Neurological Infections: A Comprehensive Overview

1. Institute for MicrobiologyMedical Faculty of Masaryk Universityand St. Anna Faculty Hospital in BrnoN e u r o i n f e c t i o n s Ondřej Zahradníček (with use of prof. Votava's slideshows from 2011) Lecture for 3rd-year students – Week 5 30th of October, 2015

2. Neurological infections • Damage of peripheral nerves (viruses of herpes simplex and herpes zoster) • Infections of central nervous system • Important are also infections that do not affect the neural system directly, but they occur e. g. between the skull and the brain; they may affect the CNS indirectly (by pressure)

3. Neurological and neurosurgical infections • Pyogene (= pus containing) inflammations of meninges (meningitides) – acute and chronical • Brain abscesses (formations with pus inside) • Basilar meningitis (on the basis of the skull, usually TB origin) • „Aseptic“, usually viral meningitis • Encephalitis (inflammations of the proper brain) • Abscesses and empyemas around meninges There exist also neurological diseases that are not infections, but they are related with previous infections (e. g. autoimmunity polyneuropathias)

4. Brain abscess http://www.aic.cuhk.edu.hk/web8/Hi%20res/0286%20Brain%20abscess%201%20contrast.jpg

5. Importance of central nervous system infections CNS infections are relatively rare, but they may have a very serious course Incidence • bacterial meningitis: 2/100.000/year • viral meningitis: 10/100.000/year Lethality • bacterial meningitis, non-treated: > 70 % • bacterial meningitis, treated: ~ 10 %

6. Pathogenesis of CNS infections Penetration of the microbial agent into CNS • From a peripheral focus: • by means of blood (meningococci) • per continutitatem (pneumococci or haemophili from the middle ear) • along nerves (HSV, rabies virus) • Directly: after an injury (pneumococci, staphylococci, nocardiae, aspergilli)

7. Acute purulent meningitis • Among all neuroinfections the treatment is the most urgent here. Renewal of life functions is primary, antibiotic treatment important, but secondary. • In newborns the main pathogen is Streptococcus agalactiae, Listeria, Enterobacteriaceae • In children 3–5 years formerly Haemophilus influenzae b, today less important because of vaccination (meningococcus is now „No. 1“) • In teenagers and young adults meningococcus = Neisseria meningitidis (petechias on skin!) • In seniorsStreptococcus pneumoniae

8. Clinical signs of purulent meningitis How does it look like • quick development of cognition failures (90 % of patients) • unconsciousness (different level according to scoring systems) • heavy septicaemia (sepsis and organ failure) What are the changes in the body • inflammation of meninges and oedema of brain • damage of brain cells by toxins • damage of haematoencephalic barrier • increased pressure in the intracranial cavity • disabled supply of brain by oxygen

9. Etiology of acute meningitis • Etiology of purulent meningitis by the age in %; result of a study before start of vaccination against „Hib“

10. Comparison of causative agents Importance of purulent meningitis according to etiology (lethality and sequels*) Sequels (or sequellae) = some existing damage in the body, although the infection is already absent

11. The most important causative agentNeisseria meningitidis(meningococcus)

12. Who isolated the meningococcus for the first time? • It was a women, very interesting lady, her name was Sarah Branham-Matthews (1888–1962) • In the beginning of 20th century it was not common for women to work in science • Her opportunity came with World War I (men went to the war). She started to teach bacteriology, and she did not give up after the war www.georgiawomen.com

14. http://www.waterscan.co.yu Clonal strains of Neisseria meningitidis • When meningococci cause meningitis, sepsis and other serious diseases, all that concerns so called clonal strains • Other strains are quite innocent and about ten percent of population has meningococcus in their throat

15. Why invasive meningococcal infection occurs only sometimes • An invasive infection is only possible when the strain is virulent enough (usually it means that it is one of clonal strains) and if host organism is receptive • Meningococcus can be transmitted by air to short distance and even better by direct contact. Invasive infection is supported by mucous membrane damage, e. g. by smoking or previous viral infection • Infection is often seen also when the body is week because of inappropriate physical activity following after previous inactivity

16. Where does it occur? • It occurs almost in pre-scholar children, teenagers and young adults • In some parts of the world the infection is more frequent than in Europe. Especially Africa, the region of so called meningitis belt • In Europe, there are individual cases, in Africa this disease causes much more deaths than e. g. Ebola.

