Bacterial and Non-Bacterial CNS Infections EMERGENCY NEUROLOGY LECTURE SERIES JULY 7, 2010

1. Bacterial and Non-Bacterial CNS Infections EMERGENCY NEUROLOGY LECTURE SERIES JULY 7, 2010 Dr. Abdullah Al-Salti R3

2. 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 the effects of inflammation & edema mandates prompt diagnosis with appropriate therapy if consequences to be minimized.

3. CNS INFECTIONSOUT LINE • Bacterial meningitis • Aseptic Meningitis • Viral Meningitis • Viral encephalitis

4. CNS Infections • Meningitis • Bacterial, viral, fungal, chemical, carcinomatous • Encephalitis • Bacterial, viral • Meningoencephalitis • Abscess • Parenchymal, subdural, epidural

5. INFECTIONS 4 routes which infectious agents can enter the CNS a) hematogenous spread i) most common - usually via arterial route - can enter retrogradely (veins) b) direct implantation i) most often is traumatic ii) iatrogenic (rare) via lumbar puncture iii) congenital (meningomyelocele) c) local extension (secondary to established infections) i) most often from mastoid, frontal sinuses, infected tooth, etc. d) PNS into CNS i) viruses - rabies - herpes zoster

6. BACTERIAL MENINGITIS Meningitis refers to an inflammatory process of leptomeninges and CSF. Meningoencephalitis refers to inflammation to meninges and brain parenchyma. • Meningitis classified: a) acute pyogenic i) usually bacterial meningitis b) aseptic i) usually acute viral meningitis c) chronic i) usually TB, spirochetes, cryptococcus. • Incidence of 3 cases/100,000 population/yr (~25,000 total cases).

7. 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

8. Clinical Features Signs and symptoms: • rapid onset of fever • headache • photophobia • nuchal rigidity • lethargy, malaise • altered mentation • seizure • vomiting. van de Beek D, de Gans J, Tunkel AR, et al. Community-acquired bacterial meningitis in adults. N Engl J Med 2006;354(1):44–53.

9. Clinical Features • Study of 493 adult patients with bacterial meningitis, the presence of the ‘‘classic triad’’ of fever, neck stiffness, and altered mental status was present in two-thirds of patients. • fever WAS the most common element, in 95%. (N Engl J Med 1993;328(1):21–8. ) • Older patients with S. pneumoniae meningitis are more likely to have the classic triad. Weisfelt M, van de Beek D, Spanjaard L, et al. Community-acquired bacterial meningitis in older people. J Am Geriatr Soc 2006;54(10):1500–7. • Other studies have shown the classic triad to be less common, with estimates ranging from 21% to 51%. • All cases studied had at least one of the three signs; the absence of the all components of the classic triad excludes the diagnosis in immunocompetent individuals.

10. Physical examination • A careful neurological examination is important to evaluate for : • focal deficits • increased intracranial pressure (ICP). • Examination should include assessment for meningeal irritation • Brudzinski’s sign • Kernig’s sign • findings include purpura or petechia of the skin, which may occur with meningococcemia.

11. Bacterial meningitis Investigations

12. LP • Single most impt diagnostic test. • Mandatory, esp if bacterial meningitis suspected. • Tube #1 – glucose and protein • Tube #2 – cell count and differential • Tube #3 – gram stain and rountine culture, cyrptococcal antigen, AFB stain and culture • Tube #4 – VDRL, or viral studies (PCR)

13. CSF Characteristics

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

15. CT head 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 CT had none of features present at baseline • CT normal in 93 of these 96 pts (NPV 97%). • Of the 3 remaining patients, only 1 had mild mass effect on CT, and all 3 underwent lumbar puncture with no evidence of brain herniation Hasbun, NEJM 2001;345:1727

16. Consideration for lumbar puncture without neuroimaging David Somand, MDa,WilliamMeurer, MD Department of Emergency Medicine, University of Michigan, Taubman Center B1354 SPC #5303, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5303, USA Department of Neurology, University of Michigan, Taubman Center 1914 SPC #5316, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-5316, USA • Age less than 60 • Immunocompetent • No history of CNS disease • No recent seizure (less than 1 week) • Normal sensorium and cognition • No papilledema • No focal neurologic defecits

