1. CNS Infections ELS Wednesday, August 6th 2008 Amal Al-Hashmi

2. Outline Viral meningitis Viral meningitis Viral encephalitis Viral encephalitis Bacterial meningitis Bacterial meningitis EtiologyEtiology PathophysiologyPathophysiology Clinical PresenationClinical Presenation PathophysiologyPathophysiology Diagnostic toolsDiagnostic tools CT, MRI head, LP,EEG CT, MRI head, LP,EEG TreatmentTreatment

3. Viral meningitis Definition Definition an inflammatory response to viral infection of leptomeningeal cells and the subarachnoid space an inflammatory response to viral infection of leptomeningeal cells and the subarachnoid space account for the majority, at least 70%, of cases of aseptic meningitis account for the majority, at least 70%, of cases of aseptic meningitis

4. Etiology In Europe and US In Europe and US nonpolio enteroviruses are the most common case of viral meningitis ( Kupila et al 2006) for both children & adults nonpolio enteroviruses are the most common case of viral meningitis ( Kupila et al 2006) for both children & adults (coxsackie & enteric cytopathogenic human orphan virus [echovirus]), are the most common causal agents (coxsackie & enteric cytopathogenic human orphan virus [echovirus]), are the most common causal agents

5. Etiology followed by mumps mumps arboviruses arboviruses herpesviruses herpesviruses lymphocytic choriomeningitis lymphocytic choriomeningitis HIV at the time of seroconversion HIV at the time of seroconversion

6. Clinical presentation Children under 2 years of age show fever, irritability, or seizures, but may never develop signs of meningeal irritation Children under 2 years of age show fever, irritability, or seizures, but may never develop signs of meningeal irritation Adult pts present with fever, malaise, headache, nausea, vomiting, nuchal rigidity, & photophobia Adult pts present with fever, malaise, headache, nausea, vomiting, nuchal rigidity, & photophobia

7. CSF 1- slightly elevated opening pressure 1- slightly elevated opening pressure 2- mild to moderate pleocytosis with 10–500 white blood cells (WBC)/µl, predominantly lymphocytes 3- mildly elevated protein (<100 mg/dl), 4- normal glucose

8. CSF RT-CRP has now replaced viral cultures as diagnostic procedure of choice for establishing enteroviral infections ( Ramers et al 2000) RT-CRP has now replaced viral cultures as diagnostic procedure of choice for establishing enteroviral infections ( Ramers et al 2000) computed tomography or magnetic resonance imaging (MRI) scans in general are normal computed tomography or magnetic resonance imaging (MRI) scans in general are normal

9. Viral Encephalitis Etiology Etiology C/F C/F CSF findings CSF findings Neuroimaging Neuroimaging

10. Viral Encephalitis Most common cause are herpes simplex and arboviruses Most common cause are herpes simplex and arboviruses HSV-1 most common cause of fetal encephalitis in US HSV-1 most common cause of fetal encephalitis in US accounting for 10% overall& 90% in adult accounting for 10% overall& 90% in adult frequency 1/250,000 frequency 1/250,000 HSV-2 more commonly isolated in monophasic or recurrent meninigitis & congenitally acquired neonatal HSV meningoencephalitis HSV-2 more commonly isolated in monophasic or recurrent meninigitis & congenitally acquired neonatal HSV meningoencephalitis

11. Viral Encephalitis C/F C/F Fever 90% Fever 90% Headache 80% Headache 80% Altered mentation 70% Altered mentation 70% Personality changes 70-80% Personality changes 70-80% Seizures 40-67% Seizures 40-67% Memory disturbance 25-45% Memory disturbance 25-45% Motor deficit 30-40% Motor deficit 30-40% Aphaisa 33% Aphaisa 33% Olfactory hallucination Olfactory hallucination

12. Viral Encephalitis No set of signs or symptoms is pathognomonic of HSE No set of signs or symptoms is pathognomonic of HSE (Whitly 2006) (Whitly 2006)

