1. Central nervous system infections

2. Central nervous system: Brain Spinal cord Rigid containers: the skull and vertebral column ◦ act as barriers to the spread of infection.

3. Central nervous system infections Blood vessels Nerves that traverse the walls of the skull and vertebral column are the main routes of invasion.

4. Central nervous system infections Blood-borne invasion is the most common route of infection: polioviruses Neisseria meningitidis.

5. Central nervous system infections Invasion via peripheral nerves is less common: herpes simplex, varicella-zoster and rabies viruses.

6. Central nervous system infections Local invasion : -from infected ears or sinuses, -local injury -congenital defects such as spina bifida -invasion from the olfactory tract : amebic meningitis: rare.

7. INVASION OF THE CENTRAL NERVOUS SYSTEM Natural barriers act to prevent blood- borne invasion Blood-borne invasion takes place across: the blood-brain barrier: encephalitis the blood-cerebrospinal fluid (CSF) barrier: meningitis.

8. Structures of the blood-brain and blood-cerebrospinal fluid (CSF) barriers.

9. CNS invasion rare most microorganisms fail to pass from blood to the CNS across the natural barriers. CNS involvement by polio, mumps, rubella or measles viruses is seen in only a very small proportion of infected individuals. The factors that determine such CNS invasion are unknown.

10. Downloaded from: StudentConsult (on 23 March 2010 10:32 AM) © 2005 Elsevier The mechanism of central nervous system (CNS) invasion by poliovirus.

11. THE BODY'S RESPONSE TO INVASION CSF cell counts increase in response to infection

12. The response to invading viruses is reflected by an increase in -lymphocytes in CSF

13. The response to invading viruses -A slight increase in protein also occurs, the CSF remaining clear. This condition is termed 'aseptic' meningitis.

14. The response to invading bacteria more spectacular and more rapid increase in polymorphonuclear leukocytes and proteins the CSF becomes visibly turbid. This condition is termed 'septic' meningitis. Certain slower growing or less pyogenic microorganisms induce less dramatic changes, such as in tuberculous or listerial meningitis.

15. Change in CSF in response to invading microorganism

16. The pathologic consequences of CNS infection depend upon the microorganism Invading bacteria and protozoa generally induce more dramatic inflammatory events, which limit local spread so that infection is soon localized to form abscesses.

17. Pathologic changes For viruses: several days occasionally, years ( subacute sclerosing panencephalitis (SSPE) Bacteria Rapid

18. MENINGITIS Bacterial meningitis Acute bacterial meningitis is a life- threatening infection, needing urgent specific treatment Bacterial meningitis is more severe, but less common, than viral meningitis and may be caused by a variety of agents

19. Bacterial MENINGITIS Haemophilus influenzae type b (Hib): Prior to the 1990s before the vaccine Neisseria meningitidis Streptococcus pneumoniae All have a polysaccharide capsule.

20. Meningococcal meningitis Neisseria meningitidis is carried by about 20% of the population, but in epidemics higher rates are seen Meningococcal septicemia showing a mixed petechial and maculopapular rash on the extremities and exterior surfaces.

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22. Meningococcal meningitis Neisseria meningitidis Gram-negative diplococcus The bacteria are attached by their pili to the epithelial cells in the nasopharynx. Invasion of the blood and meninges is a rare and poorly understood event.

23. Meningococcal meningitis Neisseria meningitidis Person-to-person spread:by droplet infection Overcrowding such as prisons, military barracks and college dormitories contribute to the frequency of infection in populations During outbreaks of meningococcal meningitis, which most frequently occur in late winter and early spring, the carrier rate may reach 60-80%.

