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ACUTE CNS INFECTIONS James E. Peacock, Jr. MD

ACUTE CNS INFECTIONS James E. Peacock, Jr. MD.

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ACUTE CNS INFECTIONS James E. Peacock, Jr. MD

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  1. ACUTE CNS INFECTIONS James E. Peacock, Jr. MD

  2. “The precise and intelligent recognition and appreciation of minor differences is the real essential factor in all successful medical diagnosis…Eyes and ears which can see and hear, memory to record at once and to recall at pleasure the impressions of the senses, and an imagination capable of weaving a theory or piecing together a broken chain or unraveling a tangled clue, such are the implements of his trade to a successful diagnostician.” Joseph Bell

  3. CNS INFECTIONSOverview • Life-threatening problems with high associated mortality and morbidity • Presentation may be acute, subacute, or chronic • Clinical findings determined by anatomic site(s) of involvement, infecting pathogen, and host response • Vulnerability of CNS to effects of inflammation & edema mandates prompt diagnosis with appropriate therapy if consequences to be minimized

  4. ACUTE CNS INFECTIONS 1. Bacterial meningitis*** 2. Meningoencephalitis 3. Brain abscess 4. Subdural empyema 5. Epidural abscess 6. Septic venous sinus thrombophlebitis

  5. THE PATIENT WITH ACUTE CNS INFECTIONOverall Goals in Management 1. To promptly recognize the patient with an acute CNS infection syndrome 2. To rapidly initiate appropriate empiric therapy 3. To rapidly and specifically identify the etiologic agent, adjusting therapies as indicated 4. To optimize management of complicating features

  6. Does the patient have a “CNS infection syndrome”? • Prodromal/concurrent URI sxs • Fever, HA, altered MS • Compatible PE findings - Meningismus - Active RT infxn - Exanthems - Focal neuro signs

  7. Symptoms HA & fever HA, N/V HA, fever, N/V HA, fever, N/V, photophobia HA, fever, N/V, photophobia, stiff neck Odds of Meningitis .42 .49 .56 .54 .57 Symptoms and the Likelihood of Meningitis

  8. Diagnostic Accuracy of Signs of Meningeal Irritation in Pts with Suspected Meningitis SignSensSpecPPVNPV+LR-LR Nuchal 30% 68% 26% 73% 0.94 1.02 rigidity Kernig’s 5% 95% 27% 72% 0.97 1.0 Brudzin- 5% 95% 27% 72% 0.97 1.0 ski’s From:Thomas KE et al, CID 2002, 35:46-52

  9. If the patient has a “CNS infection syndrome”, is it antimicrobial requiring? • Untreated/partially Rx’ed bacterial meningitis • Parameningeal suppurative foci • M. tuberculosis/Fungi • Syphilis/Borrelia/Rickettsia • HSV/CMV/VZV • Others (amebae, parasites, etc)

  10. APPROACH TO THE PATIENT WITH POSSIBLE CNS INFECTION If the patient has a CNS infection syndrome, is it antimicrobial or non-antimicrobial requiring? Crucial and recurring question addressed sequentially over time Points in Decision- Available Data Base Making Process For Decision-Making Within the 1st 30 mins Clinical assessment of patient contact After 1-2 hours CSF analysis At 24-48 hours CSF cultures Thereafter as clinically indicated

  11. APPROACH TO THE PATIENT WITH SUSPECTED MENINGITIS Decision-Making Within the First 30 Minutes Clinical Assessment Mode of presentation Acute (< 24 hrs) Subacute (< 7 days) Chronic (> 4 wks) Historical/physical exam clues Clinical status of the patient Integrity of host defenses

  12. CSF STUDIES • Color/Clarity • Cell counts/WBC diff • Chemistries (protein, glucose) • Stains/Smears (Gram) • Cultures (routine) • +/- Antigen screens

  13. APPROACH TO THE PATIENT WITHSUSPECTED MENINGITIS Decision-Making at 1-2 Hours CSF Analysis CSF smears/stains CSF antigen screens CSF “profile”

  14. CSF SMEARS & STAINS • GmS + in 60-90% of pts with untreated bacterial meningitis • With prior ATB Rx, positivity of GmS decreases to 40-60% • REMEMBER: + GmS = Heavy organism burden & worse prognosis

