Central Nervous System Infections Etiology Septic

Please supplement and learn theory on the basis of the lecture, Mim’s book and supplementary materials before class!!!

Invasion of BBB – ………………………………………… causes ……………………………….. Invasion of BCSFB – ………………………………………………………….. causes …………………………..

ETIOLOGY

SEPTIC MENINGITIS

According to age Most common bacteria: ……………………………………………… NEONATES ……………………………………………… ……………………………………………… …………………………………………….. ……………………………………………… Less common bacteria: ……………………………………………… ……………………………………………… CHILDREN 2 mo. – 5 y

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ASEPTIC MENINGITIS ENCEPHALITIS

VIRUSES PRIMARY VIRUSES …………………………………………………… ……………………………………………………… …………………………………………………… ……………………………………………………… ………………………………………………… ………………………………………………………

BACTERIA …………………………………………………… …………………………………………………… LESS COMMON VIRUSES …………………………………………………… ……………………………………………………… …………………………………………………… ……………………………………………………… …………………………………………………… ………………………………………………………

FUNGI …………………………………………………… …………………………………………………… BACTERIA – RARE …………………………………………………… ……………………………………………………… …………………………………………………… ……………………………………………………… …………………………………………………… ……………………………………………………… ……….. …….. 1

CENTRAL NERVOUS SYSTEM INFECTIONS

BRAIN ABSCESSES

Polymicrobial ROUTES of ENTRY into the BRAIN ……………………………………………………… 1. ……………………………………………...... ……………………………………………………… ………………………………………………………… ……………………………………………………… ………………………………………………………… ……………………………………………………… 2. ……………………………………………………. ……………………………………………………… ………………………………………………………… …………………………………………………….. ………………………………………………………… 3. ……………………………………………………. In immunocompromised: ………………………………………………………… ……………………………………………………… ……………………………………………………… ……………………………………………………… ……………………………………………………… ……………………………………………………….

SPECIFIC PROPHYLAXIS

STUDENT NOTES

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DIAGNOSIS of CNS INFECTIONS In normal conditions CSF is crystal clear and sterile

PATIENT’s SAMPLES:

CSF obtained during lumbar puncture and transferred into pre-warmed (37° C) special culture- transport medium (meningomedium); Small amount of CSF should be also transferred into small tube (pilot tube) to perform rapid tests detecting polysaccharides of common pathogens and to make Gram staining or other staining techniques depending on provisional diagnosis e.g. ink stain to visualize Cryptococcus, Giemsa stain to observe parasites etc.

TRANSPORT to the LABORATORY – CSF samples in culture-transport media should be transported immediately to the lab at 37° C !!!! (thermo-bag keeping human body temperature). Cooling of samples may kill off pathogens present in CSF !!!!

For viral testing CSF samples can be stored at 4° C (for 48 h) or longer at -70° C

Other analyses facilitating microbial diagnosis include: cytology (number and type of immune cells) and chemistry (glucose and protein levels).

BLOOD since more than 70% of all cases with septic meningitis is associated with bacteremia/sepsis taking blood samples facilitate and sometimes enable proper diagnosis of CNS infections. Blood samples should be taken according to principles obligatory for samples in blood infections (on special culture-transport media).

PHARNGEAL SWABS since common pathogens causing bacterial meningitis are acquired via respiratory route and colonize oropharynx before entering blood and then CNS, taking pharyngeal swabs may facilitate diagnosis as very often pathogen is still present in the upper respiratory tract.

CENTRAL NERVOUS SYSTEM INFECTIONS

CSF sample in pilot tube:

a) Staining: CSF should be centrifuged 1000 x g / 15 min. Sediment serves to perform staining b) Rapid tests: CSF should be heated 100° C for 3 min to remove any cells, enzymes etc. and centrifuged 1000 x g / 15 min. Supernatant serves to perform rapid tests detecting: - polysaccharides of S. pneumoniae, N. meningitidis A, C, B, W135, Y; streptococci group B and H. influenzae type B, and E. coli K1 - fungal antigens: Cryptococcus neoformans capsule polysaccharide and Candida albicans mannans present in the cell wall or genetic material of microorganisms using NAATs Rapid tests are superior in sensitivity to staining and may be used to detect bacterial antigens in CSF, serum, blood and urine samples.

