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Institute for Microbiology
Medical Faculty of Masaryk University
and St. Anna Faculty Hospital in Brno
Neuroinfections
Ondřej Zahradníček (with use of prof. Votava's
slideshows from 2011)
Lecture for 3rd-year students – Week 5
30th of October, 2015
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)

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)

Brain abscess
http://www.aic.cuhk.edu.hk/web8/Hi%20res/0286%20Brain%20abscess%201%20contrast.jpg
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 %
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)
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 seniors Streptococcus pneumoniae
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
Etiology of acute meningitis

Etiology of purulent meningitis by the age in %; result of a
study before start of vaccination against „Hib“
age
0–1 m.
1–4 y.
Group Haem. Neiss.
Str.
List.
other
B str. infl. b men.
pneu. mono.
50
33
70(↓)
15
10
10
5–29 y.
45
25
20
30–59
10
40
33
25
50
≥60 y.
15
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
impor- Group Haem. Neiss.
Str.
List.
other
tance B str. infl. b men.
pneu. mono.
lethality
†
†
†
†
+
+
sequels
+++
+
The most important causative agent
Neisseria meningitidis (meningococcus)
Classification
Gram-negative coccus
Pathogenicity Lethal meningitis, also others
Transmission Contact, short distance air transmission
Care about basic functions + antibiotics
Treatment
Pictures
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
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

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
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.

The worst situation is in Sahel
(south from Sahara, north from rain
belt“,
forest) „Meningitis
where
meningococccal
meningitis is
common
všechny obrázky: http://www.infektionsbiologie.ch
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

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)

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 (
) pilgrims
need get vaccinated against W135

www.baxter-ecommerce.com
Different serotypes in the world
http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/09vol35/acs-dcc-4/index-eng.php
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
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)
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

Meningococci
http://www.infektionsbiologie.ch
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

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)

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 prescholar children (meningitis, pneumonia,
epiglottitis)

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

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

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)

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
Meningitis in newborns
Typical causative agents of newborn
meningitides are Streptococcus agalactiae,
Listeria monocytogenes, but also Gramnegative 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.

Streptococcus agalactiae (SAG, GBS)

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

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
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.

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

Liquorologic differentiation –
purulent meningitis × „aseptic“ meningitis
sign
normal
purulent
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)
aseptic
meningitis
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
Quickly
available
– Culture: enriched media (chocolate agar)
– Strain identification (in meningococci even to serogroup
level, because of vaccination)

Interpretation: attention to skin contamination
(coagulase negative staphylococci)
CSF taking
http://www.infektionsbiologie.ch
So we have two quick methods:
1. CSF microscopy
We find big amounts of leucocytes, almost
polymorphonuclear neutrofiles
 In meningococcal meningitis we find Gramnegative 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

http://www.microbelibrary.org
2. Antigen analysis

Foto O. Z.
We use a set for CSF agglutination, that
enables the proof of the most frequent
agents
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 pneumoniae seniors
 Streptococcus agalactiae newborns
Typical age group is in green, but it is always
possible to find any of the pathogens!

Culture is important, but slow
Foto O. Z.
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
Treatment of purulent meningitis

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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)
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
Protection against professional
infection
Droplet infection is a danger
 mouthpiece + gloves
 antibiotics to contacts including medical
staff: V-penicillin for 7 days
 vaccination?
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.
 Chronical Mycobacterium tuberculosis, Nocardia,
fungi, some parasites (cysticercus of a tapeworm)
 Spirochetal infection (borreliosis, neurolues) are
more like viral infections
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
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

Borreliosis diagnostics

Direct diagnostics – not frequent
– Microscopy with use of dark field or
fluorescence microscopy
– Cultivation so difficult that not used in
practice
– Genetic methods developing
Nevertheless, basis is
 Indirect diagnostics – serology
– Indirect immunofluorescence
– Various variants of ELISA and Western
blotting.
– IgG and IgM antibodies not very sure
Borreliosis treatment

An important difference against viral
neuroinfections: we can use antibiotics (in
first stage penicillin or doxycyklin, in second
ceftriaxon or doxycyklin)
http://www.presse.uni-wuppertal.de/archiv/output/okt98/Borrelia.jpg
„Aseptic“ („sterile“) meningitis
meninges, become inflamed and a pyogenic bacterial
source is not to blame.
 diagnosis: characteristic symptoms and certain
examination findings (e.g., Kernig's sign).
 increase in the number of leukocytes present in the
cerebrospinal fluid (CSF), obtained via lumbar
puncture (but rather lymphocytes, not
polymorphonuclears)
 the term „aseptic“ would mean a lack of infection, but
many cases of aseptic meningitis represent infection
with viruses or mycobacteria
When CSF findings are consistent with meningitis, and
classical bacteriological testing is unrevealing,
clinicians typically assign the diagnosis of aseptic
meningitis—making it a relative diagnosis of exclusion.

