Bakteri, Virus dan Jamur Penyebab Infeksi Otak

Andi Yasmon, Beti Ernawati Dewi, T Mirawati, CR Tjampakasari, Agus

Sjahrurachman
Department of MicrobiologyFKUI
2012
 C Mims, et al. Medical Microbiology 3rd ed. Mosby,
Edinburg, 2004, 323-341.

JK Struthers and RP Western. Clinical Bacteriology, ASM

Press, Washington DC, 2003, 115-128

SJ Flint, et al. Principles of Virology : Molecular Biology,

Pathogenesis and Control, ASM Press, Washington DC,
2000, 595-628.

Abigail Walker and Miles Denton. Central Nervous System

Infections.
http://homer.myftp.org/eBooks/Neurocritical%20Care/05
%20CNS%20Infections.pdf
 Brain
Spinal Cord
Neuron
Defenses
* Meninges
* Cerebrospinal fluid
* Bone casing
* Blood brain barrier
*Immunologically privileged
Figure 2. Structure of the brain and spinal cord
that provide defenses
 Nervous System Defenses
* Nervous system
- Central Nervous System (CNS)
- Peripheral Nerves
* Normal Flora

Nervous System Diseases

Figure 1. Diagram of Central Nervous system

and peripheral nerves
 Absent
Viruses can exist in a dormant state in the Nervous system
 Meningitis
Neonatal meningitis
Meningoencephalitis
Acute encephalitis
Sub-acute encephalitis
Rabies
Poliomyelitis
Tetanus
Botulism
African sleeping sickness
Prion, Virus, Bacteria, Fungus, Protozoa, Nematode, Intoxication,
Medication, SOL, Systemic illness

Meningitis
Encephalitis
Cerebral Abscess
Subdural Empyema
Ventriculitis
Intracranial Epidural Abscess
Myelitis

Acute, chronic, sub-acute

1. Passing through Blood brain/spinal barrier
Passive transfer through intracellular vacuoles carried by leucocytes
Replicate in stroma of the barrier and penetrate into CNS
2. Invasion through axon
 CSF
Direct spread from
adjacent structures Cerebral blood vessel
( eg mastoid )
Choroid flexus
blood vessel

Ventricle

Ependymal
cells

Nerve ending

Meningeal blood vessel

 Positive Gram Bacteria:
* Streptococcus pneumoniae
Nervous System Diseases:

* Group B Streptococcus
* M tuberculosis
* Listeria monocytogenes
* Staphylococcus aureus

Negative Gram Bacteria:

* Haemophilus influenzae *Pseudomonas
* Neisseria meningitidis * Salmonella
* E.scherichia coli * Proteus
* K pneumoniae * Bacteroides
* Enterobacter * Acinetobacter
* Citrobacter
 Bacterial attachment & colonization

Local invasion

Bacteremia

Choroid flexus epithel and vascular endothel

Vascular thrombosis Cell injury and meningeal invasion

Increased BBB Bacterial replication & inflamation in the SAS

permiability
CSF outflow resistance
Increased Cerebral vasculitis
Hydrocephalus
CSF prot
Vasogenic edema Cytotoxic edema Interstitial edema Cerebral infraction

Decreased blood flow Increased intracranial pressure

Cerebral hypoxia Encephalopathy

Decrease CSF glucose Anaerobic glycolysis Increased CSF lactate CSF acidosis
Events
Attachment & Colonization
Replication & Local invasion
Bacteremia
Replication at circulation
Meningeal invasion
Meningeal inflamation
Cerebral edema
Increased intracranial pressure
Symptoms
None
URTI
None or non specific symptoms
Non or non specific symptoms
Non or headache, irritable, back pain
Irritable, Kernig sign, Nerve palsy, stiff neck
Convulsion, photophobia, comatous
Buldging fontanelle, papilla edema, severe headache
 REPLICATION OF THE VIRUS AT PORT DENTRE
( GI : Enterovirus ; oropharynx : mumps; Genital : HIV,HSV ; Circulation : arbovirus )

