CENTRAL NERVOUS SYSTEM INFECTIONS

Ateef A. Qureshi, PhD

Professor of Microbiology
Fall 2010

Ateef Qureshi
Department of Microbiology
St. Georges University
School of Medicine
Phone 2083
Aqureshi@sgu.edu

LEARNING OBJECTIVES
At the end of this series of lectures you should be able to;
1. Understand the terminology and anatomy of CNS in relation to infectious disease
2. Describe the routes of entry, reservoirs and predisposing factors associated with
various infectious agents
3. Compare and contrast: meningitis; encephalitis, myelitis, meningoencephalitis, brain
abscesses and empyema on the basis of symptoms and microbes involved.
4. Explain mechanisms of pathogenesis and virulence factors of the infectious agents of
CNS
5. Discuss immediate symptoms and complications of viral and bacterial agents in the
CNS
6. Identify a syndrome and probable causative agent on the basis of CSF profiles
7. Understand the differences between normal infectious agents and the prions

REFERENCES
Murray, Rosenthal & Pfaller (2009) Medical Microbiology, 6th Edition
Chapter 21, Staphylococci, p209-210
Chapter 22, Streptococci, p233-242
Chapter 25, Listeria, p255-258
Chapter 29, Neisseria, p296-299
Chpater 30, Enterobacteriaceae, p303, 313
Chapter 34, Hemophilus, p343-348
Chapter 42, Spirochetes, p405-419
Chapter 51, Papovaviruses, p499-502
Chapter 53, Human Herpes viruses, p517-539
Chapter 56, Picornaviruses, p553-560
Chapter 58, Paramyxoviruses, p571-579
Chapter 60, Rhabdoviruses, Filoviruses and Bornaviruses, p593-597
Chapter 62, Togaviruses and Flaviviruses, p609-620
Chapter 63, Arenaviruses and Bunyaviruses, p621-625
Chapter 66, Prions, p661-665
Chapter 68, Pathogenesis of Fungal Diseases, p679-682, 684, 686-688
 INTRODUCTION

Given proper opportunity and environment hundreds of microorganisms are capable of

infecting the human Central Nervous System which includes bacteria, viruses, fungi,
protozoa and parasites. Depending upon the actual site of CNS involvement, specific
clinical pictures emerge which are described as Meningitis, Encephalitis, meningo-
encephalitis, myelitis, abscesses and empyema. These infections are among the most
serious as they may kill the patients quickly; however, those who survive will have a life
long impairment of one kind or the other. These range from minor discomforts, physical
disabilities and psychological problems to behavioral changes. Modern antimicrobial
therapies have reduced the serious outcomes but they still range from 8-10%, which is
unacceptably high. Prompt diagnosis and medical help is essential to maximize the
positive outcome of these infections.

The brain and the spinal cord are suspended in the cerebrospinal fluid (CSF), which are
surrounded by three layers of meninges: Pia mater and the arachnoid mater
(Leptomeninges) and the dura mater (pachymeninges). These structures are provided
further protection from injury and infection, by the skull and the vertebral column.
However, this leaves very little space for any inflammation or swelling to occur.
Inflammation and swelling of the brain or the spinal cord can lead to dramatic changes in
the intracranial pressure resulting in serious damage or death.

The Blood-Brain Barrier including the endothelial cells lining the capillaries and are
cemented together by intracellular tight junctions provide a barrier for microorganisms
and toxic substances. It also impedes the passage of the antibodies and antibiotics into
the CSF resulting in poor prognosis.

It is the entry and replication of the infectious agents that results in many different
outcomes of disease syndromes. We will be studying only the very common and
prominent infectious agents and their role in the diseases of the CNS. For these lectures
we will focus the organisms that are not covered in detail at other areas of this course.
The list of chapters and reading references are only for your convenience to find the
related information.

Why do we want to study the whole system instead of individual infectious agents?
The Organ System approach in Medical Microbiology provides a framework and
prospective for the clinical syndromes. To study each causative agent individually is
mostly repetition and loses focus from the patient and his/her symptoms.
There are three organ systems in the body which are closed systems (no direct
connection to the outside environment)
1. Bone and Joints,
2. Vascular system
3. Central Nervous System.

