There are 4 main routes through which infectious agents can enter the central nervous system: 1) hematogenous spread, 2) direct implantation, 3) local extension from adjacent infections, and 4) spread from the peripheral nervous system. Meningitis refers to inflammation of the meninges and cerebrospinal fluid, while meningoencephalitis refers to inflammation of both the meninges and brain parenchyma. Meningitis is often classified based on the type of inflammatory exudate in the cerebrospinal fluid, such as acute pyogenic (bacterial), aseptic (viral), chronic, etc. The most common causes of acute pyogenic meningitis vary with patient age.

1. 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 o ften is traumatic ii) iatrogenic (rare) via lumbar puncture iii) congenital (meningomyelocele) c) local extension (secondary to established infections) www.freelivedoctor.com

2. i ) most often from mastoid and frontal sinuses, infected tooth, etc. d) PNS into CNS i) viruses - rabies - herpes zoster ACUTE MENINGITIS Meningitis refers to an inflammatory process of leptomeninges and CSF Meningoencephalitis refers to inflammation to meninges and brain parenchyma www.freelivedoctor.com

3. Meningitis often associated with infection a) may be chemical i) agent introduced into subarachnoid space Meningitis classified: a) acute pyogenic i) usually bacterial meningitis b) aseptic i) usually acute viral meningitis c) chronic i) usually TB, spirochetes, cryptococcus d) these types are based on the inflammatory exudate of CSF www.freelivedoctor.com

4. Acute Pyogenic (Bacterial) Meningitis Microorganism vary with age of the patient a) neonates i) E. coli ii) Strep. pneumonia iii) Listeria monocytogenes b) adolescents and young adults i) Neisseria meningitidis (most common) ii) Haemophilus influenza - immunizations have markedly reduced this pathogen - most common among infants now is S. pneumoniae www.freelivedoctor.com

5. Clinical S & S a) systemic signs of infection superimposed on clinical evidence of meningeal irritation and neurologic impairment i) headache ii) photophobia iii) irritability iv) neck stiffness v) nausea, vomitting b) spinal tab yields i) cloudy or frankly purulent CSF ii) increased pressure iii)  neutrophils www.freelivedoctor.com

6. iv)  CSF protein concentration v) markedly  glucose concentration c) untreated can be fatal d) Waterhouse-Friderichsen syndrome i) results from meningitis-associated septicemia - hemorrhagic infarction of the adrenal glands - cutaneous petechiae - common with menigococcal and pneumococcal meningitis In immunosuppressed patients, other pathogens may be involved a) Klebsiella www.freelivedoctor.com

7. 2. Acute Aseptic (Viral Meningitis) Actually a misnomer a) refers to absence of any recognizable organism b) generally viral c) clinical course is less fulminant compared to bacterial Clinical S & S: a) CSF glucose near normal b) protein only moderately elevated c) lymphocytic pleocytosis d) usually self limiting e) most common is the enterovirus i) polio, echovirus, coxsackievirus www.freelivedoctor.com

8. f) no distinctive macroscopic characteristics, except i) brain swelling ii) mild, if any, infiltration of the leptomeninges with lymphocytes Some class of drugs have been implicated with a true noninfectious meningitis (“drug- induced aseptic meningitis” ) a) NSAID b) antibiotics c) CSF is sterile d) glucose normal (CSF) e) pleocytosis with neutrophils f)  CSF protein www.freelivedoctor.com

9. ACUTE FOCAL SUPPURATIVE INFECTIONS Brain abscess a) may arise from a variety of routes (see slides # 1 and 2 for details) i) often from primary infected site in the heart (acute bacterial endocarditis), lungs, tooth decay, bones b) Strep and Staph are the most common bacteria c) cerebral abscesses are destructive lesions www.freelivedoctor.com

10. i) central liquefactive necrosis surrounded by fibrous cap - edema in surrounding area ii) common sites (in descending order) - frontal lobe - parietal lobe - cerebellum iii) present with progressive focal deficits - signs of  ICP www.freelivedoctor.com

11. - CSF under  pressure - WBC and protein  - glucose normal iv) rupture of abscess can cause ventriculitis, meningitis and venous sinus thrombosis v) surgery and antibiotics have decreased lethality to less that 10 % Subdural Empyema a) bacteria and fungus can spread to subdural space  subdural empyema b) arachnoid and subarachnoid spaces usually unaffected www.freelivedoctor.com

12. c) thrombophlebitis may develop in bridging veins  venous occlusion and infarct d) clinical: i) febrile ii) headache iii) neck stiffness iv) untreated may develop lethargy and coma v) CSF profile similar to abscess Extradural Abscess a) commonly associated with osteomyelitis b) usually arise from adjacent site of infection www.freelivedoctor.com