Viremia , ascending route via axon

CNS infection
FAMILY VIRUS

Togaviridae Kunjin, Ross River, Rubella, WEE,EEE,VEE

Flaviviridae JE, MVE, Dengue, Powasan, SLE
Paramyxoviridae Mumps, Parainfluenza, Rubeola
Myxoviridae Influenza A and B
Picornaviridae Polio, Coxsackie A & B, Echovirus, Enterovirus
Rhabdoviridae Rabies, Vesiculovirus
Retroviridae HIV 1 & 2 , HTLV 1 & 2
Herpesviridae HSV 1&2, VZV,EBV,HCMV,HHV6, B virus
Adenoviridae Adenoviruses

VIRAL CAUSES OF MENINGITIS AND MENINGOENCEPHALITIS

AGENTS EXAMPLES
Bacteria H influenazae, S pneumoniae, N meningitidis, M tuberculosis, etc
Viruses Enterovirus, herpesvirus, flavivirus, togavirus, etc
Fungi Cryptococcus sp, histoplasma sp, aspergillus sp , etc
Rickettsia Rickettsia sp, Coxiella sp, Erhlichia sp
Protozoa Acanthamoeba,Toxoplasma, Paragonimus, etc
Nematode Trichinella sp, Taenia sp, Angiostrongylus sp, etc
Systemic illness SLE, Sarcoidosis, RA, Sjorgen syndrome, etc
Medication NSAID, immunoglobulin,antibiotic( cotrimoxazole/ciprofloxacin ), etc
Malignancies Leukemia,cyst, medulloblastoma, etc
Intoxication Heavy metal
Onset
Age of the patient
Epidemiological factors
Underlying conditions or previous illness
Physical examination
Gram stain of CSF

Strategy of empiric therapy

Etiologic agents of bacterial meningitis by age group

H influenzae
L monocytogenes
Group B Sreptococci
N meningitidis
S pneumoniae
Others

0-1 mo 1 mo-5 y 5-29 y > 29 y

US 1986
Neonate E coli, SHBG, Listeria, HSV-2
< 2 mos SHBG, Listeria, E coli
< 10 year Virus, H influenzae, Pneumococcus, Meningococcus
Young adult Virus, Meningococcus
Adult Pneumococcus, Meningococcus,Gram negative bacilli
Elderly Pneumococcus, Listeria, Gram negative
 FACTORS ETIOLOGIC AGENT
Summer session Coxsackievirus, Echovirus
Rainy session Leptospira, arboviruses
Nosocomial infection Gram negative bacteria, S aureus, Candida sp
Twin infection Meningococcus, H influenzae
Swimming at lake Amoeba
Contact with mice LCM virus
Contact with rodents Leptospira
Contact with Tb patients M tuberculosis
Uncooked meat Nematode
Contaminated food L monocytogenes, Salmonella
Serous type
Upper respiratory tract infection Virus, H influenzae, Pneumococcus, Meningicoccus
Pneumonia Pneumococcus, Meningococcus
Sinusitis Pneumococcus, Meningococcus, Anaerob
Otitis Pneumococcus, H influenzae, anaerob
Cellulitis Streptococci, Staphylococci
Brain abcess Anaerob, Staphylococci
Closed skull fracture Pneumococcus, Gram negative bacilli,SHGA
Open skull fracture Gram negative bacilli, Staphylococci.SHGA
Otorheae CSF Penumococcus, Gram negative bacilli,Staphylococcus, H influenzae
Diabetes mellitus Pneumococcus,Gram negative bacilli,Staphylococci, Cryptococcus
Alcoholism Pneumococcus
Steroid therapy Cryptococcus, M tuberculosis
Leukemia/lymphoma Pneumococcus, Gram negative bacilli, Cryptococcus,M tuberculosis
Immunocompromised Pneumococcus,N meningitidis, L monocytogenes, gram negative
bacilli, Cryptococcus
 Fever, neck stiffness, Kernigs sign, headache