13. CSF increased opening pressure increased opening pressure Normal glucose Normal glucose Moderalty elevated protien Moderalty elevated protien Lymphocytic pleocytosis 10- 1000/microlitter Lymphocytic pleocytosis 10- 1000/microlitter Xanthochromia and red cells may occur Xanthochromia and red cells may occur Cultures negative in 95% Cultures negative in 95%

14. CSF PCR of HSE is the diagnostic procedure of choice ( lakeman & whitely 1995) PCR of HSE is the diagnostic procedure of choice ( lakeman & whitely 1995) False negative ( Weil et al. 2002) False negative ( Weil et al. 2002)

15. Neuroimaging particularly MRI,may show temporal or orbitofrontal cortex enhancement or edema in HSE ( Raschilas et al 2002) particularly MRI,may show temporal or orbitofrontal cortex enhancement or edema in HSE ( Raschilas et al 2002) In most other acute viral encephalitis, neuroimaging findings are nonspecific In most other acute viral encephalitis, neuroimaging findings are nonspecific Brain MRI or CT serve to exclude brain abscess, subdural empyema, cranial extradural abscess, or septic venous thrombosis Brain MRI or CT serve to exclude brain abscess, subdural empyema, cranial extradural abscess, or septic venous thrombosis

16. EEG Diffuse slowing Diffuse slowing Focal abnormalities in the temporal region ( 75% with +ve PCR) Focal abnormalities in the temporal region ( 75% with +ve PCR) PLEDS PLEDS

17. Brain Biopsy Atypical cases Atypical cases Poor response to treatment Poor response to treatment Findings: Findings: hemorrahgic necrosis hemorrahgic necrosis HSV antigen in infected neurons HSV antigen in infected neurons acidophilic intranuclear inclusions acidophilic intranuclear inclusions

18. Treatment Empiric therapy with acyclovir should be started immediately Empiric therapy with acyclovir should be started immediately Stander Rx course is IV acyclovir Stander Rx course is IV acyclovir 10mg/kg Q8h in adults 10mg/kg Q8h in adults 20mg/kg Q8h in neonate and children 20mg/kg Q8h in neonate and children Duration 14-21 days Duration 14-21 days

19. Treatment Steroid ? Steroid ? Retrospective studies suggested no obvious harm and be some benefit ( Kamie et al 2006) ( Kamie et al 2006) Controlled clinical trails are needed

20. Prognosis Mortality rate in untreated cases is 70% which reduced to 19-27% with rx Mortality rate in untreated cases is 70% which reduced to 19-27% with rx Morbidity remains high only 37% of all pt PCR proven and treated with acyclovir survive with no or mild residual deficits (Raschilas et al2002) Morbidity remains high only 37% of all pt PCR proven and treated with acyclovir survive with no or mild residual deficits (Raschilas et al2002)

21. Prognosis Clinical relapse can occur and more often in children and neonate Clinical relapse can occur and more often in children and neonate Consider Foscarnet in cases of acyclovir resistant stains or in who are allergic Consider Foscarnet in cases of acyclovir resistant stains or in who are allergic

22. Bacterial meningitis Incidence of 3-5/100 000/year in US (quagliarello 1997) Incidence of 3-5/100 000/year in US (quagliarello 1997) More than 1500 death/yr in US More than 1500 death/yr in US

23. Etiology - General Pneumococcus (Streptococcus Pneumoniae) Pneumococcus (Streptococcus Pneumoniae) Most common in adults >20Most common in adults >20 Account for ½ of reported casesAccount for ½ of reported cases 2° to pneumonia/otitis, splenectomy/DM22° to pneumonia/otitis, splenectomy/DM2  ’ing incidence of pen-resistance in pneumococcus (25-45% to pen, 10% to Ceph,+ to chloramphenicol)  ’ing incidence of pen-resistance in pneumococcus (25-45% to pen, 10% to Ceph,+ to chloramphenicol)

