This document provides an overview of central nervous system (CNS) infections, including: 1. CNS infections can be classified by the organ involved (e.g. meningitis, encephalitis) or by pathogen (e.g. bacteria, viruses, fungi). 2. Common causes of acute bacterial meningitis include Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. Viral meningitis is usually caused by enteroviruses. 3. Chronic CNS infections include tuberculosis (TB), neurosyphilis, fungal infections (e.g. cryptococcosis), and prion diseases (e.g. Cre

1. CNS Infections Dr Kamran Afzal Asst Prof Microbiology

2. Classification Classification by organ involvement Meningitis Encephalitis Myelitis Classification by pathogen Bacteria Viruses TB bacilli Fungi Spirochetes Parasites

3. Definitions Meningitis Inflammation of the leptomeninges Usually caused by bacteria Encephalitis Inflammation of the brain itself Usually caused by viruses Myelitis Inflammation of the spinal cord Meningoencephalitis Meningomyelitis Encephalomyelitis Meningo-encephalomyelitis Brain abscess

4. Meningitis

5. Meninges

6. Meningitis Classification - I Acute Pyogenic usually bacterial meningitis Aseptic usually viral meningitis Chronic Usually TB, spirochetes, cryptococcus

7. Meningitis Classification - II Purulent meningitis - polymorphonuclear cell - WBC >1000 cells/mm 3 - pyogenic bacteria Lymphocytic meningitis Viral Chronic Eosinophilic meningitis - eosinophils > 5% - parasitic

8. Routes of Spread Hematogenous spread Parameningeal structures sinusitis, mastoiditis, otitis media, dental caries Direct infection to the subarachnoid space fracture base of skull, ruptured meningocele Direct infection surgery, lumbar puncture

9. Etiology of Acute Bacterial Meningitis Escherichia coli Group B streptococci Neonates Listeria monocytogenes

10. Hemophilus influenzae Neisseria meningitidis Streptococcus pneumoniae >1 months to 5 years

11. Mycobacterium tuberculosis >5 years and Adults Streptococcus pneumoniae Neisseria meningitidis Haemophilus influenzae

12. Immunocompromised Patients Enterobacteriaceae Hemophilus influenzae Pseudomonas aeruginosa

13. Post surgical procedures OR Post cranial/spinal trauma Enterobacteriaceae Pseudomonas aeruginosa Staphylococcus aureus Streptococcus pneumoniae Persistant CSF leak Streptococcus pneumoniae

14. Ventriculo - Peritoneal shunt Staphylococcus epidermidis Enterobacteriaceae Diphtheroids

15. Viral Meningitis (Aseptic meningitis) Etiological Agents Enteroviruses (Coxsackie and Echovirus) Adenovirus Arbovirus Measles virus Herpes Simplex virus Varicella Zoster virus

16. Chronic Meningitis Mycobacterium tuberculosis Treponema pallidum Cryptococcus neoformans Toxoplasma gondii

18. Seed and traverse blood brain barrier Organism multiplication, liberation of endotoxin and teichoic acid Release of TNF-α, IL-1 Activation and release of prostaglandins, leukotreines, PAF and other cytokines

19. Symptoms

20. Symptoms

21. Signs Kernig’s sign Flexion of hip, extension of knee hamstrings contract Brudzinski’s sign Passive neck flexion hips and knees flex Skin Purpura Petechial hemorrhages

22. Signs of meningococcaemia with or without meningitis prominent rash on extremities Waterhouse-Friedrichsen syndrome

23. Laboratory Diagnosis Acute Bacterial Meningitis CSF Routine Examination CSF Culture CSF Immunological Tests Polymerase Chain Reaction Blood Culture

24. Collection and Transportation of CSF Must be collected by an experienced medical officer L-3, L-4 space (L-4, L-5 in new-born) Strict aseptic measures Ideally two screw capped sterile tubes, each containing 1 ml of CSF CSF for C/S should not be refrigerated Must be transported to the lab without delay

25. CSF Routine Examination Appearance in acute meningitis Cloudy, viscid or purulent Elevated pressure

26. CSF Routine Examination Cell Count >1000/Cmm Neutrophils predominantly Glucose <2.2mmol/L Proteins >200 mg/Dl CSF : PLASMA GLUCOSE RATIO <40%

27. CSF Routine Examination GRAM NEGATIVE COCCI GRAM POSITIVE COCCI GRAM NEGATIVE RODS GRAM POSITIVE RODS GRAM STAIN

28. CSF Evaluation Normal Bacterial Viral TB Cells 0-5 >1000 <1000 <500 Polymorphs 0 Predominate Early +/- increased Lymphocytes 5 Low Predominate Increased Glucose 60-80 Decreased ++ Normal Decreased+ CSF : plasma Glucose ratio 66% <40% Normal < 30% Protein 5-40 Increased+++ +/- Increased Increased+ Culture Negative Positive Negative Positive (MTB)

29. CSF Culture Specimens Blood and CSF for smear and culture Nasophyrangeal swab for carrier state Culture media Blood agar Chocolate agar Selective medium (Modified Thayer-Martin medium) To avoid contamination, add vancomycin amphotericin B and colistin