Maculopapular rash Enterovirus

Vesicular rash Herpesvirus
Ptechiae-purpura Meningococcus
Bullneck Mumps
Biphasic fever Enterovirus
 Diseases onset
Acute :
Symptoms and signs develop within 24 hours
Progressive
Pyogenic bacteria
Subacute
Symptoms and signs develop in 1-7 days
Virus, pyogenic bacteria,leptospira, M tuberculosis, fungi, SOL
perimeningeal
Chronic
Symptoms and signs last > 4 weeks
Fungi, M tuberculosis, syphilis, Toxoplasma, Brucella, Nematode,
etc
 Laboratory Investigestion
Specimen :
CSF or abcess aspiration, aseptic technique, as much as possible
Divide into 3 tube : cell, microbiology, chemistry-serology
Proper label : identity, antimicrobial given, information on specimen,
type of investigation
Transport to lab, incubate at 35 C.

Microbiological investigation :
1. Gram/Giemsa/Methylen blue staining
2. Isolation and identification of etiologic agent
2. Antigen/nucleic acid detection
3. Intrathecal antibody synthesis
 CELLULAR AND CHEMICAL
EXAMINATION OF CSF
Purulent meningitis :
Turbid, PMN 100-2000 ( protein 0.5-3 g/l, Glucose 02-2 mmol/l )
Bacterial/amoebal meningitis, ruptured brain abcess
Aseptic meningitis:
Clear, Limphocyte 15-500 ( ptotein 0.5-1 g/l, glucose 0.5-1 mmol/l )
Viral/leptospiral/tuberculosis meningitis, brain abcess, encepalitis.
BACTERIAL MENINGITIS ON TREATMENT COURSE )
Tuberculosis:
Clear ( plus fibrin web ), limphocyte 30-500 ( protein 1-6 g/l, glucose
< 2.2 mmol/l )
Tuberculosis/cryptococcus meningitis, brain abcess
 VALUE OF CSF FINDINGS IN PREDICTING THE
MOST LIKELY CAUSES

Type Dominant cell Glucose Stain Other test

Becterial PMN < 50 %1 Gram Culture,PCR,EIA
Tuberculous Lymphocyte <50 % Z-N Culture,PCR
Fungal Lymphocyte Low India ink Culture,Ag,Ab
Viral Lymphocyte Normal - Culture,PCR
Carcinomatous Lymphocyte Very low Cytology
 MICROBIOLOGY OF MENINGO -
ENCEPHALITIS

Encephalitis may occur at any age but most often affects

children and young adults
Viruses cause the great majority of encephalitis
Most patients have no symptom or only mild illness. A minority
of patients develop classic clinical features :
Drowsiness, confusion, personality changes, headache,
localized CNS signs and coma in severe cases.
Regeneration of CNS is poor. Be aware of late sequelae
i.e : emotional instability, locomotor disbility, lost of
memory, loss of intelectual ability
 ETIOLOGIC SPECTRUM OF ENCEPHALITIS
OTHER CAUSES CEREBRITIS
ACUTE ENCEPHALITIS
Herpes simplex virus Meningococcus
Mumps Pneumococcus
Sterptococcus
Varicella Zoster virus
Anaerobes
Epstein-Barr virus Gram negative bacilli
Rabies Legionella
Japanese B encephalitis virus Leptospira
Herpes simian B virus Treponema
Coxsackie A and B Coxsiella
Echovirus Rickettsiae
Toxoplasma
Poliovirus
Plasmodium
Enterovirus
Trypanosoma
Murray Valley Encephalitis virus Amoeba
West Nile virus Cryptococcus
EEE,WEE,SLE, etc Histoplasma
Taenia
Trichinella, etc
Rubella, HSV,CMV
 Clostridium tetani : TETANUS

Gram stain, drumstick

Photo collection of Dept
of Microbiology FKUI

Peritrichous flagella, obligate anaerobe

Toxigenic and non-toxigenic strain
Toxin : Tetanospasmin (lethal dose 130g) and
tetanolysin
 Pathogenesis

Trauma to host tissue contamination with

C.tetani
Tissue damage oxidation-reduction
potential growth is initiated
Organism is confined to the necrotic tissue
and elaborate the lethal toxin that invades
systemically
Incubation period : infectious dose and the
site of the wound (4-5 days many
weeks)
 Clostridium tetani : TETANUS

