment after the culture and
  sensitivity result
• If Gram positive cocci seen in community acquired
  meningitis- consider pneumococci
• - If in the setting of neurosurgery, head
  trauma, a neurosurgical device, or a CSF leak-
  Staphylococci are common and Rx with vancomycin.
• In patients with Gram ve rods- replace
  ceftriaxone with ceftazidime
• - history of neurosurgery
• - head trauma
• - a neurosurgical device
• - a CSF leak

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ctd

• Empiric treatment during epidemics
• - meningococcal meningitis in sub-Saharan
  Africa
• - WHO recommends Rx with one IM injection of
  long acting CAF( oily suspension)-
• - Single IM dose of ceftriaxone compared to
  oily CAF- in a RCT in Niger- showed comparable
  results

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ctd

• Adjuvant dexamethasone
• - significant reduction in mortality and
  neurologic disability- seen particularly with
  pneumococcal meningitis
• - Recommendations IV dexamethasone be given
  at .15mg/kg shortly before or at the time of
  antibiotic administration to patients with
  bacterial meningitis with GCS of 8-11
• - should be continued for 4 days.

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Tuberculous Meningitis

• CNS TB includes
• - Meningitis
• - Intracranial tuberculoma
• - Spinal TB arachnoiditis
• All encountered in regions of the world where
  incidence of TB is high
• 300-400 cases of Tb meningitis in US
• - 1 of all cases of TB
• Case fatality ratio- remains high- 15-40 despite
  effective RX
• Early recognition of TB meningitis- important-
  b/c outcome depends on the stage Rx is initiated

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ctd

• Pathogenesis
• - scattered Tb foci- demonstrated in brain,
  meninges, adjacent bone- during primary
  bacillemia or reactivation disease.
• - chance occurrence of sub-ependymal tubercle-
  with progression and rupture in to the SAS- is a
  critical event
• - Meningitis devps most commonly as a
  complication of post primary TB in infants and
  young children and from chronic reactivation
  bacillemia in adults with immune deficiency
• - aging, alcoholism, malnutrition,
  malignancy, or HIV.
• - Spillage of TB proteins in to SAS- intense
  inflammation most marked at the base of the brain

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ctd

• - Three features dominate the pathology
• - Proliferative arachnoiditis, most marked
  at the base of the brain, produces a fibrous mass
  involving cranial nerves and penetrating vessels
• - Vasculitis with resultant thrombosis and
  infarction involves vessels that traverse the
  basilar or spinal exudate or are located within
  the brain substance itself
• - multiple lesions are common and a
  variety of stroke syndromes involving the BG,
  cerebral cortex, pons, and cerebellum
• - Communicating hydrocephalus results
  from extension of the inflammatory process to the
  basilar cisterns and impedance of CSF circulation
  and resorption.

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ctd

• Clinical features
• - Three stages
• - A prodromal phase, lasting two to
  three weeks, is characterized by the insidious
  onset of malaise, lassitude, headache, low-grade
  fever, and personality change.
• - The meningitic phase follows with
  more pronounced neurologic symptoms, such as
  meningismus, protracted headache, vomiting,
  confusion, and varying degrees of cranial nerve
  and long-tract signs.
• - The paralytic phase is the stage
  during which the pace of illness may accelerate
  rapidly confusion gives way to stupor and coma,
  seizures, and at times hemiparesis.
• May be accompanied by choroidal involvement and
  evidenced by fundoscopic exam.