MICROSCOPY allows prompt provisional diagnosis – differentiates septic from aseptic and fungal meningitis

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TREATMNENT of CNS INFECTIONS

Antimicrobials used to treat CNS infections: 1. β-lactams: penicillin, ampicillin (Listeria monocytogenes), cephalosporins, monobactams, carbapenems 2. Aminoglycosides (gentamycin, amikacin, netilmycin) – intrathecal application 3. Fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin) – therapy for GN aerobic rods, Listeria monocytogenes 4. Tetracyclines – neuroboreliosis, brucellosis 5. Linezolid – S. aureus, enterococcal CNS infections 6. Rifamycin (rifampin) – tuberculosis meningitis, S. aureus, S. pneumonia CNS infections 7. Glycopeptides (high dose of vancomycin) – therapy for CNS infections caused by MRSA, multi- resistant S. pneumoniae 8. Acyclovir, gancyclovir – HSV infections of CNS 9. Fluconazole, flucytosine, voriconazole, amphothericin B – fungal infections of CNS

EMPIRIC TREATMENT according to the age and most common etiology

Newborns (perinatal infections): ampicillin + aminoglycoside or ampicillin + cefotaxime

Children from 1 to 3 years of age cefotaxime or ceftriaxone + vancomycin or ampicillin

Children from 3 to 5 years of age cefotaxime or ceftriaxone + vancomycin

Children 5 years of age and adults up to 50 years of age cefotaxime or ceftriaxone + vancomycin

Adults over 50 years of age cefotaxime or ceftriaxone + ampicillin + vancomycin

CENTRAL NERVOUS SYSTEM INFECTIONS

VIRAL MENINGITIS TREATMENT In most cases, there is no specific treatment for viral meningitis. Most people who get mild viral meningitis completely recover on their own usually within 7 to 10 days. People with meningitis caused by certain viruses such as herpesvirus may need treatment with antiviral drugs (acyclovir). CNS infections caused by measles, mumps, rubella viruses should be prevented by vaccination.

ENCEPHALITIS TREATMENT Up to 85% encephalitis are of unknown etiology. Encephalitis caused by HSV, VZV can be treated with acyclovir. There is no specific treatment or vaccination in encephalitis caused by enteroviruses (supportive treatment). Exception includes Polioviruses type 1, 2 and 3 – infections with these viruses has been eradicated all over the world (except with some endemic regions in Pakistan, Afghanistan and Nigeria).

TREATMENT of FUNGAL MENINGITIS Cryptococcus neoformans – amphotericin B + flucytosine Coccidioides immitis – amphotericin B or fluconazole Candida albicans – amphotericin B + flucytosine or amphotericin B + fluconazole Aspergillus spp. – amphotericin B or vorikonazole

STUDENT NOTES

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CLASS TASKS:

Task 1. Your patient is a newborn with suspected meningitis. CSF and blood samples were collected in the hospital and sent to the laboratory.

1. Plate a blood sample from patient onto blood agar and Mac Conkey agar plates. First, wear the gloves, disinfect the cap of the bottle with blood sample using alcohol. Next, using syringe take some medium in a sterile way and drop onto both agar media 3-4 drops. Then, spread the material on the surface of agar according to streak plate technique. Dispose syringe into designated container. Label both plates with your initials and put them into incubation at 37° C for 24 hours.

Meningomedium – demonstration of bacterial growth Pilot tube – make Gram-stained slide from CSF in the pilot tube. Observe the slide under microscope and record results, and draw the picture from the field of view. Shape ...... Arrangement ...... Gram-staining ...... Suspected species ......