Toxin binds to receptors on the

presynaptic membranes of motor
neurons It blocks release of
inhibitory glycine and -aminobutiric
acid. Negative signal is inhibited
spasms of voluntary muscles
hyperreflexia, spastic paralysis.
 Clostridium botulisme :
BOTULISM
A strain produces only one of seven similar neurotoxin
types
Pathogenesis :
Food Poisoning
Ingestion of toxin in improperly preserved food
Wound Botulism
Growth of C.botulinum in the necrotic tissue of a
wound
Infant Botulism
Organism grows and produces toxin in the
intestinal of infants
 Clostridium botulinum toxin
The toxin travels through the blood and lymphatic
system and fixed to cranial and peripheral nerves
It binds to receptor sites at the neuromuscular junctions
of parasympathetic nerves
It interferes with the release of acethylcholine, a
transmitter substance
It prevents impulses from passing from motor nerves to
parasympathetic nerves
 Clostridium botulisme :
BOTULISM
Toxin muscle paralysis, cranial descending ,
symmetric paralysis of motor nerves flaccid
paralysis

Symptoms : begins 18-24 hours after ingestion

Cranial nerves problems with eyesight,
hearing, speech
Descending paralysis with critical involvement of
the respiratory
Death : respiratory/cardiac failure (type A, E, B)
 Photo collection
Dept of Microbiology, FKUI

Neisseria meningitidis

A Gram-negative intracellular diplococcus

13 serogroups, most important : A, B, C, Y, and W-135
Normal oropharyngeal flora in 5-15% of healthy adults
and children
Higher carriage rates : in crowded or closed populations
(boarding schools, military camps)
Transmission : respiratory route through nasopharyngeal
secretion
Exposure to pathogenic strains most often leads to a
carrier state, but not always to active infection
 Pathogenesis
Portal of entry : nasopharynx. Attach to epithelial cell with
the aid of pili
Incubation period : 1 3 days
Adherence (the PilC molecule and the OMPs Opa and
Opc), colonization, and invasion (capsular
polysaccharide, expression of Opa)
Play a role : Host genetic factors and cofactors (passive
smoke, concurrent infection in upper respiratory tract)
Protective factors of host : complement system, specific
IgG and IgM
 Pathogenesis
Meningococcal endotoxin ........ meningococcal sepsis
Production of cytokines (TNF-, IL-1, IL-6, IFN-),
results in increased endothelial permeability,
myocardial depression, hypotension. Damage of
vascular results in petechial or purpuric skin lessions
(multiple organ failure shock)

Production of prostaglandins, leukotrienes, platelet-

activating factors enhance granulocytic function and
intravascular clotting and trombosis disseminated
intravascular coagulation, adrenal hemorrhage,
decreased vascular resistance, circulatory collapse,
death
 Clinical Features
Sore throat,
Headache, and rapidly progressing within
several hours to drowsiness
Signs of meningitis (irritability, Fever, Neck
stiffness, Kernigs sign,Coma)
 Diagnostic
Laboratory Tests
Specimens :
blood for culture
spinal fluid for smear, culture, and chemical
analysis
Nasopharyngeal swab : carrier surveys
Puncture material from petechiae for smear
and culture

SEND AT ROOM TEMPERATURE

CULTURE WITHIN 1 HOUR
 Gram-stained smears :
typical neisseriae within polymorpho-nuclear
leucocytes or extracellulary

Culture :
on chocolate agar (heated blood agar),
Thayer Martin agar with antibiotics vancomycin,
colistin, amphotericin), 370C with 5% CO2

Further identified by carbohydrate fermentation

reaction and agglutination with type specific
or polyvalent serum
 Prevention
A quadrivalent vaccine for meningococcal serogroups A, C, Y, and
W-135 is available. The serogroups B is poorly immunogenic in
human, a candidate vaccine has been created from some of the
outer protein surface

Vaccine protection decreases over time and more rapidly in young

children

Vaccine is recommended in the high risk group :

Complement deficient hosts (C3, C5-9)
Asplenic individuals
Travelers to endemic areas
Research or laboratory personnel
Military recruits