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ctd

• For the majority of untreated pts- death ensues
  with in 5-8 weeks
• Signs of active TB outside the CNS- of diagnostic
  aid- but often absent or no-specific
• - CXR abnormalities- seen in 50 of cases
• - PPD- positive in majority
• - negative result doesnt r/o the
  Dx.
• Atypical presentations
• - Pts may present with and acute, rapidly
  progressive illness mimicking pyogenic meningitis
• - some- slowly progressive dementia over
  months or years
• - less common- encephalitic picture with
  stupor coma, and convulsions without signs of
  meningitis

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ctd

• HIV infection
• - co-infection- in 20 in US
• - here- ?
• - clinical features, lab findings, and
  mortality rates- similar to non infected
• - Tuberculoma- more common in HIV
• - response to Rx- the same
• - A study from Zaire- 200 pts with
  meningitis
• - 12 TB meningitis
• - 45- cryptococcal meningitis
• - 80 0f all patients with suspected
  meningitis- HIV
• - HIV seropositivity- 88 and 100 for TB
  and cryptococcal meningitis respectively

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• Diagnosis
• - maintaining a high degree of suspicion
• - CSF- typical formula
• - high protein, low glucose,
  and with a mononuclear pleocytosis.
• - protein- 100- 500
• - glucose- lt 45mg/dl
• - cell count- 100-500mg/dl
• - Early in the course- may be PMN cell
  predominant rapidly change to mononuclear on
  subsequent analysis

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ctd

• AFB smear
• - important to do repeated smear and culture
• - In one report-of 37 patients
• - 37- diagnosed on the basis of initial
  smear.
• - yield increased to 87 when up to 4
  serial samples were examined
• - recommendation- a minimum of 3 LPs at
  daily intervals
• - Empiric Rx need not be delayed.

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ctd

• Sensitivity of AFB may be enhanced
• - It is best to use the last fluid removed at
  lumbar puncture, and recovery of the organism
  improves if a large volume (10 to 15 mL) is
  removed.
• - Organisms can be demonstrated most readily
  in a smear of the clot or sediment. If no clot
  forms, the addition of 2 mL of 95 percent alcohol
  gives a heavy protein precipitate that carries
  bacilli to the bottom of the tube upon
  centrifugation.
• - 0.02 mL of the centrifuged deposit should
  be applied to a glass slide in an area not
  exceeding one centimeter in diameter and stained
  by the standard Kinyoun or Ziehl-Neelsen method.
• - Between 200 and 500 high-powered fields
  should be examined (approximately 30 minutes),
  preferably by more than one observer.

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ctd

• PCR
• - potentially useful test
• - variable sensitivity
• - one report of 15 patients- sensitivity
  of PCR was- 60
• Neuroradiology
• - CT with contrast- can define the presence
  and extent of
• - basilar arachnoiditis,
• - cerebral edema and infarction
• - hydrocephalus
• - MRI- superior to CT in detecting lesions of
  the BG, BS, and midbrain

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• Treatment
• - Specific anti-TB Rx should be started on the
  basis of strong clinical suspicion
• - shouldnt be delayed until proof of
  infection
• - clinical outcome depends on the stage at
  which Rx is initiated
• - WHO- estimates- at least 10 of isolates
  are resistant to at least one drug
• - Study from Vietnam- in 180 pts-
• - resistance to at least one anti-TB- 40
• - MDR TB in 5.6
• - strong predictor of death and
  independently associated with HIV infection

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ctd

• Recommended regimen
• - four drug regimen that includes INH,
  Rifampicin, PZA, and either ETM or STM for two
  months followed by INH and Rifampicin alone.
• Duration of therapy no randomized trials
• - CDC- therapy be administered for at least
  12 months- in drug sensitive infection
• - If PZA is omitted- 18months
• - MDR TB- no guidelines
• - advisable to extend Rx-
  18-24 months