24. A diagnosis of acute Meningococcal meningitis is usually suspected on clinical examination Laboratory identification of the bacterial cause of acute meningitis is essential so that appropriate antibiotic therapy can be given and prophylaxis of contacts initiated. Preliminary microscopy results involving white cell counts and Gram-staining for bacteria should be available within an hour of receipt of the CSF sample in the laboratory. Results of culture of CSF and blood should follow after 24 h Antigen detection NAT

25. A diagnosis of acute Meningococcal meningitis is usually suspected on clinical examination !!! Close contacts in the family referred to as 'kissing contacts' should be given rifampin chemoprophylaxis for 2 days. vaccine

26. Haemophilus meningitis Haemophilus meningitis Type b H. influenzae causes meningitis in infants and young children H. influenzae is a Gram-negative coccobacillus. Maternal antibody protects the infant up to 3-4 months of age, but as it wanes, there is a 'window of susceptibility' until the child produces his/her own antibody.

27. Acute H. influenzae meningitis is commonly complicated by severe neurologic sequelae It is important to note that the organisms may be difficult to see in Gram-stained smears of CSF, particularly if they are present in small numbers.

28. H. influenzae type b (Hib) vaccine effective for children from 2 months of age

29. Pneumococcal meningitis Streptococcus pneumoniae is a common cause of bacterial meningitis, particularly in children and the elderly

30. Pneumococcal meningitis Strep. pneumoniae a capsulate Gram-positive diplococcus carried in the throats of many healthy individuals Invasion of the blood and meninges is a rare event, but is more common: in the very young (<2 years of age), in the elderly, in those with sickle cell disease, in debilitated or splenectomized patients and following head trauma. The protection is type-specific and there are more than 85 different capsular types of Strep. pneumoniae.

31. Pneumococcal meningitis Since penicillin-resistant pneumococci have been observed worldwide, attention must be paid to the antibiotic susceptibility of the infecting strain, and empiric chemotherapy usually involves a combination of vancomycin and either cefotaxime or ceftriaxone.

32. Laboratory diagnosis Microscopy is highly sensitive, as is culture, unless the patient has been treated with antibiotics Antigen test for pneumococcal C polysaccharide is sensitive with CSF (meningitis) but not with urine (meningitis, pneumonia, other infections) Nucleic-acid-based tests are not commonly used for diagnosis Culture requires use of enriched-nutrient media (e.g., sheep blood agar); organism highly susceptible to many antibiotics, so culture can be negative in partially treated patients

33. Pneumococcal meningitis Immunization with 7-valent conjugated vaccine is recommended for all children younger than 2 years of age; a 23-valent polysaccharide vaccine is recommended for adults at risk for disease (e.g. sickle cell disease, HIV infection, chronic illness or weakened immune systems) for serious pneumococcal infection.

34. Listeria monocytogenes meningitis Listeria monocytogenes causes meningitis in immunocompromised adults Gram-positive coccobacillus

35. Neonatal meningitis especially those with low birth weight

36. Although mortality rates due to neonatal meningitis in resource-rich countries are declining, the problem is still serious the most frequent agents: group B hemolytic streptococci (GBS) E. coli nosocomial infection from the mother

37. Tuberculous meningitis always have a focus of infection elsewhere approximately 25% may have no clinical or historic evidence of such an infection In >50% of cases, meningitis is associated with acute miliary tuberculosis In areas with a high prevalence of tuberculosis: ◦ Most common: in children from 0-4 years of age In areas where tuberculosis is less frequent ◦ Most common: adults

38. Tuberculous meningitis usually presents with a gradual onset over a few week Spinal tuberculosis is uncommon now except in resource-poor countries; bacteria in the vertebrae destroy the intervertebral disks to form epidural abscesses. These compress the spinal cord and lead to paraplegia.

39. Fungal meningitis Cryptococcus neoformans : major cause Coccidioides immitis

40. Cryptococcus neoformans meningitis Common in patients with depressed cell- mediated immunity Common in patients with depressed cell- mediated immunity capsulate yeasts: India-ink-stained preparations of CSF and can be cultured. Antigen ◦ a useful diagnostic tool ◦ a measure of successful therapy.

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42. Protozoal meningitis Naegleria the free-living ameba If inhaled they can reach the meninges via the olfactory tract and cribriform plate. rapid onset mortality rate is high. Under the microscope, Naegleria appear as slowly motile amebae on careful examination of a fresh wet sample of CSF.