Causative agents of „aseptic“
meningitis I
There exist many viral participating on this
disease, many of them are „arboviruses“ (=
ARthropod BOrne, belonging to more families)
Flaviviridae



virus of tick-borne encephalitis (Central European
and other subtypes)
West-Nile virus
Dengue fever virus (tropical countries)
Enteroviridae




Poliovirus
Coxsackieviruses
Echoviruses
Other enteroviruses
Causative agents of „aseptic“
meningitis II
Paramyxoviridae


morbillivirus (measles)
rubulavirus (mumps, CNS infection usually
asymptomatic)
Bunyaviridae

viruses Ťahyňa, Uukuniemi, Bhanja and many others
Alphaviridae


Viruses of equine encefalitides (west, east,
Venezuelan – WEE, EEE, VEE)
Viruses chikungunya and o‘nyong‘nyong
Herpesviridae


herpes simplex virus
varicella zoster virus
Causative agents of „aseptic“
meningitis III
Retroviridae
 virus HIV
Rhabdoviridae
 lyssavirus (lyssa / rabies)
And many other viruses
Non-viral agents
 prionic agents („mad cow disease")
 Mycobacterium tuberculosis
 Aspergillus sp.
 Cryptococcus neoformans
Encephalitis
Encephalitis is an acute inflammation of
the brain.
 Encephalitis with meningitis is known as
meningoencephalitis.
 Symptoms include headache, fever,
confusion, drowsiness, and fatigue.
 More advanced and serious symptoms
include seizures or convulsions, tremors,
hallucinations, and memory problems.

Most frequent agents
Virus of tick-borne
encephalitis (on
the picture)
 Virus of herpes
simplex
 Enteroviruses
 Mumps virus

http://vietsciences.free.fr/khaocuu/nguyenlandung/virus01.htm
Polioviruses
Poliomyelitis is already absent in many
countries, unfortunately, worldwide eradication
it still quite far away
 Nearly 95 % of infection were asymptomatic,
and only 1–2 % infections had the typical
paralytic form. Exceptionally degenerative
muscle atrophy occurred
 Vaccination is performed using living Sabin of
dead Salk vaccine
 Virus may be cultured on cell cultures
 Antibodies can be detected using CFT and
neutralisation test

Poliovirus
http://vietsciences.free.fr/khaocuu/nguyenlandung/virus01.htm
Poliomyelitis accuta anterior
www.bimcbali.com/polio-may-2005.asp.
http://www.henriettesherbal.com/eclectic/thomas/pics/poliomyel-2.jpg
Already in
old Egypt
polio was
present…
www-ermm.cbcu.cam.ac.uk/9900085Xh.htm.
Still not erradicated (2011)
http://www.scientificamerican.com/article.cfm?id=polio-timeline-milestones-erradicate
Diagnostics of viral neuroinfections
Direct diagnostics: Virus cultivation on cell
cultures and newborn mice; PCR
 Indirect diagnostics: Clotted blood for
antibody detection. Sometimes the laboratory
is able to prepare a packet „neuroviral
serology“ – without need of making list of
requested examination the serum is examined
for antibodies against the most frequent viral,
but also bacterial agents. Sending of acute
and later also reconvalescent specimen is
useful.

Treatment and prevention of
viral neuroinfections
Treatment varies with the cause. No specific
treatment available for most cases; supportive
therapy used (analgesics, anti-nausea
medications, intravenous fluids, prevention and
treatment of complications)
Specific prevention – e. g. vaccination against
Central European Tick Borne Encephalitis
(three doses, typical vaccination scheme: first
winter – Dose 1 and Dose 2, second winter –
Dose 3; there exist also shortened schemes
Polyradiculitis (Syndrome
Guillain-Barré)
Post-infection inflammatory process of
peripheral nerves (damage of axons and
myelin)
 Quick development of perception failures
and motoric weakness on lower extremities
 Lesion of head nerves
 Progression of respiratory failure
 Association with some infectious agents:
Borrelia burgdorferi, CMV, HIV, influenza and
Campylobacter jejuni

Polyradiculitis (polyradiculoneuritis):
Incidence and clinical description
Incidence
 USA: 4 new cases in a year for 100 000
persons (but maybe underestimated?)
Clinical description
 Usually a not serious respiratory or intestinal
infection in anamnesis
 Symmetric damage of peripheral sensoric
nerves and motoric nerves of lower extremities
 Later also upper extremities involved, and also
breathing muscles in 5–10% patients
Diagnostics
characteristic clinical picture
 CSF examination: elevated protein level
(>1,0 g/l) without WBC presence
 typical EMG finding
 positive antibodies against certain
infectious agents: EBV, CMV, HIV,
respiratory viruses, Borrelia burgdorferi and
Campylobacter jejuni

Treatment
Patients should be monitored to show
eventual ventilation failure in time (early
signs of head nerve disablement)
 Intensive or intermediary care
 Breathing assuring and artificial lung
ventilation
 High doses of immunoglobulins (i. v.)
 plasmaferesis (alternative treatment method)

Complications and prognosis
Complications
 Progression of pareses of head nerves,
respiratory failure, continuing residual
pareses
Prognosis
 Full recovery in 60% patients, lethality:
5–10%
Prionic diseases of CNS
Prions are „proteinaceous infectious particle“.
For prionic hypothesis Stanley Prusiner
obtained Nobel price for 1997
 They cause diseases known as transmissible
spongiform encephalopathias. This group
contains scrapie in sheep, „mad cow disease“
or bovine spongiform encephalopathia (BSE) in
cattle and Creutzfeld-Jakob disease (CJD) and
kuru in humans
 One of BSE variants may possibly lead to
CJD formation, but it is not sure.

Epidemiology, prevention, treatment
Because of possible transmission from
cattle there exist strict veterinary directives
concerning cattle breeding from farms with
BSE, but also altogether directions
(concerning farms with detected BSE, but
also global directions – ban of use of meatbone meal as food for cattle)
 Prionic particles are very resistant. It is
necessary to use prolonged exposition to
ensure sufficient sterilisation
 Treatment is in state of research

Thanks for your attention
http://vietsciences.free.fr/khaocuu/nguyenlandung/virus01.htm