24. Etiology - General HiB (Haemophilus Influenzae type B) HiB (Haemophilus Influenzae type B) Before vaccination, most common case in US 45% of meningitis caused by HibBefore vaccination, most common case in US 45% of meningitis caused by Hib Now accounts for less than 10%–Now accounts for less than 10%– still in elderly, HIV pts still in elderly, HIV pts

25. Etiology - General Meningococcus (Neisseria Meningitidis) Meningococcus (Neisseria Meningitidis) Mainly children and young adults (army/college)Mainly children and young adults (army/college) 2° to asymptomatic nasopharyngeal colonization2° to asymptomatic nasopharyngeal colonization

26. Etiology – Special Populations Neonate Neonate GBS, E. coli & other gram neg., Listeria (10%)GBS, E. coli & other gram neg., Listeria (10%) Post head trauma/Neurosurgery Post head trauma/Neurosurgery Staph Aureus & CNS, Enteric gram neg.Staph Aureus & CNS, Enteric gram neg. Elderly Elderly Listeria and Hib Listeria and Hib Listeria = Impaired cellular immunity Listeria = Impaired cellular immunity Pregnancy, Chronic disease, Elderly, AlcoholPregnancy, Chronic disease, Elderly, Alcohol

27. Clinical Presentation Triad of Headache, fever and neck stiffness: 85% of patients Triad of Headache, fever and neck stiffness: 85% of patients N/V, photophobia, myalgia ( common) N/V, photophobia, myalgia ( common) Alteration in LOC, Seizures (40%) Alteration in LOC, Seizures (40%) Nuchal rigidity: resistance to passive flexion Nuchal rigidity: resistance to passive flexion Kernig’s: extension of the knee with thigh flexed  pain, neck flexion Kernig’s: extension of the knee with thigh flexed  pain, neck flexion Brudzinsky’s Brudzinsky’s Flexion of neck causes hip flexionFlexion of neck causes hip flexion

28. Clinical Presentation Cranial nerve palsies 3 rd, 6 th, 7 th (10-20%) Cranial nerve palsies 3 rd, 6 th, 7 th (10-20%) Occasionally focal neurological deficit Occasionally focal neurological deficit hemiparesis, dysphasia hemiparesis, dysphasia

29. Clinical Presentation Classical c/f are commonly absent in neonates Classical c/f are commonly absent in neonates look for high pitched crying, refusal to feed, irritability look for high pitched crying, refusal to feed, irritability In elderly less act onset of lethrgy, mild or no fever In elderly less act onset of lethrgy, mild or no fever

30. Certain clinical features Promient rash particually extrimities (Meningococcus) Promient rash particually extrimities (Meningococcus) erythemaous, macular evolving into petechial erythemaous, macular evolving into petechial Rhinorrhea or otorrhea with S pneumoniae Rhinorrhea or otorrhea with S pneumoniae

31. Pathophysiology Bacteria spread by droplets and colonize nasopharynx Bacteria spread by droplets and colonize nasopharynx bacteremia then meningeal spread thru chroroid plexus epithelial cells bacteremia then meningeal spread thru chroroid plexus epithelial cells Multiply rapidly because of absence of immune cells Multiply rapidly because of absence of immune cells Lysis of bacterial cell wall in SAS Lysis of bacterial cell wall in SAS Stimulate microglia inflammatory cytokine production of IL-1 and TNF Stimulate microglia inflammatory cytokine production of IL-1 and TNF

32. Roos, seminars in neurology 2000

33. Pathophysiology Alteration of BBB w/ vasogenic edema + loss of autoregulation AND entry of PMN w/ cytotoxic edema SO formation of purulent exudate Alteration of BBB w/ vasogenic edema + loss of autoregulation AND entry of PMN w/ cytotoxic edema SO formation of purulent exudate  Hydrocephalus  narrows arteries in SAS and invades wall (vasculitis; leads to CVA)  Continous rise of ICP and coma