43. Protozoal meningitis Acanthamoeba spp. In immunocompromised enter via the skin or the respiratory tract. Acanthamoeba causes a chronic condition (granulomatous amebic encephalitis). can be visualized in brain biopsies.

44. Viral meningitis Viral meningitis is the most common type of meningitis milder disease than bacterial meningitis The CSF is clear in the absence of bacteria, the cells are mainly lymphocytes, although polymorphonuclear leukocytes may be present in the early stages NAT

45. Viral meningitis Viral meningitis is the most common type of meningitis There are five groups of human enteroviruses which include the echoviruses, coxsackie Group A and B viruses, and the three polioviruses. E nteroviruses are common causes of seasonal aseptic meningitis. In contrast to bacterial meningitis, viral meningitis usually has a benign course, and complete recovery is the rule.

46. Viral meningitis

47. Diagnosis NAT techniques Spesific antibody index (Serum and CSF antibody and albumin or Immunoglobulin values)in (SSPE)

48. ENCEPHALITIS Encephalitis is usually caused by viruses, but there are many cases where the infectious etiology is not identified

49. Encephalitis

50. HSV ENCEPHALITIS In neonates: after vaginal delivery: HSV-2 In older children and adults: HSV-1, of which most are due to virus reactivation in the trigeminal ganglia

51. HSV ENCEPHALITIS Herpetic skin or mucosal lesions may be present. HSV DNA in CSF sample using PCR. In untreated patients : 70% mortality early and prolonged treatment with intravenous aciclovir

52. Enteroviral infections Poliovirus used to be a common cause of encephalitis There are successful vaccines. The disease is completely preventable by vaccination and has been disappearing in resource-rich countries since vaccination programs were first carried out in the 1950s.

53. Enteroviral infections Enterovirus-71-associated hand, foot and mouth epidemic resulted in a high rate of neurologic complications Other enteroviruses such as coxsackieviruses and echoviruses occasionally cause meningoencephalitis. Treatment is supportive and there is no vaccine.

54. Paramyxoviral infections Mumps virus is a common cause of mild encephalitis Asymptomatic CNS invasion may be common because there are increased numbers of cells in the CSF in about 50% of patients with parotitis; on the other hand, meningitis and encephalitis are often seen without parotitis.

55. Paramyxoviral infections Nipah virus encephalitis, an emerging zoonotic paramyxovirus infection In 1998, an outbreak of encephalitis with a high mortality rate was reported among pig farm workers in Malaysia. In total, there were 105 deaths among 265 patients with Nipah virus encephalitis.

56. Rabies encephalitis The causative agent of rabies is a rhabdovirus, a bullet- shaped single-stranded RNA virus. The Lyssavirus genus sits within the Rhabdoviridae family.

57. Rabies encephalitis The virus is excreted in the saliva of infected dogs, foxes, jackals, wolves, skunks, raccoons and vampire and other bats, and transmission to humans follows a bite or salivary contamination of other types of skin abrasions or wounds. The infection is eventually fatal, although the course of the disease varies considerably between species. If an apparently healthy dog is still healthy 10 days after biting a human, rabies is extremely unlikely. However, the virus may be excreted in the dog's saliva before the animal shows any clinical signs of disease.

58. Rabies encephalitis The incubation period in humans is generally 4-13 weeks, although it may occasionally be as long as 6 months, possibly due to a delay in virus entry into peripheral nerves. The virus travels up peripheral nerves and, in general, the further the bite is from the CNS, the longer the incubation period. For instance, a bite on the foot leads to a longer incubation period than a bite on the face.

59. Rabies encephalitis Rabies can be diagnosed by detecting viral antigen or RNA -skin biopsies -corneal impression smears -brain biopsy. Characteristic intracytoplasmic inclusions called Negri bodies are seen in neurones.