Next week: Estimate bacterial colonies on culture media (color, surface, size, presence of hemolysis) and record results:  blood agar ------ MacConkey agar ------ How bacteria isolated from patient’s blood and CSF sample may be indentified to species?

Give therapeutic options that can be used for newborn meningitis: ------

Task 2. Your patient is a 40-year-old adult with suspected meningitis. CSF and blood samples were collected in the hospital and sent to the laboratory.

Plate a blood sample from patient onto blood agar and Mac Conkey agar plates. First, wear the gloves, disinfect the cap of the bottle with blood sample using alcohol. Next, using syringe take some medium in a sterile way and drop onto both agar media 3-4 drops. Then, spread the material on the surface of agar according to streak plate technique. Dispose syringe into designated container. Label both plates with your initials and put them into incubation at 37° C for 24 hours.

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Answer questions: Which groups of antimicrobials may be used to treat the infection caused by the isolated microorganism? Read and record antimicrobial susceptibility testing results. ------What mechanisms of resistance isolated species may present? ------Penicillin G ...... Cefotaxime ...... Vancomycin ...... Teicoplanin ......

CENTRAL NERVOUS SYSTEM INFECTIONS

CLINICAL CASES

Case 1 The parents came to the doctor with a 6-month-old child with a 39° C fever lasting several hours. Child was vomiting at home, showed lack of appetite and convulsions with a short loss of consciousness. The child was tearful and restless. During the study 39° C fever was found, lungs auscultation without changes, circulatory without changes, abdomen without peritoneal symptoms. All symptoms suggested meningitis that was confirmed by chemical examination and cytology of CFS. Cerebrospinal fluid examination: CSF - turbid, milky, clear after centrifugation cytosis 423 cells per mm3 (neutrophils 65%) protein 219 mg / dl (normal: 15-50 mg / dl) glukoza 0,5 mg / dl (normal: 32-82 mg / dl)

What is the most likely infectious agent of the meningitis in the child? ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………..

What tests should be performed to find out etiologic agent? ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………..

Should the treatment be started immediately or doctor should wait for the results of CSF examination? ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………..

Is the infection preventable by vaccination? ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………..

Case 2 Andrew, a 20-years old student, presents with a 5-day history of fever, malaise, anorexia, nausea, and headache. He also reports difficulty in sleeping and, when he does sleep, he is disturbed by vivid nightmares. Over the same period, he has noticed a tingling sensation in a patch of the skin on his left arm. He has no significant past history and is on no regular medication. On examination he is febrile, but there is little else note, apart from a ragged healed scar on his left arm, which Andrew confirms is the site of abnormal sensation. On further enquiry, it transpires that Andrew was bitten by a dog 3 months ago whilst backpacking in South America. Apart from thoroughly washing the area of the bite, he took no further action.

What diagnosis should you consider? ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………..

Over the next 3 days he becomes increasingly restless and agitated, exhibiting purposeless movements of his limbs in response to tactile and auditory stimuli. He suffers intense spasms affecting the muscles involved in swallowing and accessory muscles of respiration, lasting for 10 9

CENTRAL NERVOUS SYSTEM INFECTIONS seconds or so, and accompanied by frothing at the mouth. The frequency and severity of these spasms initially increase, but begin to decline after 2 days, when Andrew’s conscious level declines into coma, and he dies 24 hours later.

Why is rabies sometimes referred to as hydrophobia? ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………..

How may rabies be classified clinically? ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………..

What is the pathogenesis of rabies infection? ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………… …………………………………………………………………………………………………………………………………………………………………….. ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………..

What factors influence the transmission of rabies from animal to man? ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………..

What is the likely outcome of a patient suspected of rabies? ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………..

How can the diagnosis be confirmed? ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………… …………………………………………………………………………………………………………………………………………………………………….. ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………..

Could Andrew’s fatal attack of rabies have been prevented? ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………..

Who should be offered rabies vaccine? ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………..

