1. CNS Infections Margrit Carlson, M.D. November 2003

2. How are infections in the CNS different? l Separated by the blood brain barrier l Immunologically distinct l Unique anatomic considerations dictate the spread of infection within the CNS l Closed space l Limited capacity for regeneration or compensation for injury

3. Blood Brain Barrier l Between blood and brain formed by the tight junctions of the cerebral capillary endothelium l Between blood and CSF formed by the tight junctions of the choroid plexus epithelium

4. Immune Response in the CNS l Access of immune effector cells to CNS is limited by the BBB l T lymphocytes can enter and exit the CNS in small numbers l Low expression of MHC molecules limits antigen presentation

5. Entry into the CNS Bypassing the blood brain barrier l direct extension from a local focus, sinuses middle ear or mastoid dental source l foreign body l trauma

6. Entry through the BBB l direct penetration of the choroid plexus epithelium into the CSF (meningitis) l direct penetration of the capillary endothelium into the brain parenchyma (encephalitis) l disruption of the tight junctions l transportation across the barrier inside leukocytes

7. Types of infections l Meningitis- subarachnoid l Encephalitis-brain parenchyma l Abscess subdural brain epidural

9. Cerebrospinal Fluid in Meningitis PressureGlucoseProteinWBC Normal 180mm2/3 of serumup to500-5 Bacterial I<4050-150050-5000P ViralNNN <100L ChronicI10-4545-50025-1000L I=Increased N =Normal P=polymorphonuclear leukocytes L=Lymphocyte

10. CSF Parameters PressureGlucoseProteinWBC Normal 180mm2/3 of serum500-5 Abscess IN30-20010-500L Encephalitis NN20-12520-200L I=Increased N =Normal P=polymorphonuclear leukocytes L=Lymphocyte

11. Acute Meningitis l 19 yo student is seen for sore throat x2 days. His symptoms worsen and he develops a terrible headache and photophobia. He is brought to the ER the next morning by his roommate. In the ER he is hypotensive, confused, complaining of headache and photophobia. He has a seizure.

13. l He is given antibiotics and taken for a CT scan which is unremarkable. l CSFRBC 10 WBC 1230 93% PMNs glucose 33 protein 276

17. Acute meningitis Meningeal signs and symptoms worsen over a few days l symptoms: headache, fever, neck stiffness, photophobia and vomiting. l signs: nuchal rigidity, altered level of consciousness, seizures and cranial nerve palsies(sensorineural hearing loss)

18. Bacterial Meningitis l 0-4 weeksStreptococcus agalactiae, E. coli, Listeria monocytogenes l 4-12 weeks H. influenzae, E. coli, L. monocytogenes, S.agalactiae, l 3mo-18 years H. influenzae, N. meningiditis, S. pneumoniae l 18-50 years S. pneumoniae, N. meningiditis

19. l 36 YO G3P2, 33 week IUP brought in by her sister for chest pain and confusion increasing over the last 3 days. l PE: temp was 38.5, she had photophobia but no nuccal rigidity. A vesicular rash was seen on her L chest

21. l CSF: 320 RBC, 460 WBC, 50% lymphs and 34% monos l protein 623, glucose 91 l Her MRI had diffuse meningeal enhancement

22. Meningitis in the Immunocompromised Host Bacterial Syphilis, Listeria, Nocardia ViralVZV, HSV Fungal cryptococcus, coccidioidomycosis, histoplasmosis Mycobacterial tuberculosis

23. 44 yo construction worker had upper respiratory symptoms 1 month ago. He has had worsening fevers, a constant headache and photophobia for a month. His thinking has been slowed and he had an episode of aphasia lasting 1 day.

24. l CSF: glucose 27 protein203 RBC<1 WBC203 l 45%lymphs/40% mono/5% eos l MRI: enhancement of the basal cisterns, along the midbrain, pons, right optic tract, and the right caudate head.

25. Chronic meningitis l Gradual onset and progression l Focal symptoms l Increased intracranial pressure l History of exposure l Immunocompromised ?

26. Symptoms of Increased Intracranial Pressure l headache l nausea, vomiting l altered mental status l ataxia l incontinence l papilledema l 3rd or 6th nerve palsy

27. Infectious causes of chronic meningitis l Coccidioidomycosis, Cryptococcus, Histoplasmosis, Sporotrichosis l Tuberculosis l Syphilis, Lyme Disease l HIV, Enterovirus

28. Non-infectious causes of Chronic Meningitis l Behcet’s disease l Systemic lupus erythematosis l Sarcoidosis l Carcinomatous or lymphomatous meningitis l Granulomatous angiitis

29. Complications of Chronic Meningitis l hydrocephalus l vasculitis, cerebrovascular occlusion l cranial nerve palsies

30. 32 yo Hispanic man has new onset confusion developing over 24 hours, aphasia, hallucinations and seizures following a bone marrow transplant for CML. He has no known ill contacts. He has had mucositis

31. Putting it all together l Sudden or gradual onset? l Meningeal symptoms, encephalopathy? l Focal findings? l Fever ? l Predisposing conditions and exposures l Imaging l LP results

32. F CSF: glucose 67 protein 158 RBC 179 WBC 124 25% P /74% L F His MRI shows diffuse periventricular white matter disease and enhancement in the temporal lobes.