13. i) sinusitis or a surgical procedure ii) when occurring in spinal epidural space  spinal compression - neurosurgical emergency CHRONIC BACTERIAL MENINGOENCEPHALITIS TB a) headaches b) malaise and confusion c) vomiting www.freelivedoctor.com

14. d) CSF: i) moderate pleocytosis - PMN and MN ii) proteins markedly  iii) glucose slightly  or normal e) Subarachnoid space  fibrous exudate i) most often at base of brain ii) often obliterating the cisterns iii) encasing cranial nerves f) development of a single intraparenchymal mass  tuberculoma i) may cause significant mass effect www.freelivedoctor.com

15. g) clinical: i) most serious is arachnoid fibrosis and - hydrocepahlus ii) obliterative endarteritis - arterial occlusion and infarction iii) spinal cord roots may be involved Neurosyphilis a) tertiary stage i) ~ 10% of untreated patients b) major forms of meningovascular neurosyphilis are i) paretic, and tabes dorsalis www.freelivedoctor.com

16. - meningovascular neurosyphilis is chronic meningitis involving base of the brain, spinal leptomeninges and cerebral convexities. Obliterative endarteritis (Heubner arteritis) - paretic neurosyphilis caused by invasion of the brain by T. pallidum. Progressive loss of mental and physical functions with mood alterations - Tabes dorsalis is a result of damage by the spirochete to the sensory nerves in dorsal roots, causing locomotor ataxia and sense of position, loss of pain sensation, www.freelivedoctor.com

17. Neuroborreliosis (Lyme disease) a) Borrelia burgdorferi b) S & S vary i) aseptic meningitis ii) facial nerve palsies iii) mild encephalopathy iv) polyneuropathies VIRAL MENINGOENCEPHALITIS Viral encephalitis a) parenchymal infection i) meningeal inflammation (i.e., meningoencephalitis) www.freelivedoctor.com

18. ii) and sometimes spinal cord involvement (encephalomyelitis) b) most characteristic features i) perivascular and ii) parenchymal mononuclear cell infiltration c) intrauterine viral infections may cause congenital malformations i) rubella d) slowly progressive degenerative disease may occur many years after viral illness i) postencephalitic parkinsonism - post WW 1 www.freelivedoctor.com

19. Arthropod-borne viral encephalitis a) arboviruses i) important cause of epidemic encephalitis - especially in tropical regions b) most important types in Western world are i) western and eastern equine ii) Venezuelan iii) St. Louis iv) La Crosse v) recently in USA, west nile virus www.freelivedoctor.com

20. c) Clinical: i) generalized neurologic deficits - seizures - confusion - delirium - stupor and coma ii) CSF usually colorless - slightly  pressure - initially a neutrophilic pleocytosis, which rapidly - converts to lymphocytes - proteins are  - glucose is normal www.freelivedoctor.com

21. HSV type 1 (HSV-1) a) occur at any age i) most common in children and young adults b) most common S & S are mood and memory change c) most often begins in the temporal lobes d) and orbital gyri of frontal lobes HSV type 2 (HSV-2) a) in adults as meningitis b) ~ 50% of neonates develop severe encephalitis to mothers having active primary genital HSV infections www.freelivedoctor.com

22. Varicella-Zoster virus (Herpes Zoster) a) childhood chickenpox b) reactivation in adults (i.e., “shingles”) i) painful vascular skin eruptions ii) usually is self limited, however iii) may be a persistent postherpetic neuralgia syndrome - ~ 10% of patients c) overt CNS manifestations are rare i) however, when present do produce more severe signs - granulomatous arteritis www.freelivedoctor.com

23. Cytomegalovirus a) occurs in fetuses and immunosupprressed i) outcome in utero is periventricular necrosis - severe brain destruction with later microcephaly and periventricular calcification b) most common opportunistic viral pathogen in patients with AIDS i) affects 15-20% of patients c) localize in paraventricular subependymal regions of the brain i) severe hemorrhagic necrotizing www.freelivedoctor.com

24. Poliomyelitis a) picorra group of enteroviruses b) Clinical: i) CNS infections manifest with - meningeal irritation - CSF similar to aseptic meningitis ii) with spinal cord involvement, produces flaccid paralysis - muscle wasting - hyporeflexia in corresponding portion of the body - acute affects can cause death by respiratory muscle paralysis www.freelivedoctor.com

25. - myocarditis as complicating factor iii) late neurologic syndrome: - “postpolio syndrome” develops 25-30 years after initial resolution  progressive weakness, decreased muscle mass and pain  pathogenesis is unclear Rabies a) severe encephalitis b) transmitted to humans via rabid animals www.freelivedoctor.com

26. c) Clinical: i) virus enters the CNS in ascending fashion - along PNS around wound site - incubation 1-3 months - as infection advances, patients exhibit extraordinary excitability where slightest touch is painful. Violent motor responses  seizures ii) contraction of pharyngeal muscles on swallowing  foaming at the mouth  aversion to swallowing, even water (hydrophobia) www.freelivedoctor.com