17. Acute bacterail meninigitsMRI • 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.

18. Laboratory Testing Helpful in DistinguishingBacterial from Viral Meningitis. CSF lactate . • Elevated CSF lactate concentrations may be useful in differentiating bacterial from nonbacterial meningitis in patients who have not received prior antimicrobial therapy. • study of 78 patients with acute meningitis in which CSF lactate concentrations of >4.2mmol/L were considered to be a positive discriminative factor for bacterial meningitis . SensSpecPPVNPV 96%, 100%, 100%, 97%. • Furthermore, other factors (e.g., cerebralhypoxia/ischemia, anaerobic glycolysis,vascular compromise,and metabolism of CSF leukocytes) also may elevateCSF lactate concentrations. • Therefore, measurement of CSF lactate concentrations is not recommended for patients with suspected community-acquired bacterial meningitis. Practice Guidelines for the Management of Bacterial Meningitis Allan R. Tunkel,1 Barry J. Hartman,2 Sheldon L. Kaplan,3 Bruce A. Kaufman,4 Karen L. Roos,5 W. Michael Scheld,6and Richard J. Whitley7

19. Laboratory Testing Helpful in DistinguishingBacterial from Viral Meningitis. C-reactive protein (CRP). • Serum CRP concentrations were capable of distinguishing Gram stain–negative bacterial meningitis, with a sensitivity of 96%, a specificity of 93%, and a negative predictive value of 99%. • Measurement of serum CRP concentration may be helpful in considering withholding antimicrobial therapy, on the basis of the data showing that a normal CRP has a high negative predictive value in the diagnosis of bacterial meningitis. Provided the CSF Gram stain result is negative. Practice Guidelines for the Management of Bacterial Meningitis Allan R. Tunkel,1 Barry J. Hartman,2 Sheldon L. Kaplan,3 Bruce A. Kaufman,4 Karen L. Roos,5 W. Michael Scheld,6and Richard J. Whitley7

20. Laboratory Testing Helpful in DistinguishingBacterial from Viral Meningitis. procalcitonin concentration. • Elevated serum concentrations of the polypeptide procalcitonin, which are observed in patients with severe bacterial infection, were shown to be useful in differentiating between bacterial and viral meningitis . • In a study of 59 consecutive children hospitalized for meningitis , the sensitivity of measurements of the serum procalcitonin concentration (using a cutoff of 15.0 mg/L) for the diagnosis of bacterial meningitis was 94%, and the specificity was 100%. • In adults, serum concentrations 10.2 ng/mL had a sensitivity and specificity of up to 100% for the diagnosis of bacterial meningitis . • At present, because measurement of serum procalcitonin concentrations is not readily available in clinical laboratories, recommendations on its use cannot be made at this time. Practice Guidelines for the Management of Bacterial Meningitis Allan R. Tunkel,1 Barry J. Hartman,2 Sheldon L. Kaplan,3 Bruce A. Kaufman,4 Karen L. Roos,5 W. Michael Scheld,6and Richard J. Whitley7

21. Laboratory Testing Helpful in DistinguishingBacterial from Viral Meningitis. PCR. • In patients who present with acute meningitis, an important diagnostic consideration is whether the patient has enteroviral meningitis. • Enteroviral RT-PCR has been tested in clinical settings by numerous investigators and has been found to be more sensitive than viral culture for the detection of enterovirus, with a sensitivity and specificity of 86%–100% and 92%–100%, respectively. • lead to shortened patient hospitalization, decreased use of antimicrobial therapy for treatment of bacterial meningitis, and reduced need for ancillary diagnostic tests . Practice Guidelines for the Management of Bacterial Meningitis Allan R. Tunkel,1 Barry J. Hartman,2 Sheldon L. Kaplan,3 Bruce A. Kaufman,4 Karen L. Roos,5 W. Michael Scheld,6and Richard J. Whitley7

22. BACTERIAL MENINGITIS Managements

23. 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 (ABCD) • Integrity of host defenses

24. Management algorithm for adults with suspected bacterial meningitis.Practice Guidelines for the Management of Bacterial Meningitis

25. Overall 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

26. BACTERIAL MENINGITISAntimicrobial Rx • Therapy is generally 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)

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

28. 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

29. 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

30. 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]

31. 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]

32. 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 NEJ1997;336:708

33. 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 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.