Close contacts of meningococcemia : rifampicin 10 mg/kg every

12 hours for 2 days or ceftriaxone, or Meningococcal vaccine.
 Mycobacterium tuberculosis

Characters of M. tuberculosis ---- refer to

respiratory module
Infection of M. tuberculosis in the CNS:
- Tuberculous meningitis (more common)
- Tuberculous brain abscess,tuberculoma,
myelopathy, radiculopathy (rare)
Pathogenesis
Tuberculous meningitis (TBM)
Clinical manifestation : gradual, 3 stages
Stage I (prodromal phase)
- lasting for weeks to months
- feverishness, malaise, anorexia, irritability,
headache, backache, infrequent vomiting.
- rare case may undergo spontaneous involution
- great majority advance to stage II
 TBM clinical manifestation
Stage II
Neurological signs;
- Progressive headache, lethargy, personality
changes, disturbed memory, impaired cognition,
confusion
- Fever
- Basilar arachnoiditis signs: meningismus,
cranial nerve defects, e.g. strabismus.
- Focal seizures
 TBM clinical manifestation

Stage III
- Stupor-coma
- Hydrocephalus, intracranial hypertension,
vascular thrombosis
- Treatment starts at this stages, if survive,
the patient often have residual deficits
 Diagnosis
Clinical manifestation
LCS analysis : cells, protein,
glucose
AFB microscopy
Culture
PCR
CT Scan, MRI
 Japanese
encephalitis
Geographic distribution : Russia, Asia, Australia
Epidemiologic pattern :
Sporadic ( occasional cases, widely distributed in
time and place ) Japan, Taiwan,Sri Lanka,
Indonesia, Singapore, Malaysia, Korea,The
Philippines, Myanmar
Regional, seasonal outbreaks ( May-September, April-
October in warmer area; follow migratory pattern of
avian hosts ) : Thailand, Nepal, India, Sri Lanka
 Japanese
encephalitis
Reservoir : pigs, wading birds and ducks ( herons, egrets, pigeons,
swallows ), horse, bovines, mules and donkeys, Goat and
sheep,bats.
Vectors : The virus has been recovered from 30 species mosquitos
belonging to : Culex, Aedes, Mansonia and Amergeres
Cx trtaeniorhyncus, Cx gelidus, Cx vishnui, Cx
pseudovishnui, Cx fusocephala are the main vectors
An annularis, An subpictus, An agus, M annulifera, Cx
epidemus, Cx whitmorei were also implicated in
some countries
 NATURAL CYCLE
Mosquito
Man
Mosquito
Horse

Mosquito

Transovarial cycle

Pigs
Wading birds & ducks

Viral amplification
 PATHOGENESIS
Mosquito bites

Local replication
Disease spectrum
Replication in lymph node Subclinical
FUO
Viremia
Encephalitis