17. The worst situation is in Sahel(south from Sahara, north from rain forest) „Meningitis belt“, where meningococccal meningitis is common všechny obrázky: http://www.infektionsbiologie.ch

18. Treatment • In is necessary to ensure patient‘s survival (to follow haemorrhagia and acidobasic equilibrium) • In the same time, antibiotics are administered • Drug of choice in meningococcal diseases is even now classical penicillin. Among other drugs it is also common to use one of 3rd generation cephalosporins (ceftriaxon – good access to the CSF), or other antibiotics

19. Prevention by vaccination • As the incidence is not high in Europe (although the lethality is), usually not the whole population, but just risk groups are vaccinated (soldiers, people in contact with a risky strain) • The problem exists with serogroup B, as its antigenic determinant is not a sufficiently strong antigen and so it is not possible to get a vaccine that would be sufficiently protective. Nevertheless, it is possible to protect people against some B serogroup meningococci (see later)

20. Vaccines • There are differences between them. Old polysaccharide vaccines give less protection than new conjugated vaccines • There exist also difference in serogroups (C only, A + C or tetravaccine A + C + W135 + Y) • B and C are the most common types in Czechia, but e. g. Mecca hajj (حجمكة‎) pilgrims need get vaccinated against W135 www.baxter-ecommerce.com

21. Different serotypes in the world http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/09vol35/acs-dcc-4/index-eng.php

22. Polysaccharide and conjugated vaccines • Still in use, there exist bivalent* or tetravalent** polysaccharide vaccines against meningococcal groups A and C or A, C, Y + W135. There is short „immunological memory“ for them. • This problem is solved by modern conjugated vaccines. Recently, in Europe almost monovalent conjugated vaccines against C meningococcus are used. All vaccines are highly immunogenic and safe. * = functioning against two serogroups ** = functioning against four serogroups

23. Vaccine against B group meningococci • High similarity between capsullar polysaccharide of B type and human tissue causes impossibility to prepare a protective vaccine • Nevertheless, by cultivation in liquid media meningococci release vesicles (outer membrane vesicles), and those enable preparation of a soluble and safe vaccine. • The problem is that these OMPs (outer membrane proteins) are very variable, it is still impossible to make a vaccine protecting globally against B group. There exist only vaccines against individual strains (only for Cuba and New Zealand)

24. Available vaccines (Czechia) • MENINGOCOCCAL POLYS. A+C VACCINE – polysaccharide • MENJUGATE – conjugated (C) • MENVEO – conjugated (ACYW) • NEISVAC-C – conjugated (C) • MENPOVAX A+C – not available recently

25. Meningococci http://www.infektionsbiologie.ch

26. Haemophilus influenzae ser. b (Hib) • Hemophili are short Gram-negative rods. Meningitis is less common now in Europe and other countries because of vaccination. Nevertheless, not all children are vaccinated • Meningitis is just one of invasive infections caused by haemophili – other are epiglottitis, pneumonia etc. www.4to40.com/health/print.asp?id=13

27. Treatment of meningitis caused by a Haemophilus • Although haemophili are typically susceptible to amoxicillin or amoxicilin + clavulanic acid (AMOKSIKLAV, AUGMENTIN), these drugs are rather used for respiratory infections caused by haemophili, not meningitis • As we need to ensure sufficient concentrations in the CSF, we rather use again ceftriaxon (ROCEPHINE)