These systems are normally sterile and have no normal flora which resides there.
Therefore, introduction of any organism into these body organ systems, is going to have
a high morbidity and mortality.
 Central Nervous System (CNS) Infections
The CNS has the following special features which play an important role in the disease
outcome;
1. There is no direct communication with the external environment. It is protected by
the Blood Brain Barrier.
2. Pathogens reach CNS either by direct extension from a contiguous structure or
by hematogenous dissemination from a distant site.
3. In order to institute appropriate empiric therapy, it is critical to know the normal
flora and most common pathogens associated with each of these distant sites
from where the infectious agent is coming.

Comparison of
Blood-Brain, Blood-CSF and Brain-CSF Barriers

B-B-B B-CSF-B

ICAM Fenestrated
Junctions Blood Vessel endothelium

B-B-B B-CSF-B

Thick Thin Basement

Basement Membrane
Membrane Choroid plexus
epithelium

Brain CSF*
Gap Junctions

*Low antibody, little/no phagocytes and complement Brain-CSF-B

©A.Qureshi, S10

Terminology
Before we embark upon any discussion of CNS infections we should familiarize
ourselves with the proper terminology of the syndromes associated with these infections.

1. Meningitis- infection of the CNS coverings (meninges)

2. Encephalitis- infection of brain parenchyma
3. Myelitis- infection of spinal cord
4. Meningoencephalomyelitis- infection of many areas of brain
5. Abscess- localized pockets of infection in spinal cord or brain
6. Empyema- epidural or sub epidural abscess

CNS Syndromes
Meningitis
Meningitis is divided into two categories depending upon the length of the disease
syndrome
–– Acute Meningitis- Describes the severity of symptoms, and is usually caused by
a variety of viral or bacterial agents which have a short life cycle. Bacterial
 meningitis is more severe and death usually follows within hours of development
of symptoms. Viral meningitis is milder and death occurs rarely.
–– Chronic Meningitis- The severity of symptom here is not the issue because both
the fungi and tubercle bacilli have a long life cycle; therefore, control of the
infection is comparatively easier.

Encephalitis- Infection of brain parenchyma usually by a viral agent. Depending upon

the specific virus the outcome of the disease varies, ranging from a mild disease to
severe brain damage leading to paralysis and death.

Myelitis- Infection of the spinal cord by a variety of viral agents. Here again the disease
outcome ranges from mild to severe depending upon the virus involved.

Abscesses (including Empyema)

Abscesses are also divided into two categories according to the causative agent’’s
generation time. Fast growing agents like bacteria cause acute abscesses and slow
growing agents such as tubercle bacilli, fungi and protozoa cause chronic abscesses.
–– Acute Brain Abscess- generally poly microbial
–– Chronic Brain Abscess- tubercle bacilli, fungi and protozoa

Entry, Replication and Spread

Since the CNS is supposed to be sterile the infections have to gain entrance through;
Hematogenous (Blood)
–– Meningococci come through respiratory epithelium into the meninges
–– West Nile virus spreads through mosquito bites
–– Rubella virus infects through Transplacental transmission

Neural Route
–– Rabies virus spreads through peripheral nerves to nerve axons to ganglia and
spinal cord and finally to brain
–– Human Herpes viruses 1-3 travels through nerves

Direct inoculation through trauma or injury. Infectious agents many be introduced

due to any kind of trauma and injury resulting in compromising the blood-brain barrier.