27. iii) Death from respiratory center failure HIV/AIDS a) ~ 60% of AIDS patients develop neurologic dysfunction (see chapt. 6 for details) b) HIV aseptic meningitis occurs within 1- 2 weeks of seroconversion in ~ 10% of patients HIV meningoencephalitis (subacute encephalitis) a) remarkable neurologic disorder i) present with dementia (AIDS dementia complex- - - ADC) www.freelivedoctor.com

28. - mental slowing - memory loss - mood disturbances - motor abnormalities (ataxia) - bladder/bowel incontinence - seizures b) chronic inflammatory reaction i) microglial infiltrates (microglial nodules) - multinucleated giant cell Vacuolar Myelopathy a) spinal cord disorder i) 20-30 % of AIDS patients in USA www.freelivedoctor.com

29. ii) similar to subacute combined degeneration (Vit B 12 deficiency) iii) Vit B 12 is not changed in Vacuolar myelopathy iv) pathogenesis unknown 3. Myopathy and Peripheral Neuropathy a) inflammatory myopathy i) most often described disorder in patients with HIV - proximal weakness - pain -  serum CK www.freelivedoctor.com

30. b) most commonly reported syndromes i) acute and chronic inflammatory demyelinating polyneuropathy - segmental dymyelination - axonal degeneration 4. AIDS in children a) microcephaly with mental retardation b) motor development delay i) spasticity of limbs c) most frequent abnormality i) calcification of small and large vessels and parenchyma within basal ganglia www.freelivedoctor.com

31. ii) Delay in myelination iii) opportunistic infections rare in children with AIDS as compared with adults. Progressive Multifocal Leukoencephalopathy a) PML progressive viral encephalitis caused by: i) JC polyomavirus - preferentially infects oligodendrocytes - demyelination is primary pathology ii) almost always occurs in immunosuppressed individuals www.freelivedoctor.com

32. iii) thought to be from reactivation of virus as a result of immunosuppression - ~ 65% of normal people have titers of virus Subacute Sclerosing Panencephalitis a) rare progressive disease i) characterized by cognitive decline ii) spasticity of limbs iii) seizures b) occurs in children and young adults i) months or years after initial infection with measles - altered measles virus www.freelivedoctor.com

33. c) myelin degeneration d) viral inclusions (within nuclei) of oligodendrocytes and neurons e) inflammation of white and grey matter with neurofibrillary tangles f) with widespread measles vaccinations, disease nearly has disappeared (rare cases around world) FUNGAL MENINGOENCEPHALITIS Encountered primarily in immunosuppressed individuals www.freelivedoctor.com

34. a) brain involved late in disease i) blood borne b) types: i) Candida albicans ii) Mucor iii) Aspergillus fumigatus iv) Cryptococcus neoformans - chronic meningitis signs - affecting basal leptomeninges - may obstruct outflow of CSF Three major patterns of fungal infections a) chronic meningitis www.freelivedoctor.com

35. b) vasculitis (thrombosis and infarcts) i) Mucor ii) Aspergillus c) parenchymal invasion i) granulomas or abscess ii) occur with most of the organisms iii) Candida and Cryptococcus are most common here iv) Candida  multiple micro abscesses www.freelivedoctor.com

36. OTHER INFECTIOUS DISEASES Protozoan diseases (review chapter 8 for details) Cerebral toxoplasmosis (T. gondii) a)  importance since AIDS epidemic i) one of most common causes of neurologic symptoms - ~ 4 – 30% on autopsy b) Clinical (subacute in nature): i) evolving over 1-2 weeks ii) focal or diffuse www.freelivedoctor.com

37. iii) “ring” enhancing lesions - other pathologies also show these lesions. CNS lymphoma, TB and fungal infections iv) brain frequently shows multiple abscesses (necrotic lesions) - cortical areas near white-grey matter junction and deep grey nuclei - areas of necrosis v) may occur in the fetus (i.e., early during pregnancy) www.freelivedoctor.com

38. Naegleria sp. a) rapidly fatal necrotizing encephalitis Acanthamoeba a) chronic granulomatous meningoencephalitis PRION DISEASE Transmissible spongiform encephalitis a) Creutzfeldt-Jacob disease b) Gerstmann-Sträussler-Scheinker syndrome c) fatal familial insomnia d) kuru www.freelivedoctor.com

39. All these disease are associated with an abnormal form of a specific protein a) prion protein (PrP) i) infectious and transmissible b) predominantly characterized by spongiform changes. i) caused by intracellular vacuoles - neurons - glia c) most patients develop progressive dementia i) most common clinical picture is Creutzfeldt-Jacob disease www.freelivedoctor.com