Transport through endotel Disease severity

Age
CNS Genetic factors
Other infections ?
 Clinical Features
INCUBATION TIME : 5-16 days
PRODROMAL STAGE ( 1-14 days ):
High fever, acute onset
Rigors
Headache, severe either frontal or
generalized
Nausea and vomiting
SEQUELAE : Mental imparment, emotional
instability, paralysis
 Clinical Features
ACUTE ENCEPHALITIC STAGE
Altered sensorium ( clouding of consciuosness, excitement,
disorientation, stupor, coma )
Convulsion, muscular rigidity, mask-like face, abnormal
movement, nuchal rigidity
High fever
Leucocytosis
LATE STAGE ( slow recovery )
SEQUELAE : Mental imparment, emotional instability, paralysis
 Laboratory Diagnosis
SPECIMENS :
Serum : Taken ASAP in the acute stage and 2-4 weeks later
CSF : Collect at acute stage ( virus isolation ) . Store and transport at 40 C
Brain tissue : Cortex, cerebellum, basal nuclei and brain stem. Immersed in
10 % glycerol saline. Transport in dry ice or liquid nitrogen
METHODS
IgM anti JBE detection in CSF by Elisa test
Fourfold rise of antibody in the acute & convalesecent sera by HI test
Viral isolation from brain tissue , blood/CSF ( only at early stage ) using
mosquito, cell cultures
Antigen detection from brain tissue by FA /immunoperoxidase test
Genome detection from brain tissue, CSF and blood ( 1-2 days from fever
onset ) by PCR
 Management
CASE TREATMENT : SYMPTOMATIC-SUPPORTIVE
INDIVIDUAL PREVENTION
Immunization
Avoidance of mosquito bite
DISEASE CONTROL :
Vector control
Aerial ULV application of insecticide
Water management in irrigated rice fields
Use of insecticide to control agricultural pests
Selection varieties of rice with minimum water requirement
Use of larvivorous fish
Other enviromental manipulations such as sorce
reduction by drainage, filling and weeding Pig rearing
regulation
 Immunization
1. Inactivated mouse-brain derived
Lyophylised and liquid preparation.
(Once reconstitued, vaccine should be used immidiately.
Discrad the rest)
Schedule : 6 months of age and 7-14 days later for primary
immunization. The third dose given several month later (
before 1 year of age )
Booster after 3 year
Vaccinees should be observed for 30 min after injection and
warned about possibility of delayed urticaria and
angioedema of the head and respiratory tract . Person with
allergic history appear to have a greater risk for developing
adverse reactions
 Immunization
2. Inactivated Primary hamster Kidney Cell-derived vaccine
Schedule : 6 months of age and a week later fro primary
vaccination
Booster at six to ten years of age
Adverse reaction less than SMB derived vaccine
3. Live attenuated vaccine
Schedule : 1 year of age and 2 year of age for primary
immunization
Booster at six years
Adverse reaction less than SMB drived vaccine
 INDICATION OF JE VACCINATION

Children living in endemic area.

Primary immunization is indicated between 1 and 2 years of age
More effective when given at inter epidemic periods
Expatriates working in endemic area
Travelling to endemic area for more than 30 days
A 3 doses of smb-derived vaccine @ 1 ml on days 0,7 and 30 or
0,7 and 14. The last dose should be administered at least 10 days before
travelling
Research laboratory workers
 RABIES
Family : Rahbdoviridae
Genus : Lyssaviurs
Virus characteristic : Bullet shape O 70-85 nm &
130-380 nm length, Enveloped virus with helical
nucleocapsid containing ss RNA
Reservoir : Dogs, Cats, Raccoon, Skunks,
Foxes, Ferrets, Other carnivores. Bats. (Rabbits,
Hares, Woodchucks, Beavers )
 RABIES
In animal : Rabies produce encephalitis and
thereafter the virus spread down to other organs.
Incubation time : 14-180 days. Viral shedding in saliva
start 3-6 days before visible symptoms ( Rabies
transmission to human from apparently normal dogs
for min 10 days has not yet been reported ) .
No of virus in the saliva varies. Transmitted to human
by bites, scratches by claws, inoculation into cornea.
Aerosol transmission occur at bats cave and
laboratories
Human to human transmission theoritically possible
but occurs rarely,if at all ( Saliva and tracheal
secretion contain rabies virus )
 ANIMAL SUSCEPTIBILITY TO RABIES
Susceptibility of species
Very high High Moderate Low
Foxes Hamsters Dogs Opossums
Coyotes Skunks Sheep
Jackals Raccoons Goats
Wolves Cats Horses
Cotton rats Bats Nonhuman
Rabbits primates
Cattles
 PATHOGENESIS
Virus
inoculation