60. Rabies encephalitis After exposure to a possibly infected animal, immediate preventive action should be taken This action includes: Prompt cleaning of the wound (alcoholic iodine, debridement) Confirmation of whether or not the animal is rabid (clinical observation of suspected dogs, histologic observation of the brain of other suspected species) Administration of human rabies immunoglobulin (HRIG) to ensure prompt passive immunization. Half of the dose is given into the wound and half intramuscularly If the risk is definite, active immunization with killed diploid cell- derived rabies virus (HDCV). The chances of preventing the disease are greater when vaccination is started as early as possible after infection. (0,3,7,28,90)

61. Multiple cytoplasmic Negri bodies in pyramidal neurones of the hippocampus in rabies.

62. Togavirus and Flavivirus(Arboviruses) meningitis and encephalitis Numerous arthropod-borne togaviruses can cause meningitis or encephalitis sometimes cause outbreaks of infection In different parts of the world, different mammals, birds or even reptiles act as reservoirs and there are a variety of arthropod (mosquito and tick) vectors. Usually, <1% of humans infected develop neurologic disease. There may be a febrile illness, but asymptomatic infection is common. In California: ◦ Western equine encephalomyelitis (WEE) virus ◦ St Louis encephalitis (SLE) virus : transmitted by the mosquito Culex tarsalis; a WEE vaccine is available, but only for horses. Japanese encephalitis virus infection: in India a vaccine for humans has been developed. West Nile virus, another emerging viral cause of encephalitis

63. Retrovirus meningitis and encephalitis HIV can cause subacute encephalitis, often with dementia HIV often invades the CNS İ ndistinguishable from the neurologic disease caused by microorganisms such as T. gondii, C. neoformans, cytomegalovirus and JC virus. JC virus, a polyomavirus, occasionally invades oligodendrocytes in immunodeficient people, particularly in AIDS, and eventually gives rise to progressive multifocal leukoencephalopathy (PML).

64. Viral myelopathy inflammation of the spinal cord, a myelitis: by polio, coxsackie, enterovirus 71 and West Nile virus infection, a number of herpes viruses including HSV, CMV, EBV and VZV Chronic myelopathy :HTLV-1,HIV-1 infection

65. Post-vaccinial and post-infectious encephalitis Encephalitis following viral infection or vaccination possibly has an autoimmune basis inflammatory demyelinating condition of the peripheral nervous system Guillain-Barré syndrome has been associated with a variety of viral infections, as well as with immunization with non-infectious material.

66. NEUROLOGIC DISEASES OF POSSIBLE VIRAL ETIOLOGY ? NEUROLOGIC DISEASES OF POSSIBLE VIRAL ETIOLOGY ? neurologic diseases of unknown origin: multiple sclerosis amyotrophic lateral sclerosis Parkinson's disease Schizophrenia senile dementia

67. SPONGIFORM ENCEPHALOPATHIES CAUSED BY SCRAPIE-TYPE AGENTS prion spongiform appearance of nervous tissues, caused by vacuolation and plaque formation. Infections in animals seem to have originated from sheep and goats with scrapie, which has been present in Europe for 200-300 years.

68. CNS DISEASE CAUSED BY PARASITES Toxoplasma gondii Plasmodium falciparum Toxocara cati Toxocara canis Echinococcus granulosus Taenia solium Cysticercosis

69. BRAIN ABSCESSES Brain abscesses are usually associated with predisposing factors Since the development of antibiotics, brain abscesses have become rare and usually follow surgery or trauma, chronic osteomyelitis of neighboring bone, septic embolism or chronic cerebral anoxia. They are also seen in children with congenital cyanotic heart disease in whom the lungs fail to filter off circulating bacteria. Acute abscesses are caused by various bacteria, generally of oropharyngeal origin, including anaerobes. There is usually a mixed bacterial flora. Chronic abscesses may be due to Mycobacterium tuberculosis or C. neoformans. In immunosuppressed patients, opportunistic infection may occur with fungi and protozoan etiologic agents.

70. Brain abscess