Epidemiologic Considerations
For a disease syndrome to occur there are many epidemiologic factors which may effect
the final out come of the disease.
1. Patient demographics- age, immune status
2. Disease pattern- acute or chronic
3. Exposure history- exposure, bites etc
4. Epidemiology- geographic location, season, outbreaks
5. Etiology of infection- bacterial, viral, fungal or protozoan
This table is an example of such an effect.
 Encephalites of Viral Etiology
Virus Geographic Age Group Predominant
Distribution Season
Herpes Virus 1&2 All All None

West Nile Virus All Older adults Summer-Fall

EEE Virus Atlantic & Gulf Children Summer-Fall

Coast and Great
Lakes
WEE Virus Western US & Infants & Older adults Summer-Fall
Canada
California Midwest & NE US; Older children Summer-Fall
Encephalitis Virus S. Canada
Enteroviruses All Infants & children Summer

Varicella-Zoster All Children & Winter

Virus Immunocompromised
Modified from Table 61-3, page 593, Schaecter’’s Mechanisms of Microbial Diseases, 4th. Edition,2007 A. Qureshi, S2010

Meningitis and Meningism

Meningitis; Infection of the membranes and fluid surrounding the brain and spinal cord
(spinal meningitis) causing inflammation of the meninges
Meningism; It is the Group of Symptoms and signs associated with the inflammation;
•• Headache
•• Nuchal rigidity
•• Nausea and vomiting
•• Photophobia

Tests for Meningism

Demonstrate inability to flex the neck and touch the chin to the chest
Demonstrate inability to oppose the nose with the knees
Tripod sign- inability to sit without making a tripod with hands
Kernig’’s sign- patient’’s leg can not be straightened because of hamstring spasm
Brudzinski’’s neck sign- patient retracts the legs when neck is lifted

Warning Signs of Meningism in Children

Bulging fontanelle
Vomiting
Strange high-pitched cry
Convulsions
Opisthotonus

Meningitis
It is the inflammation of the meninges due to viral or bacterial infections.
Aseptic
–– Over 50% of the cases are due to a variety of viruses
 –– All of the other cases are due to bacteria with special growth requirements or they
are slow growers.

Causes of Aseptic Meningitis

Viruses Bacteria
Common Enteroviruses Borrelia burgdorferi*
Arboviruses* Inadequately treated bacterial
HHV-2 meningitis

Uncommon Mumps Mycobacterium tuberculosis

HHV-5 (CMV) Leptospira sp*
HHV-6 Micoplasma pneumoniae
HIV
* *Incidence varies with the region

Modified from :Neurol. Clin. 2008, 26:635

Septic
–– Caused by bacteria only
–– Associated with high Mortality and Severity
–– Etiology is AGE dependent

Causes of Septic Meningitis

AGE Most common Others
Birth to 3 months Streptococcus agalactiae Escherichia coli
L. monocytogenes
3 to 60 months Streptococcus Neisseria meningitidis
pneumoniae H. influenzae type b
> 60 months Streptococcus Neisseria meningitidis
pneumoniae L. monocytogenes
Other Gram negative
organisms
Any age (cranial Staphylococcus aureus
surgery)
Any age L. monocytogenes
(immunosuppressed) Other Gram negatives
(including P. aeroginosa)
 Symptoms associated with Meningitis
Depend upon age, microorganism and the route to meninges
Early symptoms (nonspecific)
Fever*
Malaise
Aches and pains
Nausea
Vomiting
Headache*
More specific to meningitis
Photophobia
Nuchal rigidity*
Drowsiness
Convulsions, fits
Inconsolable crying (infants/toddlers)

* HALLMARKS of Meningitis

Encephalitis
Defined as inflammation of brain parenchyma
Encephalitis is considered clinically a more severe syndrome than viral meningitis
Symptoms
Headache
Fever
Altered consciousness-lethargy to confusion and coma
Behavioral and speech disturbance
Seizures
Etiology
Viral
•• Herpes viruses, enteroviruses, arboviruses, rabies virus, HIV, HTLV-1,
Paramyxoviruses (mumps, rubeola virus and arenaviruses)
Bacterial (RARE)
•• Exceptions: Legionella pneumoniae, Borrelia burgdorferi, Treponema pallidum
Fungal
•• Cryptococcus neoformans
Parasitic
•• Plasmodium falciparum, Trypanosomes