  15. CSF ANTIGEN SCREENS • Bacterial antigen screens detect S. pneumoniae, N. meningitidis, Hib, and GBS; + in 50-100% of pts (esp. useful in pts with prior ATB Rx) • Crypto antigen screen detects C. neoformans; + in 90-95% of pts with crypto meningitis • Should NOT be a ordered routinely

  16. CEREBROSPINAL FLUID PROFILES* Neutrophilic/Low glucose (purulent) Lymphocytic/Normal glucose Lymphocytic/Low glucose *Profile designation based on WBC differential and glucose concentration. After NE Hyslop, Jr and MN Swartz, Postgrad Med 58:120, 1975.

  17. BACTERIAL VS VIRAL MENINGITIS Predictors of bacterial etiology: • CSF glucose < 34 • CSF: Serum glucose ratio < 0.23 • CSF protein > 220 • CSF WBC count > 2000 • CSF neutrophil count > 1180 [Presence of any ONE of the above findings predicts bacterial etiology with > 99% certainty]

  18. APPROACH TO THE PATIENT WITH SUSPECTED MENINGITIS Decision-Making at 24-48 hours CSF Culture Results Culture positive  Adjust therapy based upon specific organism and sensitivities Culture negative  Evaluate for “aseptic” meningitis syndrome

  19. TO LP OR NOT TO LP • Single most impt diagnostic test • Mandatory, esp if bacterial meningitis suspected • If LP contraindicated, obtain BCs (+ in 50-60%), then begin empirical Rx

  20. THE PATIENT WITH SUSPECTEDCNS INFECTIONContraindications to LP Absolute: Skin infection over site Papilledema, focal neuro signs, ↓MS Relative: Increased ICP without papilledema Suspicion of mass lesion Spinal cord tumor Spinal epidural abscess Bleeding diathesis or ↓ plts

  21. CNS INFECTIONSCCT • Over-employed diagnostic modality  Leads to unnecessary delays in Rx & added cost • Rarely indicated in pt with suspected acute meningitis • Mandatory in pt with possible focal infection • Increased sensitivity with contrast enhancement

  22. CCT Before LP in Patients with Suspected Meningitis • 301 pts with suspected meningitis; 235 (78%) had CCT prior to LP • CCT abnormal in 56/235 (24%); 11 pts (5%) had evidence of mass effect • Features associated with abnl CCT were age >60, immunocompromise, H/O CNS dz, H/O seizure w/in 7d, & selected neuro abnls Hasbun, NEJM 2001;345:1727

  23. CCT Before LP(Cont.) • Neuro abnls included altered MS, inability to answer 2 consecutive questions or follow 2 consecutive commands, gaze palsy, abnl visual fields, facial palsy, arm or leg drift, & abnl language • 96/235 pts (41%) who underwent CCT had none of features present at baseline • CCT normal in 93 of these 96 pts (NPV 97%) Hasbun, NEJM 2001;345:1727

  24. CNS INFECTIONSMRI • Not generally useful in acute diagnosis (Pt cooperation; logistics) • Very helpful in investigating potential complications developing later in clinical course such as venous sinus thrombosis or subdural empyema

  25. THE PATIENT WITH SUSPECTED CNS INFECTIONRole of Repetitive LP’s 1. Rarely indicated in proven bacterial meningitis unless clinical response not optimal or as expected, fever recurs, or infection is due to ATB resistant pathogen 2. Essential in pts with “aseptic meningitis” syndromes to monitor course &/or response to empiric therapies 3. Essential in pts with subacute/chronic meningitis of proven etiology to assess response to Rx 4. Not routinely indicated at end-of-therapy for bacterial meningitis

  26. BACTERIAL MENINGITIS • Incidence of 3 cases/100,000 population/yr (~25,000 total cases) • Fever, HA, meningismus, & altered mentation present in > 85% of pts • Other clinical findings • Cranial nerve palsies/focal signs 10-20% • Seizures 25-30% • Papilledema < 1%

  27. BACTERIAL MENINGITISCaveats re: Antimicrobial Rx • Therapy is gen’ly IV, high dose, & bolus • Dosing intervals should be appropriate for drug being administered • Utilize “cidal” therapy whenever possible • Strive for CSF bactericidal index > 10 • Initiate therapy promptly (ie, within 30 mins)