What is correct management of a patient bitten by a possible rabid animal? 1. ………………………………………………………………………………………………………………………………………………………… ………………………………………………………………………………………………………………………………………………………… ………………………………………………………………………………………………………………………………………………………… ……………………………………..

CENTRAL NERVOUS SYSTEM INFECTIONS

Case 3 Nigel, a 3-year-old boy, is referred to hospital with a 2-day history of lethargy, irritability, and poor feeding. On examination he is pyrexial and drowsy and has 2-3 purplish-red lesions on the trunk and extremities. There is no neck stiffness suggesting CNS involvement. What is the most likely diagnosis? What investigations should be carried out to confirm it? ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………..

What is the significance of age in predicting the likely etiology of meningitis? a) in this case? b) in a 3-day-old neonate? c) in a 25-year-old woman with a prodromal flu-like illness? d) in a 75-year-old comatose man? ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………… …………………………………………………………………………………………………………………………………………………………………….. ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………..

Nigel’s CSF obtained from LP at presentation is cloudy and contains 540 white cells/mm3. CSF protein is 8 g/l and glucose 0.3 mmol (blood glucose 5.7 mM). The Gram stain reveals GN intracellular diplococci. Nigel’s blood cultures are also positive for GN diplococci within 24 hrs of being taken. Which of the above CSF values are abnormal? What is the likely pathogen? ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………… …………………………………………………………………………………………………………………………………………………………………….. ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………..

If the microscopy and culture of blood and CSF are negative for N. meningitidis what other investigations might confirm diagnosis? ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………..

What is the antibiotic of choice here? ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………..

What is preferable in this instance to delay starting treatment pending investigations? ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………… …………………………………………………………………………………………………………………………………………………………………….. Nigel was started on high-dose IV penicillin and gradually improved over the next 48-72 hrs. His mother expressed some concern as to the risk to his brother Lenny, aged 2, and sister Cyntia, aged 7. What measures, if any, can be taken to minimize the risk to Nigel’s close contact? ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………………………..

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ISSUES to be DISSCUSSED DURING CLASS

1. Who should receive chemoprophylaxis and why it should be done within 24 hours? ………………………………………………………………………………………………………………………………………………………… ………………………………………………………………………………………………………………………………………………………… ………………………………………………………………………………………………………………………………………………………… ………………………………………………………………………………………………………………………………………………………. 2. Why the serology is not helpful in the diagnosis of acute meningococcal meningitis? ………………………………………………………………………………………………………………………………………………………… ………………………………………………………………………………………………………………………………………………………… ………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………….. 3. Why, when we suspect meningitis, we also take a blood sample for examination? ………………………………………………………………………………………………………………………………………………………… ………………………………………………………………………………………………………………………………………………………… ………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………….. 4. Why we do not use penicillin in the chemoprophylaxis of meningococcal meningitis? ………………………………………………………………………………………………………………………………………………………… ………………………………………………………………………………………………………………………………………………………… ………………………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………………….. 5. Why the prolonged labor predisposes to neonatal meningitis? ………………………………………………………………………………………………………………………………………………………… ………………………………………………………………………………………………………………………………………………………… ………………………………………………………………………………………………………………………………………………………… ………………………………………………………………………………………………………………………………………………………..

6. Why acute bacterial meningitis requires urgent specific treatment? ………………………………………………………………………………………………………………………………………………………… ………………………………………………………………………………………………………………………………………………………… ………………………………………………………………………………………………………………………………………………………… ………………………………………………………………………………………………………………………………………………………..