Myelitis
Acute inflammation of the spinal cord
Depending upon virus, this can lead to flaccid paralysis
Symptoms
Headache
Fever
Irritation followed by
•• Weakness of one or more extremities
Etiology
Poliovirus was the leading cause before vaccination
West Nile virus is the most significant after 2000
 Brain Abscess and Empyema
Localized bacterial infection of brain parenchyma and subdural or epidural spaces
Pressure from accumulation of exudates may permanently damage the brain tissue
May be fatal if not treated properly
Abscess- Fixed boundaries
Empyema - Lack of definable shape or size
Symptoms
Usually are rapid and associated with their location
Headache
Changes in mental status- drowsiness to coma
Generalized seizure

Fungal brain abscess

Disseminated hematogenously from remote site usually from the lungs or oropharynx
and create multiple areas of infection within brain. Meningoencephalitis occurs early
by vascular invasion
Etiology
Aspergillus, Cryptococcus and Candida spp. are usually involved.

Entry into CNS

Entry is most likely through Choroid plexus as it is highly vascularized, inflammation may
increase entry into CNS. Again, remember the modes of entry;
Direct extension
–– Infections of teeth, middle ear or mastoids or sinuses may spread into the system.
Etiology (Most common)
Aerobic and anaerobic streptococci,
Bacteroides
Enterobacteriaceae
Psudomads
Fusibacterium
Peptococcus

Hematogenous (important for abscesses)

Etiology depends upon location of the source of infection
Mouth- mixed flora
Lungs- Streptococci, Fusibaterium, Corynebacterium, and Peptococcus sp.
Heart- Strep. viridans, Staph. aureus
Urinary tract- Enterobacteriaceae, Pseudomonas
Wounds- Staph. aureus

Penetrating head trauma and surgery

Etiology
–– Most common- Staph. aureus
–– Immunodeficient patients and/or HIV infections- Nocardia, Aspergillus, Candida
 Diagnosis of CNS infections
Cerebrospinal Fluid
Chemical and cellular analysis
Culture
PCR
Neuroimaging
Helpful in partial differentiation of viral encephalitis
Japanese B virus: grey matter involvement
Nipah virus: multiple, small, white matter lesions
Human herpes virus-1: hemorrhages
Abscesses and Empyema differentiation

Features of CSF
Etiology Leukocytes Neutrophils Glucose Protein
(mm3) % (mg/dL) (mg/dL)

Normal 0-6 0 40-80 20-50

Meningitis: >1000 >50 0-10 >100

Acute Bacterial
Viral 10-1000 High for 24 40-80 50-100
Usually <300 hrs, then <50
Chronic Mycobact. 100-500 <10 ”40 >100
& Fungal (Mycobact.)
50-100
(Fungal)
Encephalitis *Viral 10-500 High for 24 40-80 50-100
hrs, then <50
Brain Bacterial 10-100 <50 40-80 50-100
Abscess Fungal
* 10-500 RBCs in HHV-1 Infection A Qureshi, S2010

Viral Infections of CNS

Viruses use at least two pathways to enter the CNS;
Hematogenous (most common)
Neural
Through Olfatory nerve for HHV-1&2
Intra-axonal entry through neuron route for Rabies
Direct injury
Can result viral infections ranging from meningitis to myelitis

Viral Meningitis

Common causes of Aseptic meningitis

–– Enteroviruses (ECHO), coxsackie and poliovirus
–– Herpes virus and other viruses are less common
–– Mumps virus meningitis is a complication of infection
CSF findings
–– Glucose ––normal
–– Protein- moderately high
–– WBC count- increased, predominantly lymphocytes
Gram stain- NO BACTERIA

From this point on, each virus family or individual virus will be discussed. Please
make a special note of the virus family and the individual virus.

Picornaviridea

Enteroviruses
Enteroviruses belong to family Picornaviridea. They are naked, small (25-30 nm),
icoshedral viruses resistant to pH 3-9, detergents and heat. They contain single-
stranded positive polarity RNA (Transfecting viruses) belonging to Baltimore
Class Iva. As is common to all RNA containing viruses, RNA replication is in the
cytoplasm. Most viruses are Cytolytic.

Over 63 serotypes involved in meningitis.