  28. THE THERAPY OF MENINGITISDesirable Antimicrobic Properties 1. Activity vs suspected pathogen(s) [preferably cidal] 2. Adequate CSF diffusion 3. Acceptable risk of toxicity

  29. Good Diffusion Penicillins 3rd & 4th Gen Cephs Chloramphenicol Rifampin TSX Poor Diffusion Early Gen Cephs Clindamycin AMGs Tetracyclines Macrolides THE THERAPY OF MENINGITISCNS Penetration

  30. Bacterial MeningitisImportant Changes in Epidemiology • Marked decline in the occurrence of Hib • ↑’ing incidence of S. pneumo (50+% of cases in US) • Shift from peds disease to adult disease • ↑’ing incidence of ATB-resistant organisms, esp. S. pneumo • PCN resistance ~ 35% (15-20% high level) • Ceph resistance 15-20% (5-10% high level)

  31. Predisposing Factor Age 0-4 wk 4-12 wk 3 mo to 18 yr 18-50 yr >50 yr Common Bacterial Pathogens Streptococcus agalactiae, Escherichia coli, Listeria monocytogenes, Klebsiella pneumoniae, Enterococcus spp., Salmonella spp. S. agalactiae, E. coli, L. monocytogenes, Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis H. influenzae, N. meningitidis, S. pneumoniae S. pneumoniae, N. meningitidis S. pneumoniae, N. meningitidis, L. monocytogenes, aerobic gram-negative bacilli COMMON BACTERIAL PATHOGENS BASED ON PREDISPOSING FACTOR IN PATIENTS WITH MENINGITIS

  32. Predisposing Factor Immunocompromised state Basilar skull fracture Head trauma; postneurosurgery Cerebrospinal fluid shunt Common Bacterial Pathogens S. pneumoniae, N. meningitidis, L. monocytogenes, aerobic gram-negative bacilli (including P. aeruginosa) S. pneumoniae, H. influenzae, group A β- hemolytic streptococci Staphylococcus aureus, Staphylococcus epidermidis, aerobic gram-negative bacilli (including P. aeruginosa) S. epidermidis, S. aureus, aerobic gram- negative bacilli (including P. aeruginosa), P. acnes COMMON BACTERIAL PATHOGENS BASED ON PREDISPOSING FACTOR IN PATIENTS WITH MENINGITIS

  33. EMPIRIC THERAPY OF MENINGITIS IN THE ADULT Clinical SettingLikely PathogensTherapy Community-acquired S. pneumoniae Ceftriaxone N. meningitidis 2 gm q12h [Listeria] + [H. influenzae] Vancomycin 1-2 gm 12h +/- Ampicillin 2 gm q4h Closed head trauma S. pneumoniae Pen G 3-4 mu q4h Streptococci + Vancomycin 1-2 gm q12h

  34. EMPIRIC THERAPY OF MENINGITIS IN THE ADULT Clinical SettingLikely PathogensTherapy High risk patients S. aureus Vancomycin 2-3 gm/d Compromised hosts Gram negative + Neurosurgical bacilli Ceftazidime 2 gm q8h or Open head injury Listeria Cefepime 2 gm q8h Nosocomial [Ceftriaxone 2 gm q12h] Elderly [Cefotaxime 2 gm q4h] +/- Ampicillin 2 gm q4h

  35. SPECIFIC THERAPY FOR KNOWN PATHOGENS PathogenRecommended Therapy S. pneumoniae* Pen G 18-24 mu/d N. meningitidis or Streptococci Ampicillin 12 gm/d [Chloro 75-100 mg/kg/d] [Ceftriaxone 2-4 gm/d] H. influenzae Cefotaxime 12 gm/d [Ceftriaxone 2-4 gm/d] Group B strep Pen G 18-24 mu/d or Ampicillin 12 gm/d [plus aminoglycoside]

  36. SPECIFIC THERAPY FOR KNOWN PATHOGENS(continued) S. aureus Nafcillin 12 gm/d [Vancomycin 2-3 gm/d] Listeria Ampicillin 12 gm/d or Pen G 18-24 mu/d [plus aminoglycoside] Gram negative Cefotaxime 12 gm/d bacilli [Ceftriaxone 2-4 gm/d] Pseudomonas Ceftazidime 6-8 gm/d or Cefepime 6 gm/d [plus aminoglycoside] *Penicillin-susceptible (i.e. PCN MIC < 0.06). If penicillin resistant, see Table 7.