28. Vaccination against „Hib“ • The vaccine protects against Haemophilus influenzae, capsular type b • The vaccine is purified polysaccharide • Usually it is used in a combination • After implementation several years ago there was an important decrease of haemophilus invasive infections in pre-scholar children (meningitis, pneumonia, epiglottitis)

29. Available anti-Hib vaccines (CZ) • INFANRIX HEXA (diphtheria, tetanus, whooping cough, Hib, viral hepatitis B and polio – dead virus) • INFANRIX-IPV+HIB and PEDIACEL (both are the same, except B hepatitis) • INFANRIX HIB (the same, except B hepatitis and polio) • ACT-HIB(only Hib, not available now) The situation changes quickly, and it is different in different countries

30. Streptococcus pneumoniae – „Pneumococcus“ • Streptococcus pneumoniae causes meningitis mostly in seniors, but it does not mean that it would not cause it in small children and other patients This bacterium is normally present in pharynx of healthy persons, but it also causes pneumonia, sinusitis, otitis media, sepsis, and also meningitis

31. Treatment and prevention of pneumococcal meningitis • Treatment again uses suitable antibiotics with good access to the CSF • Prevention is possible by vaccination. In Czechia, this vaccine is not compulsory (like some other vaccines), but it is covered by health insurance (for Czech children)

32. Available vaccines • Polysaccharide vaccine (rather for adults, e. g. patients endangered by the infection) • PNEUMO 23 (23 serotypes) • Conjugated vaccine (prolonged immunological memory and better immunity response in persons with less developed immunity, including children < 2 years) • Prevenar (7 serotypes) • Prevenar 13 (13 serotypes) • Synflorix (10 serotypes + Di-Te-Pe*) Frequently used abbreviation for „diphteria – tetanus – pertussis

33. Meningitis in newborns • Typical causative agents of newborn meningitides are Streptococcus agalactiae, Listeria monocytogenes, but also Gram-negative rods, almost members of Enterobacteriaceae family. • Enterobacteriae would be the most important especially in nosocomial infections, where the source of the infection is in the hospital. The treatment would be here very complicated due to resistant strains.

34. Streptococcus agalactiae(SAG, GBS) • GBS = SAG (Group B streptococcus = group B according to Lancefield = Streptococcus agalactiae) • Commonly asymptomatic in vagina, sometimes pathogenic in vagina or urinary bladder • Meningitis usually has a form of a late newborn infection (4th day and later). It has incidence 0,5 / 1000 children. Other infections caused by this bacterium (sepsis, pneumonia) start rather earlier. • Often preterm born children

35. Listeria monocytogenes • The infection may be both congenital (during pregnancy, through placenta)and neonatal (through vagina during delivery) • Here, too, the disease may be asymptomatic. • Usually after five days purulent meningitis, is seen, similar to that of S. agalactiae. Other serious infections may occur, too. • The microbe is find during normal cultivation. • For treatment, high dose of ampicillin is recommended. Cephalosporins are not effective.

36. Examination in purulent meningitis • At suspicion for meningitis it is necessary to follow signs of infection. Patient should be quickly transported to a suitable institution (in Czechia typically an emergency unit of an infectology clinic). • It is also recommended to take blood and CSF for biochemical examination. We check acidobasic equilibrium, bleeding etc. • CSF (and eventually blood) is also sent to microbiology

37. sign normal purulent meningitis aseptic meningitis cells 0–6/μl ↑↑↑ (>1000) ↑↑(100–500) proteins 20–50 mg/100 ml ↑↑ (>100) ↑ (50–100) glucose 40–80 mg/100 ml ↓ (<30) ~ (30–40) Liquorologic differentiation – purulent meningitis × „aseptic“ meningitis

38. Bacteriological diagnostics of purulent meningitis • Specimen: CSF (When taking it, measure CSF pressure and look at the macroscopical appearance) • After admission to the lab: • Microscopy (search for WBCs and bacteria) • Direct detection of antigen in CSF specimen • Culture: enriched media (chocolate agar) • Strain identification (in meningococci even to serogroup level, because of vaccination) • Interpretation: attention to skin contamination (coagulase negative staphylococci) Quickly available