More than 90% of meningitis cases are due to Enteroviruses. In addition to meningitis,
Other syndromes caused by this family of virus may include;
–– Hand-foot and mouth disease
–– Herpangina
–– Myocarditis
–– Pleurodynia
–– Acute hemorrhagic conjunctivitis
These clinical syndromes are determined by;
–– Virus class and serotype
–– Tissue tropism
–– Infectious dose
–– Portal of entry
–– Patient: age, sex, Immune competence
Epidemiology
–– Worldwide distribution
–– Humans are the only reservoir
–– Asymptomatic infections are common
–– Show seasonality;
•• In Temperate climates- summer to Fall, water is the main source of infection.
•• In Tropical climates- year-round infections which are invariably fecal-oral in
nature. Infants and children are MOST susceptible
Please refer to Murray et al (6th.Ed); Box 56-4 p 556

Polioviruses
Polio virus is a member of the family Picornaviridae and has only 3 serotypes and may
cause meningitis to myelitis. Because there are only three serotypes, use of oral
 vaccine against all 3 serotypes has successfully eradicated polio from the Western
Hemisphere.

The virus possesses the same characters as that of Enteroviruses, spreads through
fecal-oral route by consuming contaminated food and water, or through direct contact
with infected stool or throat secretions.
Symptoms common as those of meningeal irritation, headache, fever, nuchal rigidity,
followed by weakness in one or more extremities

Clinical syndrome:
Acute Flaccid Paralysis, due to infection of anterior horn of grey matter

Pathogenesis
The virus infects enterocytes of the GI tract, transverses intestinal wall through
basement membrane and then moves into gut-associated lymphoid tissue, e.g.
Peyer’’s patches (site of primary replication). The resulting viremia seeds peripheral
tissue, from there the virus enters into the neurons of the peripheral nervous system
that innervates the peripheral tissues, and finally, the virus traffics to the CNS using
retrograde axonal transport (Lancaster and Pfeiffer, 2010).

Outcomes of infection
a. Unapparent infections
About 95% of infections are asymptomatic, the virus can be found in the RES.
Diagnosis is by virus isolation from feces and oropharynx, and by specific serum
antibodies.
b. Abortive polio is a minor illness with flu like symptoms which are similar to any other
systemic viral infection.
c. Polio encephalitis- RARE
d. Non-paralytic polio (aseptic meningitis)
Similar to other enteroviral meningitis
e. Paralytic polio (<2% of cases)
Viral spread is normally restricted due to;
Limited replication of virus in peripheral neurons
Insufficient retrograde axonal transport in peripheral neurons
Innate resistance through IFN Į/ȕ production
When these barriers are breeched, the out come will be paralytic polio:
Spinal- flaccid paralysis due to lysis of the anterior horn cells
Bulbar- paralysis of cranial nerve IX and X, medullar/respiratory centers

Prevention
Inactivated vaccine
Formalized Salk vaccine injected intramuscularly.
Local IgA antibody is not produced
Mostly used in Western Hemisphere (where polio is considered eradicated)
Live oral vaccine
Sabin vaccine is stable at room temperature with MgCl2
Produces secretory IgA antibodies
Virus can spread to contacts and enhance herd immunity and may cause
paralytic polio (~1 in 4 million)
Please see Table 56-2 in Murray et al 6th.Ed, p 561
 Viral Encephalitis
Arboviruses
Arthropod-borne viral infections are transmitted by mosquitoes and ticks and distributed
worldwide. These viruses are the most common cause of sporadic and epidemic viral
encephalitis. Seizures are generally the complications in children.
All arboviruses are enveloped viruses with icosahedral nucleocapsid and contain a
transfecting RNA. There are two major families of arboviruses involved;
Togaviridae
Belongs to Baltimore Class IVb
Early and late proteins are made
Virus buds at the plasma membrane
Flaviviridae
Belongs to Baltimore class IVa
A Polyprotein is translated first which cleaves into many individual active proteins
Virus buds into the cytoplasmic vesicles from where the virus is released through
the process of exocytosis.