30. Antibiotic Sensitivity Testing Ampicillin/Penicillin Ceftriaxone Chloramphenicol Rifampicin Meropenem

31. CSF Antigen Screening Bacterial antigen screening detect S. pneumoniae N. meningitidis Klebsiella pneumoniae S. agalactiae Hib Crypto antigen screening detects C. neoformans + in 90-95% of pts with crypto meningitis

32. Treatment Empiric Antibiotics Ceftriaxone Add Vancomycin (till possibility of Penicillin-resistant Strep pneumoniae has been ruled out) Add Ampicillin (for Listeria infections) For patients with serious Penicillin allergies, Meropenem Ceftazidime + Vancomycin for neurosurgical patients Add Acyclovir in case of viral infection Add Amphotericin B in case of fungal infections Definitive Therapy As per C/S report

33. Chemoprophylaxis Household/school/daycare contacts last 7 days Direct exposure to secretions Kissing, sharing utensils/toothbrushes, mouth to mouth, intubation without a mask First line: Rifampicin x 4 doses Alternative: Ceftriaxone, ciprofloxacin

34. Encephalitis

35. Viral Encephalitis Parenchymal infection sometimes spinal cord involvement (encephalomyelitis) Most characteristic features perivascular and parenchymal mononuclear cell infiltration Slowly progressive degenerative disease may occur many years after viral illness Post-encephalitic parkinsonism

36. HSV Encephalitis In adult most caused by HSV-1 Primary infection in oropharyngeal or intranasal mucosa Latent ganglionic infection Reactivation leads to encephalitis Headache, fever, alteration of conciousness VZV Encephalitis Develops after varicella, VZV remain within the ganglia Reactivation, spread to spinal cord and brain

37. Japanese Encephalitis Flavivirus, Culex- borne, Southeast Asia /China Symptoms: headache and alteration of consciousness Rabies Encephalitis Rhabdovirus family, transmission through dog bites CMV Encephalitis Opportunistic infection in organ transplant, HIV

38. Diagnosis of Viral Encephalitis CSF studies CSF usually colorless - slightly  pressure - initially may be a neutrophilic pleocytosis, which rapidly converts to lymphocytes - proteins are slightly  - glucose is normal Virus isolation from CSF by PCR

39. Treatment Acyclovir for HSV and VZV given IV reduces mortality in 55% Gancyclovir for CMV

40. Chronic CNS infections

41. Tuberculous Meningitis Low grade fever Headaches Malaise and confusion Vomiting CSF: moderate pleocytosis - PMN initially then lymphocytes proteins  glucose slightly  or normal

42. Lab Diagnosis CSF routine examination – AFB on ZN smear CSF Culture for M. tuberculosis PCR for M. tuberculosis Serological tests for tuberculosis

43. Treatment 3 IRZS + 6IRZ Dexamethasone IV

44. Neurosyphilis Tertiary stage of syphilis ~ 10% of untreated patients Major forms of meningovascular neurosyphilis Paretic neurosyphilis caused by invasion of the brain by T. pallidum Tabes dorsalis is a result of damage to the sensory nerves in dorsal roots, causing locomotor ataxia and loss of pain sensation

45. Lab Diagnosis VDRL/RPR positive CSF reactive FTA-ABS or TPHA Treatment Penicillin G IV 4 mU q 4 h 14d Then benzathine penicillin G 2.4 mU IM x3

46. Fungus Candidia albicans Cryptococcus neoformans Aspergillus fumigatus Coccidiodes imitis Lab Diagnosis Gram stain, Indian ink preparation Candida, Cryptococcal Ag

47. Treatment Disease Dose Duration HIV neg. Amphotericin 0.7MKD +flucytosine 100MKD +fluconazole 400mg/d 2 wk 10 wk Amphotericin 0.7MKD +flucytosine 100MKD 10 wk HIV pos. induction Amphotericin 0.7MKD +flucytosine 100MKD +fluconazole 400mg/d 2 wk 10 wk maintanance Fluconazole 400 mg/d

48. Protozoa Protozoan Disease Toxoplasma gondii Associated with congenital defects and AIDS African Trypanosomes African Sleeping Sickness Plasmodium falciparum Cerebral Malaria Entamoeba histolytica Rare invasion of the brain Acanthamoeba Rare cases

49. Helminths

50. Prions “ Small proteinaceous infectious particles without nucleic acids which resist inactivation by procedures that modify nucleic acids&quot; Prion diseases are often called spongiform encephalopathies because of the post mortem appearance of the brain with large vacuoles in the cortex and cerebellum

52. Examples of Prion Diseases That Affects the Brain Kuru CJD: Creutzfeld-Jacob Disease Variant Creutzfield-Jacob Disease (Mad Cow Disease) FFI: Fatal familial Insomnia 􀂄

53. Aetiology Acquired infection diet and following medical procedures such as surgery, growth hormone injections, corneal transplants Apparent hereditary transmission autosomal dominant trait this is not consistent with an infectious agent

54. Lab Diagnosis Western blotting Brain biopsy - characteristic spongy change EEG studies MRI Treatment Amphotericin