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SELF-ASSESMENT 1. What are patients samples for diagnosis of blood infections and CNS infections? 2. Are there are any rapid tests allowing to detect CNS infections? What pathogens can we detect with these tests? 3. List routes of entry of microorganisms do CNS 4. Name most common agents of purulent meningitis according to the age of patient 5. Name most common agents of aseptic meningitis 6. Name bacterial species (full manes) causing purulent meningitis 7. Name bacteria causing aseptic meningitis 8. Name fungi causing aseptic meningitis 9. Name most common viruses causing aseptic meningitis 10. What are parameters of CFS specific to purulent meningitis, aseptic meningitis and brain abscesses? 11. Give parameters of: mycobacterial meningitis, fungal meningitis, meningitis caused by spiral bacteria, meningitis caused by viruses and by typical bacteria 12. Name common virulence factors of bacteria most commonly causing aseptic meningitis 13. Name antimicrobials used to treat meningitis in newborn, children and adults 14. What are treatment options in cause of meningitis associated with head trauma and in immunosuppressed individuals 15. Is there any specific prophylaxis in case of meningitis? 16. Routes of transmission of meningococcal meningitis include…. Give examples 17. Which antimicrobials are used in chemoprophylaxis of meningococcal meningitis? 18. Most commonly invasive pneumococcal diseases appear among…? 19. Fungal meningitis most commonly develops in….? 20. Risk factors for fungal meningitis include….? 21. Combine most common viruses causing meningitis with seasons 22. Name most common etiologic agents of acute and chronic brain abscesses 23. Name most common viruses causing encephalitis 24. Name bacteria that can cause encephalitis

Remember! To get credit of class all materials must be supplemented!

Credit for class...... (teacher’s signature) date......

CENTRAL NERVOUS SYSTEM INFECTIONS

SUPPLEMENTARY MATERIALS

Bacterial aseptic meningitis Spirochetes — The two major spirochetes that need to be considered in the differential diagnosis of aseptic meningitis are Treponema pallidum, the causative agent of syphilis, and Borrelia burgdorferi, the spirochete that causes Lyme disease. Leptospirosis can also cause an aseptic meningitis syndrome. Syphilis — Treponema pallidum, the causative agent of syphilis, disseminates to the central nervous system during early infection. Syphilitic meningitis can present in the setting of secondary syphilis with headache, malaise, and disseminated rash. Cerebrospinal fluid (CSF) findings include a lymphocytic pleocytosis with an elevated protein concentration; occasionally a depressed glucose concentration may also be seen. Specific serum treponemal tests are almost always positive. The CSF venereal disease research laboratory test (VDRL) has a generally accepted sensitivity of 30 to 70 percent, but is highly specific in the absence of visible blood contamination. A more detailed discussion of how to diagnose neurosyphilis is found elsewhere. Lyme disease — Lyme meningitis typically occurs in the late summer and early fall, the same time as the peak incidence of enteroviral meningitis. During the acute primary infection, some patients develop headache, neck stiffness, and photophobia. Fever is usually mild; Kernig and Brudzinski signs are usually absent on physical examination, and neurologic features can include cranial nerve palsies, especially involving the facial nerve which may be bilateral. The diagnosis of aseptic meningitis due to Lyme disease is facilitated when other characteristic findings are present, such as erythema migrans. When Lyme meningitis occurs alone, the diagnosis can be missed unless the clinician considers other risk factors, such as potential exposure to ticks or travel history. Fungal infections — The two major fungal infections that should be considered in the differential diagnosis of aseptic meningitis include cryptococcus and coccidioidomycosis. Cryptococcal infection — Cryptococcus neoformans produces infection following inhalation through the respiratory tract. The organism disseminates hematogenously and has a propensity to localize to the CNS, particularly in patients with severe deficiencies in cell-mediated immunity. Symptoms typically begin in an indolent fashion, usually over a period of one to two weeks. The three most common symptoms are fever, malaise, and headache. Stiff neck, photophobia, and vomiting are seen in one-fourth to one-third of patients. The CSF WBC count is typically low (<50/µL) with a mononuclear predominance and the protein and glucose concentrations are usually only slightly abnormal. Coccidioidal infection — Coccidioides immitis is endemic in desert regions of the southwestern United States and Central and South America. This infection has protean manifestations, and primary infection is frequently unrecognized. Meningitis is the most lethal complication of coccidioidomycosis and is therefore crucial to recognize. Symptoms of meningitis, including persistent and severe headache, usually develop within several months of the initial infection. Abnormal neurologic findings on physical examination are frequently absent early in the course of coccidioidal meningitis. The CSF WBC counts ranges from one to several hundred cells. A significant numbers of eosinophils may be present, but this finding is not specific for coccidioidal meningitis. The CSF glucose concentration may be depressed and is occasionally profoundly low in association with an elevation of the CSF protein concentration. Tuberculous meningitis — Patients with tuberculous meningitis frequently have protracted headache, vomiting, confusion, and varying degrees of cranial nerve signs. Mental status changes can occur, leading to coma, seizures, and at times hemiparesis. Signs of disseminated TB are of diagnostic importance, but are often absent. CSF analysis typically shows elevated protein and lowered glucose concentrations with a mononuclear pleocytosis.