Togaviridae (Alphavirus)

Venezuelan Equine Encephalitis (VEE)

Epidemiology
The virus spreads through Culex and Aedes species of mosquitoes.
Symptoms
During the prodromal period- fever, chills, weakness, headache, myalgia (due to viral
replication) are the major symptoms.
The symptoms progress rapidly to nuchal rigidity, confusion, somnolence, seizure in
50% of cases and coma (due to spread through microvascular permeability of brain,
from there it progresses through cell-to-cell which occurs via axon and dendritites)
–– NO DEATHS in humans, 80% mortality in horses

Eastern Equine Encephalitis (EEE)

Epidemiology
The virus is common in North America and spreads through Aedes and Culiseta spp
of mosquitoes. Aedes spp. may spread the virus from horse to human which is the
dead-end host.
Clinical symptoms are similar to that of VEE. The disease has a HIGH MORTALITY
in humans.

Western Equine Encephalitis (WEE)

Epidemiology
The virus spreads through Culex and Culiseta spp of mosquitoes. It is common in
rural areas of US in the summer months. Fatality rate ranges about 3-4%, death
usually occurs in 1-2 days. Children have a 30% chance of CNS sequelae.

Pathophysiology of Equine Encephalitides

It is characterized as defuse CNS infection. Neutrophils and macrophages infiltrate brain
parenchyma causing focal necrosis and spotty demyelination. Vascular inflammation
 with endothelial proliferation and small vessel thrombosis may also occur.
Pathogenesis for EEE and WEE differs which is as described below;

EEE: Large number of active virus entering in brain parenchyma effecting the
perikaryon and dendrites of neurons with minimal glial cell infiltration.

WEE: Damage mediated by large number of immunologically active cells that enter
brain. Cell death is by apoptosis primarily in the glial and inflammatory cells.

Flaviviridae
St. Louis Encephalitis virus (SLE)
Epidemiology
The virus is transmitted by culex mosquitoes. Overt infection depends upon at least
three important factors such as; efficiency of replication of the virus at extra neural
sites, the degree of viremia in the host and the age of the host.
Pathophysiology
Virus enters into the brain through BBB (astrocyte complex) or crosses fenestrated
endothelium in the choroid plexus.
Symptoms
Mortality (2-20%) is higher in the elderly. Generally a mild disease with malaise
and fever. Only 20% develop CNS sequelae consisting of irritability, memory loss,
movement disorders, and motor deficits. Seizures and coma are COMMON for those
who develop the sequelae and the disease never develops into a chronic illness.

Japanese B Encephalitis virus (JBE)

Epidemiology
This virus is also spread through Culex mosquitoes. Incubation period ranges from 4-
14 days and the disease is common in the rural areas of Asia.
Symptoms
During the prodromal period the symptoms are almost the same as that of SLE;
however, fever starts by the 2nd week of disease. Encephalitis syndrome remains
with tremors only and NOT seizures are observed. Patients with low CSF IgG/IgM
ratio do tend to have a higher death rate.

West Nile Encephalitis virus (WNV)