34. CSF ↑ pressure 20-50 mm H20 ↑ pressure 20-50 mm H20 ↑ WBC (100-10000 wbc/mm3, mainly PMN) ↑ WBC (100-10000 wbc/mm3, mainly PMN) ↓ glucose (less than 40% of serum glu) ↓ glucose (less than 40% of serum glu) ↑ Protein (1.0-5.0 mg/dl) ↑ Protein (1.0-5.0 mg/dl) Positive gram stain/culture in 70- 90% Positive gram stain/culture in 70- 90% Less if Abx before; sterile only after 12hLess if Abx before; sterile only after 12h Bx if skin lesions Bx if skin lesions

35. Diagnosis Blood Cultures (50%) Blood Cultures (50%) Abx before LP if CT/LP delay Tx (no change in WBC +/- in sterility for hours) Abx before LP if CT/LP delay Tx (no change in WBC +/- in sterility for hours) +/- Decadron +/- Decadron CT head (?) CT head (?) Lumbar Puncture Lumbar Puncture

36. CT Head before LP? CT will be abnormal, if you have :CT will be abnormal, if you have : Seizure Seizure clinical evidence of increased ICP clinical evidence of increased ICP Hx of CNS disease Hx of CNS disease Immuncompromised status Immuncompromised status Age>60 Age>60 Abnormal neurological exam (including mental status) Abnormal neurological exam (including mental status) Hasbun et al. CT head before LP in suspected meningitis. NEJM 345:1727, 2001 Kastenbauer et al. CT head before LP in suspected meningitis. NEJM 346:1248, 02

37. CT SCAN PRIOR TO LUMBAR PUNCTURE IN SUSPECTED MENINGITIS 235 patients with suspected meningitis underwent CT 235 patients with suspected meningitis underwent CT 56/235 (24%) had abnormal CT; 11 (5%) with mass effect 56/235 (24%) had abnormal CT; 11 (5%) with mass effect Hasbun et al. NEJM 2001;345:1727.

38. CT SCAN PRIOR TO LUMBAR PUNCTURE IN SUSPECTED MENINGITIS 96 patients without above features who underwent CT 96 patients without above features who underwent CT 93 had normal CT; 1 had mass effect93 had normal CT; 1 had mass effect All had lumbar puncture with no evidence of brain herniationAll had lumbar puncture with no evidence of brain herniation Hasbun et al. NEJM 2001;345:1727.

39. CT before LP Kastenbauer: Nothing predicts herniation (Abnormal CT in 2/10 herniations and 27/65 w/ no herniation)Kastenbauer: Nothing predicts herniation (Abnormal CT in 2/10 herniations and 27/65 w/ no herniation) of Kastenbauer et al. N Engl J Med 2002;346(16):1248-1251. (189K)

40. Age of patientLikely organismAntimicrobial therapy* 0-12 weeks Group B Strep E. Coli L. Monocytogenes 3rd generation cephalosporin + ampicillin (+ dexamethasone first 2 days in >4-8-week-old infant) 3 months-50 years S. Pneumoniae N. Meningitidis H. Influenzae 3rd generation ceph + vancomycin (± ampicillin ) >50 years S. Pneumoniae L. Monocytogenes Gram-neg. bacilli 3rd generation ceph + vancomycin + ampicillin Base of skull fracture Staphylococci Gram-neg. bacilli S. pneumoniae 3rd generation cephalosporin + vancomycin Immunocompromi sed state L. Monocytogenes Gram-neg. bacilli S. Pneumoniae H. Influenzae Vancomycin + ampicillin + ceftazidime Treatment