Multiply in
strated muscle

Ascends through
neuron

Brain

Destruction
escpecially
in brainstem
& medulla
 RABIES
Incubation period : 1-2 months ( 7 days to 6 years, speed of movement of the virus
in the neuron 3mm/ day ). Depending upon wound site, amount of inoculated virus
and virus strain
Prodome phase :
Local sensory symptoms ( paresthesia, itching, burning ) at site of wound in
1/3 of cases. Last for few hours to few days
Acute neurological phase :
Furious rabies :Fever, hyperreactivity to internal and
external stimuli ( aero & hydrophobia )., fluctuating conciousness,
spontaneus inspiratory spasms, autonomic dysfunction ( hypersalivation,
non reactive pupils). Hallucination & seizures are rare.
Generally die within 7 days
Paralytic rabies:
Fever, urinary incontinence, weakness of muscles ( facial, pharyngeal and
respiratory ). Generally die within 13 days.
 Treatment & Prevention
Treatment :
Interferon and high dose rabies immunoglobulin only prolong the course
Recovery from symptomatic rabies is extremely rare. CFR of bitten rabied animals 35-
37 % , depending on severity of wound and virus content of saliva
Prevention
Active immunization with rabies vaccine . Given to person at risk : veterinarians,
lab workers, apelunkers and traveller to rabies-endemic area
Avoids wild animals, animals with unusual behavior, vaccination of all domestic
animals
Post exposure prophylaxis :
1. Local wound care. Clean thewound with soap and water for at least 10 min.
Aplly virucidal antiseptic such as povidone iodine
2. Passive immuniation. HRIG 20 IU/kg with as much as possible infiltrated into
and around the wound. The rest is given im at distant site. Effective given
within 7 days after bites
3. Active immunization
 Enteroviruses
Family Picornaviridae
Genome : Single strand RNA, linear, positive-
sense, 7.2-8.4 kb, MW 2.5 million, infectious,
contains genome-linked protein (Vg)
Proteins : 4 major polypeptide cleaved from a
large polyprotein.
Structure proteins VP1 and VP3 : major antibody
binding sites; VP4 : associated with viral RNA
Enteroviruses
Pathogenesis
 Laboratory Diagnosis
Culture in primary cells or cell lines culture or suckling mic:e
Sample : - poliovirus : pharyngeal washing (for the first few days),
faeces (up to 30 days)
CNS : rarely positive
- coxsackievirus, enterovirus, and echovirus :
pharyngeal washing,
faeces (during infection)
CNS : from meningitis cases
Serology
Poliovirus : IgM, IgG rise > 4
Coxsackievirus, enterovirus, and echovirus : difficult because
there are many serotypes
Poliovirus
 Pathogenesis

Antibody

Paralysis

Major illness (meningitis)

Minor illness Meningeal irritation
Prodrome Fever, CNS invation
Malaise, headache
nausea

Virus in
Viremia
oropharyngs

. . . . . .
0 3 5 6 10 12 35
day
 Clinical Findings
Incubation period usually 7-14 days (3-35 days)
A. Abortive poliomyelitis
- most common, recover in a few days
- fever, malaise, drowsiness, headache, nausea, vomitting,
constipation, sore throat
B. Nonparalytic poliomyelitis (aseptic meningitis)
- above symptoms and stiffness, pain at the neck and back
- lasts 2-10 days, recovery is complete and rapid
C. Paralytic poliomyelitis
- flaccid paralysis due to lower motor neuron damage
- incoordination secondary to brain stem invasion
- painful spasm of nonparalytic muscles
- maximal recovery in 6 months, with residual paralysis lasting
much longer
D. Progressive postpoliomyelitis muscle atrophy
- muscle wasting decades after patients experience with paralytic
poliomyelitis
 Polio Vaccine
Live vaccine (Sabin)
Advantages
Effective
Life-long immunity
Induced secretory antibodies similar to those of natural infection
Indirect immunization by attenuated virus spread in community ( snow
ball )
Easily administered (oral)
Repeated boosters not required

Disadvantages
Vaccine-associated poliomyelitis in vaccine recipient or contacts
Spread of vaccine to contact without their consent
Unsafe for immunodeficient patients
 Polio Vaccine
Killed vaccine (Salk)
Advantages
Effective
Can be incorporated into routine imunization (DPT)
Good stability in transport and storage
No risk of poliomyelitis in recipients or contacts
Safe for immunodefficient patients

Disadvantages
Does not induce local (gut) immunity
Booster vaccine required for life-long immunity
Injection is less acceptable
Must achieve higher community immunization levels