Epidemiology
Wild birds are the reservoir of the virus and spreads through Aedes mosquitoes.
About 3-15% of the cases are fatal. Person to person transmission is very RARE.
Symptoms
Viral prodrome is characterized with a maculopapular rash on trunk and extremities
with headache, HIGH fever, nuchal rigidity, stupor, tremor and seizures and
paralysis.
 Bunyaviridae
At leas 200 different viruses which infect humans are included in this family.
Bunyaviridae are enveloped viruses containing single-stranded negative polarity,
segmented (3) RNA. These viruses spread through mosquitoes, ticks and flies. Two of
the virus species are important for North America which are;
–– California Encephalitis virus
–– La Crosse virus
Rhabdoviridae
Lyssavirus: Rabies virus
The virus is Bullet shaped makes identification easy under the electron microscope. It
contains a Single-stranded, negative polarity RNA enclosed in a Helical nucleocapsid
covered by an envelope. The virus codes for 5 proteins- N, P, M, G and L. Protein G is
very important for virus attachment. Surface glycoprotein (G) attaches to cell receptors
including Acetylcholine receptor at neuromuscular junctions. The virus enters into the
cell via endocytosis. Virus has a preference for nerve and salivary gland cells (travels
via axons to CNS). It spreads from brain to salivary glands, kidneys and conjunctival
cells. Virus is detected in tears.
Epidemiology
There are estimated 35000-50,000 cases reported worldwide with highest number
reported in Asia (~90% cases). It is characteristically Endozoonotic: meaning that all
warm blooded animals are susceptible. The animals are divided into two types; in the
Urban areas the dogs and cats are important and in the rural and jungle areas (Sylvatic)
the wildlife including fox, squirrels, coyotes, skunks and mongoose are susceptible.
Symptoms
Incubation period ranges from 20-90 days, may extend to a year depending upon the
distance from the brain and the degree of tissue damage. The disease is divided into
three distinct categories;
–– Nonspecific –– general malaise, fever, headache (tingling pain and weakness at the
bit site)
–– Progressive- neurologic symptoms including insomnia, confusion, slight or partial
paralysis, agitation, hyper salivation, dysphagia (hydrophobia)
–– Paralytic ––disorientation, stupor
–– Death within days after symptoms (~7 days)
Diagnosis
Saliva- virus isolation, RT-PCR
Serum and CSF for rabies antibodies (FA and ELISA)
Brain tissue- Negri bodies, Babes nodules consisting of glial cells
Treatment
Prevention
Wash all wounds with soap and water
1 dose of immune globulin and 4 doses of vaccine on days; 0, 3, 7 &14, days + 2
boosters on days 0 and 3*

* New recommendations by CDC published on Mar 18, 2010

 Rabies postexposure prophylaxis (PEP) schedule - US, 2010
(MMWR Vol.59/RR2; Mar 18, 2010)
Not previously vaccinated
Intervention Regimen*
(for ALL age groups including children)

Wound cleansing All PEP should begin with immediate thorough

cleansing of all wounds with soap and water. If
available, a virucidal agent (e.g., povidine-iodine
solution) should be used to irrigate the wounds.

Human rabies Administer 20 IU/kg body weight. If anatomically

immune globulin feasible, the full dose should be infiltrated around and
(HRIG) into the wound(s), and any remaining volume should
be administered at an anatomical site (intramuscular
[IM]) distant from vaccine administration.

Vaccine Human diploid cell vaccine (HDCV) or purified chick

embryo cell vaccine (PCECV) 1.0 mL, IM (deltoid but
never in the gluteal region), 1 each on days 0, 3, 7 and
14.
(For immunocompromised; 5 shots)

Rabies postexposure prophylaxis (PEP) schedule - US, 2010

(MMWR Vol.59/RR2; Mar 18, 2010)
Previously vaccinated
Intervention Regimen*
(for ALL age groups including children)

Wound cleansing All PEP should begin with immediate thorough

cleansing of all wounds with soap and water. If
available, a virucidal agent such as povidine-iodine
solution should be used to irrigate the wounds.

HRIG HRIG should not be administered.

Vaccine HDCV or PCECV 1.0 mL, IM (deltoid but never in the

gluteal area), 1 each on days 0 and 3.
For persons with immunosuppression, rabies PEP
should be administered using all 5 doses of vaccine on
days 0, 3, 7, 14, and 28.
 Other virus infections of the CNS
Arenaviridae- Lymphocytic Choriomeningitis
Togaviridae- Rubella virus
Herpesviridae- Human Herpes virus 1-8
Retroviridae- HIV-1
Papovaviridae- Polyoma virus (JC virus)-PML (Progressive Multifocal
Leukoencephalopathy)
Viral DNA is detected in majority of healthy humans.
Multifocal signs include; hemiparesis, visual loss, seizures, dementia, personality
changes and gait problems. Characteristic white matter lesions are commonly detected
in posterior occipital area of the brain.
Paramyxoviridae- Mumps virus and Rubeola virus are in this family. Subacute
Sclerosing Pan Encephalitis (SSPE) is a complication of Rubeola virus infection.
It is a slow fatal condition after more than 10 years of measles. Reported Worldwide,
generally the disease is more common in boys (3:1) than girls. First signs include
Behavior changes in school age children. Death occurs in 10% of cases in 3 months
during the Fulminant course and in 4-10 years during the chronic course.