Bacterial meningitis PATHOGENESIS — Bacterial meningitis develops when virulence factors of the pathogen overcome host defense mechanisms. For the most common pathogens causing bacterial meningitis in adults, such as Streptococcus pneumoniae and Neisseria meningitidis, meningeal invasion is related to several virulence factors that allow the bacteria to colonize host mucosal epithelium, invade and survive within the bloodstream, cross the blood-brain barrier, and multiply within the cerebrospinal fluid (CSF).

CENTRAL NERVOUS SYSTEM INFECTIONS

Colonization and invasion — Many of the major meningeal pathogens possess surface components, such as fimbriae or pili, that enhance mucosal colonization. Colonization of the host mucosal epithelium is facilitated by evasion of mucosal secretory immunoglobulin A (IgA) through pathogen secretion of IgA protease. IgA protease inactivates the mucosal antibody and facilitates bacterial attachment to host epithelial cells. After successful colonization, invasion occurs across the epithelium via intracellular or intercellular pathways that are mediated by specific binding adhesins of the bacterial surface. After attachment and aggregation of Neisseria meningitidis, organisms detach from the aggregates to systematically invade the host by means of a transcellular pathway that crosses the respiratory epithelium. Surface encapsulation may also be an important virulence factor for nasopharyngeal colonization and systemic invasion of meningeal pathogens.

Intravascular survival — Following invasion and entry into the bloodstream, bacteria survive through evasion of the complement system, particularly the alternative complement pathway. The bacterial capsular polysaccharide is the major mechanism for alternative complement evasion. Then, pathogens cross the blood-brain barrier into the CSF.

Upon successful invasion of the CSF, bacteria can multiply to high concentrations (e.g., up to 107 organisms per milliliter) because of inadequate humoral immunity in the CSF. Specifically, low concentrations of immunoglobulin and complement within human CSF result in poor opsonic activity, successful bacterial replication, and the subsequent development of inflammation. Despite an early influx of leukocytes in bacterial meningitis, host defenses in CSF remain suboptimal because of the lack of functional opsonic and bactericidal activity.

Mechanism of microbial traversal of the blood-brain barrier: a) transcellular traversal (e.g. encapsulated bacteria like Str. pneumoniae, H. influenzae, N. meningitidis, E. coli K1), b) paracellular traversal (spiral bacteria, some viruses), c) the “Trojan horse” mechanism (within white blood cells e.g. M. tuberculosis, some viruses e.g. EBV, CMV, Listeria monocytogenes).

CAUSES OF VIRAL ENCEPHALITIS 1. Arbovirus infections (Western equine encephalitis, Estern equine encephalitis, Venezuelan equine encephalitis, St. Louis encephalitis, Japanese B. encephalitis, Yellow fever, Dengue) 2. Arthropod tick–borne encephalitis (Russian tick-borne complex, Colorado tick fever) 3. Picornavirus (enterovirus) infections (Poliomyelitis, Coxsackievirus infections, Echovirus meningoencephalitis) 4. Myxovirus infections (Influenza, Mumps, Measles, Rabies, Rubella, Newcastle disease) 5. Herpesvirus infections (Herpes simplex, Herpes zoster and chicken pox, Virus B (herpesvirus simiae) Cytomegalic inclusion disease) 6. Poxvirus infections (Smallpox encephalitis) 7. Others