34. 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

35. Acute bacterial meningitis Antibiotic prophylaxis • Is recommended for high-risk exposures to patients with Neisseria or Hib meningitis.(potentially share secretions). • Regimens include : • single-dose ciprofloxacin or ceftriaxone. • rifampin 600 mg every 12 hours for five doses. • There is no indication for prophylaxis for exposure to pneumococcal meningitis. • Quinolone resistance has been reported to Neisseria, and this class of antibiotics is no longer recommended for prophylaxis in parts of the United States. David Somand, MDa,WilliamMeurer, MD Department of Emergency Medicine, University of Michigan, Taubman Center B1354 SPC #5303, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5303, USA Department of Neurology, University of Michigan, Taubman Center 1914 SPC #5316, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-5316, USA

36. 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

37. Aseptic Meningitis

38. Aseptic Meningitis • All non-bacterial causes of meningitis • Typically less ill appearing than bacterial meningitis • Most common cause is viral • HSV • Consider especially in infants presenting with seizure • Usually HSV type II • Treat with acyclovir • Enterovirus (coxsackie, echovirus) • Typically occurs during late summer and fall • Spread via respiratory secretions and fecal-oral • Affects all ages • Generally self-limited illness

39. Aseptic Meningitis • Other Viral • HIV • Lymphocytic choriomeningitis virus • Arbovirus • Mumps • CMV • EBV • VZV • Adenovirus • Measles • Rubella • Rotavirus • Influenza and parainfluenza

40. Aseptic Meningitis • Other infectious • Borrelia burgdorferi • Mycobacterium tuberculosis • Treponema pallidum • Mycoplasma pneumoniae • Rickettsia, erlichia, brucella • Chlamydia

41. Aseptic Meningitis • Fungal • Cryptococcus • Coccidiodes • Histoplasmosis • Parasitic • Angiostrongylus • Toxoplasmosis

42. Aseptic Meningitis • Medication • NSAID’s • Bactrim • Pyridium • Malignancy • Lymphoma and leukemia • Metastatic carcinoma • Autoimmune • Sarcoid • Behcet’s • SLE

43. Viral Meningitis • Very common • clinical course is less fulminant compared to bacterial • Often caused by enteroviruses Polioviruses Coxsackieviruses Echoviruses • Treatment is supportive

44. VIRAL ENCEPHALITIS

45. Introduction • Encephalitis is an acute inflammatory process affecting the brain • Viral infection is the most common and important cause, with over 100 viruses implicated worldwide • Symptoms • Fever • Headache • Behavioral changes • Altered level of consciousness • Focal neurologic deficits • Seizures • Incidence of 3.5-7.4 per 100,000 persons per year

46. 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 ENCEPHALITIS

47. Patient History • Detailed history critical to determine the likely cause of encephalitis. • Prodromal illness, recent vaccination, development of few days → Acute Disseminated Encephalomyelitis (ADEM) . • Biphasic onset: systemic illness then CNS disease → Enterovirus encephalitis. • Abrupt onset, rapid progression over few days → HSE. • Recent travel and the geographical context: • Africa → Cerebral malaria • Asia → Japanese encephalitis • High risk regions of Europe and USA → Lyme disease • Recent animal bites → Tick borne encephalitis or Rabies. • Occupation • Forest worker, exposed to tick bites • Medical personnel, possible exposure to infectious diseases.

48. History cont. • Season • Japanese encephalitis is more common during the rainy season. • Arbovirus infections are more frequent during summer and fall. • Predisposing factors: • Immunosuppression caused by disease and/or drug treatment. • Organ transplant → Opportunistic infections • HIV → CNS infections • HSV-2 encephalitis and Cytomegalovirus infection (CMV) • Drug ingestion and/or abuse • Trauma

49. Initial Signs • Headache • Malaise • Anorexia • Nausea and Vomiting • Abdominal pain

50. Developing Signs • Altered LOC – mild lethargy to deep coma. • AMS – confused, delirious, disoriented. • Mental aberrations: • hallucinations • agitation • personality change • behavioral disorders • occasionally frank psychosis • Focal or general seizures in >50% severe cases. • Severe focused neurologic deficits.