  37. SUGGESTED TREATMENT REGIMENS FOR ANTIBIOTIC-RESISTANT BACTERIAL MENINGITIS Suggested Regimen Bacteria Antibiotic Dosage N. meningitidis Ceftriaxone 2g q12h Penicillin MIC 0.1-1.0 µg/ml or Cefotaxime 2g q4-6h H. influenzae Ceftriaxone 2 g every 12h -Lactamase producing or Cefotaxime 2 g every 4-6h S. pneumoniae Vancomycin 1-2 g every 12h Highly resistant to + penicillin (MIC > 1 g/ml) Ceftriaxone 2 gm every 12h +/- Rifampin 600 mg every 12-24h Relatively resistant to Ceftriaxone2-3 g every 12h penicillin (MIC 0.1-1.0 g/ml) or or Cefotaxime 2 g every 4h or Vancomycin1-2g every 12h

  38. Risk Factors for Drug-Resistant S. pneumoniae (DRSP) • Extremes of age • Recent ATB Rx • Significant comorbid disease • HIV infection or other immunodeficiency • Day care or day care parent/sib • Recent hospitalization • Congregate settings (Institutions, military)

  39. CORTICOSTEROIDS AND MENINGITIS • Role of steroids still somewhat uncertain • Recent European study in adults suggested that Rx with dexa associated with ↓ in risk of unfavorable outcome (25%→15%, RR 0.59) & in mortality (15%→7%, RR for death 0.48) • Benefit primarily ltd to pts w/S. pneumo • Dose of dex was 10mg IV q6h X 4d; per protocol, dex given concurrent with or 15-20 mins before 1st dose of ATBs

  40. CORTICOSTEROIDS AND MENINGITIS(Cont) • Only pts with cloudy CSF, + CSF GmS, or CSF WBC count >1000 were enrolled • Accompanying editorial raised concerns about use of steroids in pts with DRSP who are being Rx’ed with vanc b/o ↓ in CNS conc of vanc with concurrent steroid use • Practically speaking, almost all pts with presumed bacterial meningitis are candidates for at least 1 dose of dexa NEJM 2002;347:1549

  41. PREDICTORS OF ADVERSE CLINICAL OUTCOMES IN PTS WITH COMMUNITY-ACQUIRED BACTERIAL MENINGITIS • Retrospecitve study; 269 pts (84% culture +) • Adverse clinical outcome in 36% of pts (Death 27%, neuro deficit 9%) • ↓BP, altered MS, and seizures on presentation all independently associated with adverse clinical outcome • Adverse outcomes in 5% of low risk pts (0 features), 37% of intermediate risk pts (1 feature), and 63% of high risk pts (2-3 features) • Delay in administration of appropriate ATB Rx also associated with adverse clinical outcome Aronin et al, AIM1998;129:862

  42. BACTERIAL MENINGITISDuration of ATB Rx Pathogen Duration of Rx (d) H. influenzae 7 N. meningitidis 7 S. pneumoniae 10-14 L. monocytogenes 14-21 Group B strep 14-21 GNRs 21 NEJM 1997;336:708

  43. Enteroviruses Polioviruses Coxsackieviruses Echoviruses Togaviruses Eastern equine Western equine Venezuelan equine St. Louis Powasson California West Nile Herpesviruses Herpes simplex Varicella-zoster Epstein Barr Cytomegalovirus Myxo/paramyxoviruses Influenza/parainfluenzae Mumps Measles Miscellaneous Adenoviruses LCM Rabies HIV VIRAL MENINGITIS/ENCEPHALITIS

  44. NONVIRAL CAUSES OF ENCEPHALOMYELITIS Rocky Mountain spotted fever Acanthamoeba Typhus Toxoplasma Mycoplasma Plasmodium falciparum Brucellosis Trypanosomiasis Subacute bacterial endocarditis Whipple’s disease Syphilis (meningovascular) Behcet’s disease Relapsing fever Vasculitis Lyme disease Leptospirosis Tuberculosis Cryptococcus Histoplasma Naegleria

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