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ctd

• Corticosteroids
• - recommended for all children and adults
  with , exception being adults with early stage 1
  disease
• - Specific indications for steroid Rx
• -Patients who are progressing from one
  stage to the next at or before the introduction
  of chemotherapy, especially if associated with
  any of the conditions listed below.
• -Patients with an acute "encephalitis"
  presentation, especially if the CSF opening
  pressure is 400 mmH2O or if there is clinical or
  CT evidence of cerebral edema
• -Patients who demonstrate "therapeutic
  paradox," an exacerbation of clinical signs (eg,
  fever, change in mentation) after beginning
  antituberculous chemotherapy
• -Spinal block or incipient block (CSF
  protein gt500 mg/dL and rising)
• -Head CT evidence of marked basilar
  enhancement (portends an increased risk for
  infarction of the basal ganglia) or moderate or
  advancing hydrocephalus
• -Patients with intracerebral
  tuberculoma, where edema is out of proportion to
  the mass effect and there are any clinical
  neurologic signs

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ctd

• Recommended steroid regimen
• - prednisolone- 60mg/day tapered gradually
  over 6weeks
• - Dexamethasone- IV for the first
  3weeks-0.4mg/kg then tapering to 1mg/kg/day.
• - followed by oral administration-4mg/d

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Tuberculoma

• Conglomerate of caseous foci with in the
  substance of the brain
• From deep seated tubercles acquired during a
  recent or remote hematogenous bacillemia
• Radiologically- single or multiple enhancing
  nodular lesions often apparent on CT.
• A distinct clinical syndrome- with focal
  neurologic symptoms and signs and signs of an
  intracranial mass lesion
• Accounts for 20-30 of intracranial mass lesions
  in children in India and Asia
• Dx- by clinical and radiographic findings or by
  needle biopsy
• Surgery- often complicated by sever, fatal
  meningitis
• - indication- obstructive
  hydrocephalus or brainstem compression.
• Corticosteroids when cerebral edema contributes
  to altered mentation and focal deficits

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Spinal TB Arachnoiditis

• Seen more in developing countries
• Pathogenesis- similar to TB meningitis with focal
  inflammatory disease at single or multiple
  levels- produces gradual encasement of the SC
• Symptoms- develop and progress slowly over weeks
  to months- terminate with meningitis syndrome
• Patients present with a subacute onset of nerve
  root and cord compression
• - spinal or radicular pain, hyperesthesia
• - lower motor neuron paralysis
• - bladder and rectal dysfn
• Vasculitis- may lead to thrombosis of ASA-
  infarction
• Dx- finding of abnormal CSF protein- spinal block
• - MRI changes of nodular arachnoiditis
• - tissue biopsy
• Treatment- as for TB meningitis

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Neurosyphilis

• May occur as early as one year after primary
  infn to 25 years
• The different forms may overlap causing
  diagnostic confusion
• Categories
• - asymptomatic
• - meningeal
• - parenchymatous
• - gummatous
• - atypical

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Asymptomatic

• Has both early and late forms
• It is a systemic disease and invasion of the CSF
  is common in early stages
• 15 of patients with primary disease and 40
  pts with secondary syphilis have CSF changes
• - and Tp can be demonstrated by animal
  inoculation
• Some untreated pts- experience spontaneous cure
  of this infn
• Persistence of CSF changes for gt5years- highly
  predictive of the dept of clinical neurosyphilis
• Those with normal CSF- gt 2years after the initial
  untreated infn- unlikely to develop neurosyphilis

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ctd

• Dx- requires LP with CSF exam
• CSF VDRL must be positive to Dx asymptomatic NS
• Nearly all pts have positive serum tests for
  syphilis
• Typically- there are 10-100 lymphocytes in CSF
• - protein- 50-100mg/dl

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Acute Syphilitic Meningitis

• Earliest clinical manifestation of NS
• Occurs with in the first year in most-
  occasionally up to 6years
• In 6 of pts with syphilis
• There are often- cranial nerve palsies and there
  may be signs and symptoms of hydrocephalus
• Serum and CSF VDRL- nearly always positive
• Isolated 8th nerve palsy- may present with normal
  CSF