39. CSF taking http://www.infektionsbiologie.ch

40. So we have two quick methods:1. CSF microscopy • We find big amounts of leucocytes, almost polymorphonuclear neutrofiles • In meningococcal meningitis we find Gram-negative cocci in pairs. Intracellular position is common • In Haemophilus meningitis they would be short G– rods, in pneumococcal meningitis or the one caused by S. agalactiae G+ cocci in pairs or short chains

41. http://www.microbelibrary.org

42. 2. Antigen analysis • We use a set for CSF agglutination, that enables the proof of the most frequent agents Foto O. Z.

43. Antigens detectable at CSF agglutination • Neisseria meningitidis A • Neisseria meningitidis B teenagers, children • Neisseria meningitidis C • N. meningitidis Y/W135 • Haemophilus influenzae b children (sooner) • Streptococcus pneumoniaeseniors • Streptococcus agalactiae newborns Typical age group is in green, but it is always possible to find any of the pathogens!

44. Culture is important, but slow Meningococci can be cultured more easily than gonococci, but less easily than oral neisseriae. They grow not only on chocolate agar, but also rich variants of blood agar Foto O. Z.

45. Treatment of purulent meningitis • ensuring a venous port • keeping function of breathing (laryngeal mask, intubation, oxygen, artificial lung ventilation) • antioedema treatment (manitol) • quick, but regardful transport to the hospital (emergency unit) • antibiotics • putting down of intracranial pressure (ICP) by aggressive treatment – controlled hypokapnia • kortikosteroids (dexamethason) – important decrease of audition damage in meningitis caused by Haemophilus influenzae b in children and also lethality of pneumococcal meningitis in adults • anticoagulation preparations against DIC (disseminated intravascular coagulopathia)

46. Treatment of an invasive meningococcal infection • assured transport – venous port, airways etc. • penicillin already during transportation • specialized emergency unit • quick diagnostic (sepsis × sepsis + meningitis × meningitis only? Sometimes hard to judge) • 10% lethality even today

47. Protection against professional infection Droplet infection is a danger • mouthpiece + gloves • antibiotics to contacts including medical staff: V-penicillin for 7 days • vaccination?

48. Other non-viral neuroinfections: may be also invazive, but do not endanger life accutely Chronical meningitis • Much less frequent than acute meningitis, caused by Mycobacterium tuberculosis(meningitis basilaris), eventually fungi – Aspergillus, Cryptococcus neoformans Brain abscessi • Accute: mixed aerobic/anaerobic flora – staphylococci and streptococci. • ChronicalMycobacterium tuberculosis, Nocardia, fungi, some parasites (cysticercus of a tapeworm) • Spirochetal infection (borreliosis, neurolues) are more like viral infections

49. Borrelia neuroinfections Borreliae are spirochets Character of CNS infections rather similar to viral infections (no pus, less acute) Borrelia burgdorferi sensu lato = species in „larger sense“. It contains several tick-borne species in „narrower sense“. All of them are causative agents of Lyme disease (starts with erythema migrans, later arthritis / CNS infection – neuroborreliosis) Most important:Borrelia burgdorferi sensu stricto, B. garinii and B. afzelii. In Europe we see almost B. garinii + B. afzelii

50. Neuroborreliosis – clinically • Chronic neurologic symptoms – up to 5% of untreated patients. • Shooting pains, numbness, and tingling in the hands or feet may develop. • Lyme encephalopathy: subtle cognitive problems, (difficulties with concentration and short-term memory, profound fatigue) • Many other symptomas may occur in chronical neuroborreliosis Among spirochetal diseases, syphilis may also have neurological complications – neurolues (neurosyphilis). It is a part of 3rd stage syphilis, today uncommon