1. Encephalitis and Meningitis CBP Yoan Lamarche, 2009

2. 46 yo male presenting to ED with progressive decreased LOC since 2 days. Able to mumble answers to questions. No history of recent travel or drug use. No allergies. On exam, patient protects A/W, Bp 110/52, HR 92, RR 29, Sat 92% RA T 38.4C. Neck N. Chest/Abdo N. Skin show no rash. WBC 14 000. CXR N. No focal signs on exam. ABG shows mild respiratory alkalosis.

3. Approach to the unconscious Pt • Naisan • Scot • Noemie • Marios • Neil • Todd

4. Initial workup, ↓LOC • Glycemia • ABCs • Physical exam: seizure-localizing-toxidrome • Labs: kidney, liver, sepsis, ABG, AG • CT Head • LP • EEG • Overlapping Tx

5. Describe the usual clinical presentation for meningitis, including the relative frequency of different signs and symptoms

6. Clinical Presentation • Classical triad • Fever: 95% on presentation • Nuchal Rigidity: 88% on initial exam • Brudzinski sign • Kernig sign • Mental status change: 77% • Triad present in 44% pts on presentation • Sensitivity of 99% if pt has at least one finding of the triad N Engl J Med 1993 Jan 7;328(1):21-8

7. How does the bug get to the brain?

9. Major mechanism • Colonization of the nasopharynx with subsequent bloodstream invasion and subsequent central nervous system (CNS) invasion. • Invasion of the CNS following bacteremia due to a localized source, such as infective endocarditis or a urinary tract infection

10. Major mechanism • Direct entry of organisms into the CNS from a contiguous infection (eg, sinuses, mastoid), trauma, neurosurgery, a cerebrospinal fluid (CSF) leak, or medical devices (eg, shunts or intracerebral pressure monitors or cochlear implants in children)

11. A)How does the bug get to the brain Emerg Clin N Am 2009

12. Clinical Presentation- Meningitis • 30% Seizure • 30% Focal Neuro signs • ↓ LOC • Fever • Neck Stiffness • Headache 95% will have > 2 of van de Beek D, de Gans J, Spanjaard L, et al. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med 2004;351(18):1849–59

13. Predictors: Bacterial • Seizure • ↓LOC • Focal • Shock • 1 of those + • Neutro > 1000/mm3 Most likely Bacterial Brivet FG, Ducuing S, Jacobs F, et al. Accuracy of clinical presentation for differentiatingbacterial fromviralmeningitis in adults: amultivariate approach. IntensiveCareMed 2005;31(12):1654–60

14. SiADH more frequent with Bacterial Meningitis • BC + in 50% Bacterial

16. Question 3: Describe the initial sequence of investigations and treatment plan in a patient with suspicion for meningitis

17. Initial investigations in suspected bacterial meningitis Ensure adequate airway, breathing and circulation. Stat blood cultures + lumbar puncture Routine septic blood work (CBC, lytes, Creat, LFTs, lactate, coags) ABG Chest X-ray

18. Contraindications to LP • Theoretical risk of brain herniation following lumbar puncture in pts with increased ICP. IDSA criteria for pre-LP CT head: Tunkel A, et al. Practice Guidelines for the Management of Bacterial Meningitis (IDSA Guidelines). CID 2004;39:1267-84

19. Other relative contraindications to LP • Thrombocytopenia (plts < 50 000) • Coagulopathy or systemic anticoagulation (INR > 1.4). • Epidural abscess or infection over LP site

20. Initial management in suspected bacterial meningitis Tunkel A, et al. Practice Guidelines for the Management of Bacterial Meningitis (IDSA Guidelines). CID 2004;39:1267-84

21. Lancet ID 2007

22. LP: Complications: IDSA Guidelines 2004

23. An LP is done after a CT of the head showing 8000 WBC/μl • Describe the findings on LP, what if traumatic?

24. LP: send for • Cell count, differential • Biochemistry (gluc-proteins) • Stains and cultures for bacteria, fungi and mycobacteria • Viral studies-HSV PCR (Sen 98%, Spe 94%,NPV suboptimal)

25. Latex Agglutination • Sen 50-100% • Spe <100 • Does not change tx in Bacterial Meningitis (treat or not with ATBX) • May be useful if received ATBX and CSF clear

26. Broad Range Real time PCR • Sensitivity of 86%-100% • Specificity of 98% when compared with culture -Deutch S, Pedersen LN, Podenphant L, et al. Broad-range real time PCR and DNA sequencing for the diagnosis of bacterial meningitis. Scand J Infect Dis 2006;38(1):27–35. -Saravolatz LD,Manzor O, VanderVelde N, et al. Broad-range bacterial polymerase chain reaction for early detection of bacterial meningitis. Clin Infect Dis 2003;36(1):40–5.