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Meningovascular Syphilis

• Probably more common than meningitis
• Occurs in 10-12 of pts
• Syphilitic endarteritis- vascular occlusion and
  infarction in the territory of great cerebral
  vessels.
• Typically occurs with in the first 5-12years of
  infection
• Should be included in the DDx of unexplained
  stroke syndromes
• May be accompanied by tabes or paresis
• Clinical manifestation depend upon w/c vessel is
  occluded
• Aphasia and hemiparesis- most common
• Onset may be sudden
• - but 50- have prodromal symptoms of
  headache and mental or emotional changes
• Seizures- occur in 15 of pts
• Dx- lymphocytosis, elevated protein, and positive
  VDRL in a pt with unexplained stroke
• R/o- other causes of aseptic meningitis and
  stroke

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General Paresis

• Formerly- quite common and accounted for many
  admissions to psychiatric hospitals
• Now- is relatively rare
• Insidious neurologic and psychiatric illness
• - typically occurs- 15-20yrs after initial
  infn
• Manifestations- due to infection of the meninges
  and cerebral cortex
• - progressive change in personality
  delusions of grandeur, emotional lability, and
  paranoia
• - increasing memory loss, carelessness, and
  eventually dementia
• - depression may be prominent and seizures
  may occur

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ctd

• P/E- may show Argyll Robertson pupils
• - more typical of tabes
• Dx- not easy b/c many other illnesses may mimic
  it
• Most have positive serum VDRL and nearly all
  have positive serum treponemal test for syphilis
• MRI and CT- may show evidence of organic brain
  disease of several types
• Most have abnormal CSF- elevated protein and
  lymphocytes
• - CSF VDRL- usually positive in the pre-HIV
  era
• - currently- 27-92 positivity

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Tabes Dorsalis

• Formerly- most common form of neurosyphilis but
  now is rare
• Disease of the posterior columns of the SC and of
  the dorsal roots
• Occur 18-25 years after initial untreated infn
• Typical manifestation paresthesias, abnormal
  gait, and sudden sever pains of extremities or
  trunk
• Physical findings diminished peripheral reflexes
  and posterior column signs
• If the Babinski sign is present- consider
  accompanying cortical disease- possibly paresis
• Vision may be poor- due optic atrophy
• Pupils- often abnormal- Argyll Robertson pupils
  are common
• Confirmation may be difficult- abnormal CSF is
  less common than in other forms and CSF VDRL-
  normal in 1/3 of the cases

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Syphilis in HIV Infected Patients

• Strong association b/n HIV and syphilis
• - both are STDs and acquisition of HIV is
  more common in the setting of genital ulcer
• - In HIV clinics in US- 6 of pts have
  serologic evidence of syphilis
• - no convincing evidence that syphilis is
  more sever in HIV infection although
  parenchymatous gummas may be more common
• NS- particularly meningitis, optic neuritis, and
  meningovascular syphilis- is a common problem in
  HIV infn
• Dx- can be confusing- b/c pts with HIV infn have
  many causes of encephalitis and meningitis-
  renders interpretation of CSF abnormalities
  difficult
• Presence of positive CSF VDRL in the absence of
  traumatic LP -remains the best evidence for NS
• - but is relatively insensitive

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Therapy

• Crystalline penicillin- 3-4million units Q 4hrs
  for 10-14days
• If patients are allergic to penicillin- most
  would try desensitization
• - alternative- ceftriaxone-2gm IV QD for
  10-14days
• HIV negative pts with asymptomatic NS- may be
  treated with benzathine penicillin
• HIV positive pts with asymptomatic NS- most would
  treat with IV penicillin G - apparent risk of
  treatment failure with B. penicillin
• Patients treated for NS- should have serum VDRL
  measured at 3 and 6 months, and then Q 6months
  for 2years
• - serum VDRL should fall four fold in a
  year
• - repeat neurologic exam and repeat CSF-
  may be used to determine the adequacy of Rx
• - CSF protein and cell count - should
  decrease over 3months
• - rising serum VDRL or worsening CSF
  parameters- indications for retreatment