RABIES is an acute and fatal viral CNS infection. Can affect all mammals. Transmitted by infected secretions (usually through a bite). Rabies involves severe neurological symptoms. CNS abnormalities include: relentless progression of excess motor activity, agitation, hallucinations, overproduction of saliva - can be an inability to swallow. First event of rabies infection is introduction of the virus. Usually through the epidermis via an animal bite. Also through inhalation of heavily contaminated material such as bat droppings. Virus replicates at the site of infection. Immunization immediately after infection keeps virus from migrating into the nervous tissue. 15

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Without intervention, virus moves into peripheral nervous system. Spreads into the CNS. Replicates exclusively in gray matter. After replication, virus moves into other tissues. Adrenal medulla, kidneys, lungs, and salivary glands. Lymphocytes and plasma cells infiltrate into the CNS - destroy nerve cells. Primary lesion is the Negri body. Rabies presents as acute, fatal encephalitis. Rabies is the only microorganism causing pure encephalitis. Once symptoms appear the infection is irreversibly fatal. Illness begins with nonspecific fever, headache, malaise, nausea, and vomiting. Involvement of respiratory centers causes respiratory paralysis. Major cause of death. Median survival after the onset of symptoms is 20 days. Prevention is the best cure. Treatment consists of a course of injections. Only beneficial if administered before the onset of symptoms. Mortality for rabies is 90%. Pathogenesis of rabies infection involves three stages: 1. Entry of virus – intact skin is impermeable to the virus, but infection may occur across undamaged mucous membranes. Rabid animals have virus present in saliva, and so can spread infection by inoculating virus ate the site of a bite or by licking abraded skin. Viral replication occurs initially in muscle cells at the site of the bite. 2. Ascent to the CNS. Following release from muscle cells, virus enters peripheral nerves via the neuromuscular junction and is transported to the spinal cord, and thence rapidly to the brain. Spread within the CNS. Virus travels back down via peripheral nerves to sites throughout the body, including salivary glands, myocardium, lung, liver, skin, retina, and cornea. Patients with infectious virus in their bodily secretions thus pose an infection risk to those involved in their care. Human-to-human transmission is however a rare occurrence. 3. The incubation period prior to the development of disease is highly variable (up to year, but on average 30-90 days). The shorter periods are seen in children, and in bites close to the CNS e.g. head.

POLIO Infection which destroys cells associated with the anterior horn of the spinal cord, and brain stem. Causes weakness or paralysis of muscle groups. Can cause respiratory difficulties. Characterized by asymmetrical paralysis. Risk of paralysis actually increases with age. Essentially nonexistent in most modern countries. There is an effective vaccine. Still a major problem in underdeveloped countries. Virus is an enterovirus with an affinity for the CNS. Normally crosses the blood-brain barrier. Can also use axons or the perineural sheath of the peripheral nervous system. Motor neurons are particularly vulnerable. Various levels of neuronal destruction cause: necrosis of neural tissue and infiltration by mononuclear cells, primarily lymphocytes. 90% of poliomyelitis infections are very mild and subclinical. Incubation time varies from 4 to 35 days. Average is about 10 days. Three types of polio infection: Abortive poliomyelitis: Nonspecific febrile illness. Lasts two to three days. No signs or symptoms Nonparalytic poliomyelitis (aseptic meningitis): Characterized by meningeal irritation, stiff neck, back pain, and back stiffness. Rapid and complete recovery Paralytic poliomyelitis: Occurs in 2% of persons infected. Characterized by asymmetric flaccid paralysis. Extent varies from case to case. Temporarily damaged neurons can regain function. Recovery can take six months. Paralysis persisting after this period is permanent. Polio vaccine essentially wiped out this infection. Two types of vaccine: Inactive form – developed by Jonas Salk Live attenuated form – developed by Albert Sabin.

