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BACTERIAL AND MYCOBACTERIAL INFECTIONS OF THE CNS

BACTERIAL AND MYCOBACTERIAL INFECTIONS OF THE CNS. Outline. Acute bacterial meningitis Tb of the CNS Neurosyphilis. ACUTE BACTERIAL MENINGITIS. An acute inflammatory disease of the leptomeninges Bacteria may gain access to the ventriculo-subarachnoid space:

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BACTERIAL AND MYCOBACTERIAL INFECTIONS OF THE CNS

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  1. BACTERIAL AND MYCOBACTERIAL INFECTIONS OF THE CNS

  2. Outline • Acute bacterial meningitis • Tb of the CNS • Neurosyphilis

  3. 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.

  4. … 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.

  5. 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%

  6. 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)

  7. 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

  8. 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 >38 Oc - small percentage- hypothermia - no pt- normal temperature

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. 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 can’t be performed due contraindications - ~ 70-75% - positive - lowest yield- with meningococcal

  14. CSF analysis- xic findings - cell count > 1000, with neutrophil predominance - protein > 500mg/dl - glucose < 45mg/dl - spectrum of values differs: - review of 296 episodes of meningitis: - 50%- glucose > 40mg/dl - 44%- protein < 200mg/dl - 13%- WBC < 100cells

  15. …ctd • Gram’s stain and culture - Gram’s 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

  16. …ctd • In a trial of 301 adults:- Gram stain was positive in 74% and culture in 78% - Gram’s 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 doesn’t r/o bacterial meningitis

  17. …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

  18. 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 >6hrs 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

  19. …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

  20. …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

  21. …ctd • Rather than empiric therapy- IV antibiotics should be directed against the presumed pathogen if the Gram’s 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

  22. …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

  23. …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.

  24. 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

  25. …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 dev’ps 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

  26. …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 - Vasculitiswith 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.

  27. …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.

  28. …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 doesn’t 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

  29. …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

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

  31. …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.

  32. …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.

  33. 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

  34. Treatment: - Specific anti-TB Rx should be started on the basis of strong clinical suspicion - shouldn’t 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

  35. …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

  36. …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 >500 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

  37. …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

  38. 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

  39. 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

  40. 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

  41. 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 >5years- highly predictive of the dep’t of clinical neurosyphilis • Those with normal CSF- > 2years after the initial untreated infn- unlikely to develop neurosyphilis

  42. …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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