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CNS INFECTIONS Overview

CNS INFECTIONS Overview. 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

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CNS INFECTIONS Overview

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  1. 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

  2. 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

  3. CNS Infections • Signs and symptoms • Fever • Headache • Altered mental status -lethargy to coma • Neck stiffness – meningismus – flex/ext • Increased intracranial pressure – papilledema, nausea/vomiting, abducens palsies, bulging fontanelle in infants

  4. Exam in suspected CNS Infection • Mental Status • Cranial nerve and fundiscopic exam • Meningeal Signs • General exam – rashes, lymphadenpathy • Labs • Radiology – CT head - uncontrasted if no focal signs, contrast if mass suspected

  5. LP Increased intracranial pressure is expected – but LP contraindicated if a mass is present or if epidural spinal abscess is suspected Left lateral decubitus position L3-L4 interspace or L4-L5 interspace Think about your studies before the LP

  6. LP • Tube #1 – glucose and protein • Tube #2 – cell count and differential • Tube #3 – gram stain and rountine culture, cryptococcal antigen, stain and culture, VDRL, viral studies (PCR)

  7. Bacterial Viral Fungal TB Opening Pressure Elevated Slightly elevated Normal or High Ususally high Gluc Low Normal Low Low Pro Very high Normal High High Rbcs Few None None None Wbcs (c/mm3) >200 <200 <50 20-30 Diff PMNs Mono Mono Mono CSF Characteristics

  8. Key CSF Features • CSF is not liquid gold – get enough to get your answer • CSF Glucose is 2/3 of serum glucose • Important in diabetic patients • Traumatic LPs – • CSF pro increases by 1 for every 1000 rbcs • Very high CSF Protein levels will make CSF yellow • Send a full tube of CSF for cytology not just a few cc’s

  9. Bacterial Meningitis • Streptococcus pneumoniae • Hemophilus influenzae • Listeria moncytogenes • Group B streptococcus • Niesseria meningitidis

  10. Chronic Meningitis • Immunocompromised patients • Cryptococcus neoformans • HIV • M. tuberculosis • M. avium • Carcinomatous meningitis • Lung, breast

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

  12. 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 Brudzinsk. 5% 95% 27% 72% 0.97 1.0 From:Thomas KE et al, CID 2002, 35:46-52

  13. 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

  14. 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

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

  16. 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

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

  18. 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]

  19. 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

  20. 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

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

  22. 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

  23. 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, 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, 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 • 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) 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 g q12h [Listeria] + [H. influenzae] Vanco 1-2 g 12h +/- Ampi 2 g q4h Closed head trauma S. pneu Pen G 3-4 mu q4h Streptococci + Vancomycin 1-2 g 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 Cefepime 2 gm q8h Nosocomial [Ceftriaxone 2 gm q12h] Elderly Listeria [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/dor Ampicillin 12 gm/d [plus aminogl] [Ceftriax 2-4 gm/d]

  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]

  37. Meningite battericaTerapia empirica Ampicillina + Cefotaxime Ampicillina + aminoglicosidi Vancomicina+ Cefalosporine di III gen Vancomicina+ Cefalosporine di III gen Vancomicina+Ampicillina + Cefal. III gen. Vancomicina + Ampicillina + Ceftazidime Vancomicina + Cefalosporina III gen Vancomicina + Cefalosporina III gen Vancomicina + Cefepime/ceftazidime/meropenem

  38. 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

  39. Original ArticleDexamethasone in Vietnamese Adolescents and Adults with Bacterial Meningitis Nguyen Thi Hoang Mai, M.D., Tran Thi Hong Chau, M.D., Guy Thwaites, M.D., Ly Van Chuong, M.D., Dinh Xuan Sinh, M.D., Ho Dang Trung Nghia, M.D., Phung Quoc Tuan, M.D., Nguyen Duy Phong, M.D., Nguyen Hoan Phu, M.D., To Song Diep, M.D., Nguyen van Vinh Chau, M.D., Nguyen Minh Duong, M.D., James Campbell, Constance Schultsz, M.D., Chris Parry, M.D., M. Estee Torok, M.D., Nicholas White, F.R.C.P., Nguyen Tran Chinh, M.D., Tran Tinh Hien, M.D., Kasia Stepniewska, Ph.D., and Jeremy J. Farrar, F.R.C.P. N Engl J Med Volume 357(24):2431-2440 December 13, 2007

  40. Study Overview • In this randomized, placebo-controlled trial involving 435 adolescents and adults with meningitis in Vietnam, the use of adjunctive dexamethasone did not reduce the rate of death or disability at 6 months • In subgroup analyses, a benefit of treatment was seen in patients with confirmed bacterial meningitis, whereas harm was identified in those with probable bacterial meningitis

  41. Enrollment and Outcomes Mai NTH et al. N Engl J Med 2007;357:2431-2440

  42. Kaplan-Meier Survival Estimates According to Study Group Mai NTH et al. N Engl J Med 2007;357:2431-2440

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