34. Acute Encephalitis l Fever l Headache l Altered level of consciousness: lethargy, confusion, stupor, coma l Seizures l Hypothalamic or pituitary dysfunction

35. Causes of Acute Encephalitis l Herpes simplex, Varicella zoster l California, St Louis, Japanese, Western and Eastern equine encephalitis viruses l Enteroviruses (coxsackie, echo and enteroviruses) l Post measles, post influenza encephalomyelitis

36. HSV Pathogenesis l Retrograde transport of virus from mucous membranes to the sensory ganglia and rarely to the CNS l Anterograde transport from the sensory ganglia to the periphery during cutaneous exacerbations

37. 33 yo with AIDS,CD4 cells 5, brought in by his partner who has noticed he has become more forgetful and withdrawn over the last 3-6 months. He’s had no fevers or headache. No recent infections. He has been off antiretrovirals because of side effects.

38. l MRI showed diffuse atrophy l CSF glucose88 protein78 RBC<1 WBC12 74% lymphs 26% monos

39. Chronic Encephalitis l Predominantly viral l Non-viral: Neurosyphilis, Lyme disease, l Neurotropic viruses: Retroviruses: HTLV I and II, HIV Herpes viruses: HSV, VZV and CMV

40. Chronic Encephalitis Other: JC virus: Progressive multifocal leukoencephalopathy Subacute Sclerosing panencephalitis (Measles) Rubella Creutzfeldt-Jakob

41. HIV Encephalopathy AIDS Dementia Complex 7-27% of persons with CD4<200 have some impairment including: l decreased attention and concentration l psychomotor slowing l personality change, loss of initiative, drive, animation l hyperreflexia, ataxia, frontal release signs

42. Pathogenesis of ADC l HIV is present in the CSF and brain in primary infection. l HIV infects cells of monocyte lineage (macrophages, microglia, multinucleated giant cells). l Viral burden (HIV qPCR) in CSF or brain correlates with neurologic disease.

43. Pathogenesis of ADC l Release of neurotoxins from macrophages (nitric oxide, arachidonic acid, quinolinic acid). l Cytokine mediated release of neurotoxins. l Direct toxicity of viral proteins, i.e. gp120.

44. 73 yo man with a fever who is brought in by his wife because he is confused and unable to move his right side. He was complaining of a headache for a few days. He started vomiting this morning and was bumping into the wall on his way to the bathroom.

46. Brain Abscess l hematogenous spread through the blood brain barrier l direct extension via the the emissary veins into the cerebral venous circulation

47. Development of an abscess l Local area of cerebritis, inflammation and edema (1-3 days) l Expansion and development of a necrotic center (4-9 days) l Formation of a ring enhancing capsule by gliosis and fibrosis (14 days)

48. Clinical Presentation l Headache with gradual worsening l Fever <50% l Focal neurologic signs l Seizures l CSF: elevated protein, normal glucose and mild leukocytosis l Increased ICP: Nausea,vomiting, lethargy

49. Brain Abscess l Location l Source l Organism l Treatment

50. Brain Abscess Paranasal SinusesFrontal lobe Otogenic InfectionTemporal lobe, cerebellum Hematogenous spreadMultiple lesions MCA distribution Post traumaticSite of wound Post operativeSite of surgery

51. Pathogens Sinuses Streptococci, Haemophilus, Bacteroides, Fusobacterium Otogenic as above, and Pseudomonas Endocarditis Staphylococcus, Viridans streptococci Lung abscess Streptococci, anaerobes, Actinomyces TraumaStaph aureus

52. l A 28 YO father of 3 develops worsening sinus headaches and is seen repeatedly at an outside ER. He has low grade fevers. His headache becomes excruciating and he subsequently becomes unresponsive during his evaluation.

54. Brain Abscess in the Immunocompromised l AIDS Toxoplasmosis, Tuberculoma, Cryptococcoma, Coccidiodomycosis, Blastomycosis l Transplant Aspergillus, Nocardia, Candida, Zygomycetes in addition to the above

55. l 35 YO man with 2 weeks of worsening headache, low grade fever and rash. He also has had myalgias and L knee pain and swelling. l He has no recent travel or outdoor activities, not sexually active x 6 months

56. l CT Scan is unremarkable l CSF: 2 RBC, 25 WBC;20%segs, 60% lymphs, 20% monocytes, glucose 64, protein 45.

58. Fever, Headache,Rash and mild CSF pleocytosis l Enterovirus l Primary HIV l Epstein Barr l Secondary syphilis l Mycoplasma l Drug Reaction

59. Neurosyphilis l Primary, chancre 10-90 days l Secondary,rash 4-10 weeks later (up to 6 months after initial infection l Meningeal within 1st year after infection l Meningovascular 4-7 years later l Parenchymal disease decades later

60. Syphilis l 50-75% of exposed partners were infected. l 30-70% of those with secondary syphilis have CSF mononuclear pleocytosis, elevated protein or + RPR in CSF l 25% untreated patients have recurrances l 1/3 of untreated patients develop late sequelae