Enhanced-potency inactivated poliovaccine

FUNGAL INFECTIONS THAT MAY BE
MANIFEST AS CHRONIC MENINGITIS OR
BRAIN ABSCESS

Cryptococcus neoformans
Coccidioides immitis
Histoplasma capsulatum
Candida albicans
Blastomyces dermatitidis*
* Disease manifest as brain abscess
 Cryptococcus neoformans
C. neoformans and C.gattii are basidiomycetous yeast
with large polisaccharide capsules.
C. neoformans are worldwide in nature, can be isolated
from dry pigeons feces
C. gattii is less common and typically associated with
trees in tropical areas
Cause cryptococcosis
Major clinical manifestation is chronic meningitis
There may be lesion in skin, lung, or other organs
About 5-8% of patients with AIDS develop cryptococcal
meningitis
Not transmitted from person to person
 Morphology and
Identification
- In culture : produce whitish colonies in 2-3 days
- Microscopy : spherical budding yeast cells (diameter 5 10 mm),
surrounded by a thick non-staining capsule.
- Able to grow at 37oC, produce laccase (a phenol oxidase which catalize
formation of melanin from catecholamine substrate)
- Capsule and laccase are virulence factors

Antigenic structure :
- capsular polysaccharides : long, unbranched polymer consisting of an
a-1,3-linked-polymannose backbone with b-linked monomeric branches
of xylose and glucuronic acid.
- during infection, the capsular polysaccharide (CrAg) is solubilized in
spinal fluid, serum, urine ----- can be detected by EIA, latex aglutination
 Cryptococcus neoformans
CNS infection mainly in immunocompromised
patients, hematogenous from lung to meninges
expanding intracerebral mass neurological defect

Acute meningitis (rare):

acute inflammation of leptomeninges
Chronic meningitis:
cranial nerve palsies and other neurological
complications
Brain abscess
Meningoencephalitis
 Diagnosis Laboratory

Specimens : LCS
Microscopic examination:
wet mount directly or +Indian Ink spherical
budding yeast with surrounding unstained capsules

Culture
Inhibited by cycloheximide
Colonies develop within a few days at 37oC
Identification : urease, laccase

Serology
Detection of capsular antigen in LCS or serum
 Aspergillus
Cerebral aspergillus:
Characters of Aspergillus spp. --- refer to respiratory
module
A. fumigatus is the most common human pathogen
Cerebral aspergillosis is rare but fatal (mortality rate
>95%)
In patients with immunosuppression mostly presents as a
cerebral mass lesion or as cerebral infartion, but rarely
meningitis

Laboratory diagnosis :
PCR of LCF
Culture : rarely positive
 Prion
Prion lacks detectable nucleic acid, consist of aggregates of protease-
resistant, hydrophobic glycoprotein (PrPSc).

Human and animals have a 33-35 kD protein (PrPc) that has identical
peptide sequence with PrPSc but different in other characters.

PrPSc : protease-resistant, in cytoplasma ( Mutated prion )

PrPc : protease-sensitive, in cell surface ( Normal protein )

Mutated prion : Resistant to a wide range of chemical

and physical treatment (e.g. formaldehyde, UV, heat to 80oC)

Sensitive to phenol 90%, ether, NaOH 2N,

10% sodium dodecyl sulphate,
5% hypochlorite solution, 1.0M sodium hydroxide and
autoclaving at 121oC 1 hour,
 Clinical Syndromes
Transmissible spongiform encephalopathy
Progressive, degenerative neurologic disease with a long
incubation period but with rapid progression to death after
the onset of symptoms.
Symptoms : loss of muscle control, shivering, myoclonic jerks
and tremors, loss of coordination, repidly progressive dementia

Progression of transmissible Creutzfeldt-Jakob disease

Infection Incubation period Prodrome Dementia/

myoclonic stage
Death
1-30 years 3-5 months 4 months
 Diagnosis
DIAGNOSIS OF PRION OR PRION DISEASE
May be made in patients on the basis of :
(a) The presence of PrPSc;
(b) Mutant PrP genome; or
(c) Appropriate immunohistology

And should not be excluded in patients with atypical neurogenerative

Disease until one or preferably two of these tests have been performed
Other microorganisms to study:
Haemophilus influenzae
Streptococcus pneumoniae
Enteroviruses
Herpes simplex viruses

Good luck !!