FUNGAL MENINGOENCEPHALITIS – encountered primarily in immunosuppressed patients; blood – borne; brain involved late in the disease; Examples of fungi causing: Cryptococcus neoformans, Candida sp., Mucor sp., Aspergillus sp. and dimorphic fungi Three major patterns of fungal CNS infections: a) chronic meningitis b) vasculitis (thrombosis and infracts) – Mucor and Aspergillus c) brain parenchyma invasion (granulomas and abscesses) – Candida and Cryptococcus Deep fungal mycoses Cryptococcus neoformans and Coccidioides immitis. Primarily opportunistic. Usually seen in immunocompromised patients.

CENTRAL NERVOUS SYSTEM INFECTIONS

Cryptococcosisis the most important fungal CNS infection. Caused by Cryptococcus neoformans. Encapsulated form of yeast. Capsule production varies with the strain and environmental conditions. Found throughout world, especially in soil contaminated with bird droppings. Birds are not infected. Causes a chronic form of meningitis. Slow, insidious onset. Symptoms include low-grade fever and headache. Progresses to altered mental status and seizures. Infection usually seen in patients immunocompromised. Common in AIDS patients. Infection begins with inhalation of the yeast cells. After inhalation, yeast cells multiply outside the lungs and move into the nervous system. Initial symptoms can continue for weeks or months. Intermittent headache, dizziness, and difficulty with complex cerebral function. Later stages of the infection show: a. Seizures, cranial nerve damage, and papilledema (edema of the optic nerve) b. Dementia and decreased levels of consciousness c. Progression of disease is accelerated in patients with AIDS. Amphotericin B and fluconazole are effective. 75% patients with cryptococcal meningitis initially respond to treatment. Significant portion relapse when therapy is stopped. Patients with chronic infection require repeated courses. Residual neurological damage occurs in more than half of cured patients.

Cryptococcal meningitis. Cryptococcus neoformans often produces an indolent infection; its symptoms occasionally may extend back months or even years before the diagnosis is made. A debilitated state, immune incompetence or suppression, and diabetes mellitus are frequently associated conditions. Headache is the most common symptom, and mental deterioration may occur. Cranial nerve palsies and focal brain stem dysfunction secondary to arteritis can be prominent. The CSF is similar to that seen in persons with tuberculous meningitis. The fungus may be seen on India ink preparations and may grow in culture. Cryptococcal antigen can often be detected in the CSF, providing a valuable aid to the diagnosis. Treatment is with systemic and intrathecal (drug administration via an injection into the spinal canal or into the subarachnoid space) amphotericin B and 5-fluorcytosine. Rarely, other fungal infections (such as Coccidioides, Mucor, Candida, Actinomyces, Histoplasma, or Aspergillus) can present with chronic meningitis (usually in an immunocompromised host).

ACUTE POLYNEURITIS (Gullain-Barre syndrome) Inflammatory infection of the peripheral nervous system. Characterized by symmetrical paralysis. Can be caused by e.g. diphtheria toxin, enteric pathogens (Campylobacter), Lyme disease, Mycoplasma pneumoniae RTI, cytomegalovirus, and Epstein-Barr virus and other.

BRAIN ABSCESSES Brain abscesses are relatively rare. Cerebral abscesses are destructive lesions. Commonly formed by bacteria (Staphylococci and streptococci are the most common; other; GN rods, anaerobes) or fungi from a distant site – may arise from a variety of routes. Complications: spreading of microorganismsm to the subdural space causing subdural empyema, rupture of an abscess causing venous sinus thrombosis, meningitis etc. CSF indicators: CSF under increased pressure, WBC and protein increased, glucose normal.

TETANUS AND BOTULISM - affect the CNS in different ways. Produce exotoxins with an affinity for CNS tissue. Antibiotic therapy is ineffective once the exotoxin has been produced.

CENTRAL NERVOUS SYSTEM INFECTIONS