27. Acute Phase reactants • Nathan BR, Scheld WM. The potential roles of C-reactive protein and procalcitonin concentrations in the serumand cerebrospinal fluid in the diagnosis of bacterialmeningitis. CurrClin Top Infect Dis 2002;22:155–65. • Gendrel D, Raymond J, Assicot M, et al. Measurement of procalcitonin levels in children with bacterial or viral meningitis. Clin Infect Dis 1997;24(6):1240–2. • Viallon A, Zeni F, Lambert C, et al. High sensitivity and specificity of serum procalcitonin levels in adults with bacterial meningitis. Clin Infect Dis 1999;28(6):1313–6. • ViallonA,Guyomarc’hP,Guyomarc’h S, et al.Decrease in serumprocalcitonin levels over time during treatment of acute bacterial meningitis. Crit Care 2005;9(4):R344–50

28. Post Neurosurgery • Lactate > 4mmol/l: higher risk of meningitis • Sensitivity was 88% • Specificity was 98%. • The positive predictive value was 96% • Negative predictive value was 94% • RT-PCR may have high SEN, research Leib SL, Boscacci R, Gratzl O, et al. Predictive value of cerebrospinal fluid (CSF) lactate level versus CSF/blood glucose ratio for the diagnosis of bacterial meningitis following neurosurgery. Clin Infect Dis 1999;29(1):69–74. Pfausler et al.

30. Lancet 2007

31. Neurol Clin 2008

32. Viral encephalitis Review Solomon 2007

33. 5. What is the bacteriology of bacterial meningitis? (Scot)

35. Historical • H influenzae (45%) • S pneumoniae (18%) • Neisseria meningitidis (14%) • Group B streptococcus (S agalactiae) (6%) • Listeria monocytogenes (3%) • Others (14%) • Children < 5 years old >70% H influenzae • HIB vaccine introduced in 1990s.

36. Since HIB vaccination • S pneumoniae (47%) • N meningitidis (25%) • group B streptococcus (12%) • Listeria monocytogenes (8%) • H influenzae (7%) • Others (1%)

38. Remains to be seen whether proportions will change with the increasingly widespread use of S pneumoniae multivalent vaccines. • In infants where it has been used, invasive S pneumoniae disease has decreased by >90%.

42. 6-What should you initiate as a treatment for your now intubated unconscious febrile patient with possible meningitis? Is there resistance to this treatment?

43. Empiric Treatment for Bacterial Meningitis • ABCs, as above. • Critical care setting, given decreased LOC and sepsis requiring airway protection and ventilatory support. • Fluid resuscitation as required. • Immediate antibiotics.

44. Empiric Treatment for Meningitis • 3rd-generation cephalosporin, i.e. ceftriaxone 2 g IV q 12 hrs (maximize CSF concentration with this dose). • Vancomycin 1.5 g IV X1, then 1 g IV q 12 hrs. • For pneicillin-resistent pneumococci • +/- ampicillin if risk factor for Listeria monocytogenes • Alcoholism, immunosuppression

45. Resistance to Initial Antibiotics • Antimicrobial resistant organisms: • Strep pneumo: may be resistant to penicillin (hence empiric vancomycin); approx 10% across VCH. • Neisseria meningitidis: often resistant to penicillin (hence empiric 3rd-generation cephalosporin) • May add rifampin if resistant to ceftriaxone (MIC > 2mg/L) • Wrong organism • Viral • Fungal

46. Van de Beek, NEJM 2006

47. Directed Pharmacotherapy of CNS Infections: What Intensivists SHOULD Know • What are the in vitro susceptibility results (if culture positive)? • Is the antibacterial bactericidal in the CNS? • Subarachnoid space/brain tissue are regions of ineffective host defence • Antibiotics must demonstrate bactericidal activity in vivo • What is the antibacterial concentration attainable in CNS?

48. Central Nervous System Compartments • The Brain and CSF cannot be viewed as 1 pharmacokinetic (PK) compartment! • Three distinct PK compartments within the CNS • CSF • Extracellular space of neuron tissue • Intracellular space (neurons, glial cells, granulocytes, lymphocytes, macrophages) • Drugs penetrate into each of these compartments to varying degrees • CSF is not homogeneous (drug concentration higher in lumbar versus ventricular CSF)

49. Blood-Central Nervous System Interfaces • Blood-Brain Barrier • Located in endothelial cells of vessels of brain and spinal cord • Linked by tight junctions • Only 0.02% of brain capillaries possess fenestrated endothelium • Blood-CSF Barrier • Choroid plexus is characterized by fenestrated vascular endothelium

50. Blood-Central Nervous System Interfaces Blood-CSF Barrier Blood-Brain Barrier