41. Treatment Based on age Based on age Always bactericidal Always bactericidal Consider intrathecal Vanco Consider intrathecal Vanco Alternatives: Alternatives: Cefepime or meropenem instead of 3rd generation CephCefepime or meropenem instead of 3rd generation Ceph If severe Pen allergy: Vanco + chloramphenicol or Vanco + septra (listeria)If severe Pen allergy: Vanco + chloramphenicol or Vanco + septra (listeria) 3rd generation Cephalosporin 3rd generation Cephalosporin Ceftriaxone 2g q12h – jaundice in neonatesCeftriaxone 2g q12h – jaundice in neonates Cefotaxime 2g q4hCefotaxime 2g q4h Ceftazidime 2g q 8hCeftazidime 2g q 8h

42. Tx of contacts Contact Public Health for meningococcus and HiB Contact Public Health for meningococcus and HiB Need to treat close contacts (potentially share secretions) Need to treat close contacts (potentially share secretions) Rifampin bid for two days CRifampin bid for two days C Or Cipro 500mg onceOr Cipro 500mg once Or zithromax 500mg onceOr zithromax 500mg once

43. Prevention Pneumovax for surgical or functional asplenia (sickle cell, chronic illness, immunosuppression, older age…) Pneumovax for surgical or functional asplenia (sickle cell, chronic illness, immunosuppression, older age…)

44. Steroids Morbidity and mortality of meningitis related of inflammatory reaction rather than bacteria themselves Morbidity and mortality of meningitis related of inflammatory reaction rather than bacteria themselves Decadron inhibits IL-1 and TNF m- RNA production and  CSF outflow resistance and stabilizing BBB Decadron inhibits IL-1 and TNF m- RNA production and  CSF outflow resistance and stabilizing BBB Lots of small studies 1950’s-2002; big studies are rare, especially in adults. Lots of small studies 1950’s-2002; big studies are rare, especially in adults.

45. Steroid The available evidence on adjunctive dexamethasone therapy confirms a benefit for treating H influenza type b in reducing audiological sequelae and suggest benefit in reducing the audiological and neurological sequelae in H influenza type b and pneumococcal in children The available evidence on adjunctive dexamethasone therapy confirms a benefit for treating H influenza type b in reducing audiological sequelae and suggest benefit in reducing the audiological and neurological sequelae in H influenza type b and pneumococcal in children (sebire et al 2006) …….( weisfelt et al 2006) (sebire et al 2006) …….( weisfelt et al 2006)

46. Cochrane Review 2003 18 RCT 18 RCT Mainly kids Mainly kids General General Lower mortality RR 0.76 [.59-.98]Lower mortality RR 0.76 [.59-.98] Hearing loss 0.36 [.22-.60]Hearing loss 0.36 [.22-.60] Neuro Sequelae 0.66 [.44-.99]Neuro Sequelae 0.66 [.44-.99] In Children In Children Lower hearing loss in non Hib meningitis 0.42 [.2 -.89]Lower hearing loss in non Hib meningitis 0.42 [.2 -.89] In adults In adults Lower mortality 0.48 [0.24-0.96]Lower mortality 0.48 [0.24-0.96]

47. Systematic Review in adults 5 RCT in adults 5 RCT in adults Overall mortality and neuro sequelae 0.6Overall mortality and neuro sequelae 0.6 Pneumococcus mortality 0.5Pneumococcus mortality 0.5 Meningococcal sequelae 0.5 and mortality 0.9Meningococcal sequelae 0.5 and mortality 0.9 No increased side effects with steroids No increased side effects with steroids

48. Vanco level controversy Experimental evidence of decreased absorption if steroids given Experimental evidence of decreased absorption if steroids given One RCT study in children demonstarted reliable penetration of vanco if 60mg/kg doses used. One RCT study in children demonstarted reliable penetration of vanco if 60mg/kg doses used. 4/11 pts in adults failed vanco with steroids but used lower dosages 4/11 pts in adults failed vanco with steroids but used lower dosages

49. Steroids Do not use if immunosuppressed

50. Thank You! Questions?