Bacterial Infections of CNS

There are over 25 bacterial infectious agents are involved in serious life threatening
infections requiring prompt diagnosis and treatment. Except for the Mycobacterium
spp, all of the bacterial infections of the meninges, cause Septic meningitis (Bacterial
meningitis). Only the very common bacteria involved in Meningitis will be discussed
here. This is by no means the COMPLETE list of bacterial meningitis.

Bacterial invasion into CNS

The invasion may take place either from a nearby site such as Middle ear or chronic
sinusitis or spreads from a distant site which may be a hematogenous invasion or from
direct introduction which may be RARE, sometimes the source can not be identified.

Bacterial Meningitis
(Reported by Dr. Jungkind)
•• Neonates- Strep agalactiae, Coliforms and Listeria monocytogenes
•• Infants- Streptococcus pneumoniae, Neisseria meningitidis and H. influenzae
•• Children- Strep pneumoniae, N. meningitidis and Listeria monocytogenes
•• Streptococcus pneumoniae is most common except in the neonates
•• >75% of infections are caused by N. meningitidis, Strep. pneumoniae and H.
influenzae
 Causes of Septic Meningitis
AGE Most common Others
Birth to 3 months Streptococcus agalactiae Escherichia coli
L. monocytogenes
3 to 60 months Streptococcus Neisseria meningitidis
pneumoniae H. influenzae type b
> 60 months Streptococcus Neisseria meningitidis
pneumoniae L. monocytogenes
Other Gram negative
organisms
Any age (cranial Staphylococcus aureus
surgery)
Any age L. monocytogenes
(immunosuppressed) Other Gram negatives
(including P. aeroginosa)

(Modified from: Table 61-2, page 592, Schaechter’’s Mechanisms of Microbial Disease, 4th Edition)

Bacterial Virulence Factors

Neisseria meningitidis
–– Capsule, IgA protease, pili, endotoxin
Haemophilus influenzae
–– Capsule, IgA protease, pili, endotoxin
Streptococcus pneumoniae
–– Capsule, IgA protease only
Neisseria meningitidis

Coffee bean-shaped intracellular (PMNs) Gram negative bacteria which are exclusively
human pathogens. Many members of the genus are commensals of upper respiratory
tract. About 30% of the population may transiently carry N. meningitidis. It is responsible
for more than 75% cases of septic meningitis. Transmission is via droplet inhalation
and more than 1/3 of the cases occur in the first five years of age. High rates of
morbidity and mortality, ~50% survivors have neurologic or other sequelae.

Diagnosis
Clinical signs include rash, sepsis, fever and nuchal rigidity.
CSF tap is the most important sample to check protein, glucose and WBC count
Culture- fastidious organism requires 5-10% CO2; therefore, samples for culture
must be sent in slight anaerobic conditions;
Blood or CSF samples are plated on chocolate agar.
Nasopharyngeal swabs are plated on to Modified Martin-Thayer agar, which
contains antibiotics to inhibit normal flora of the nasopharyngeal region.
 Rapid techniques
•• Latex agglutination
•• PCR
Prevention
Tetravalent vaccine composed of Groups A, C, Y, and W135 (Group B is weakly
immunogenic)
Protection is group specific and is limited to ~3 years.
Vaccination does not protect from carriage of the organism.
Vaccine is poorly immunogenic for infants under 2 years of age.

Streptococcus agalactiae

A Beta hemolytic Taxos A resistant, Group B streptococcus

Normal female genital organism (~40% of the females are colonized). Babies delivered
by mothers colonized with S. agalactiae, have a high (60%) mortality rate. These babies
develop meningitis during the first week of life. Premature birth is an important risk
factor in neonates who develop lethargy, fever, sepsis and respiratory distress. Children
and adults may develop puerperal fever at delivery and other skin and soft tissue
infections.

Streptococcus pneumoniae

Encapsulated, Gram positive lancet shaped, alpha hemolytic, Taxos P sensitive cocci
(Optochin) organism. It is a part of normal flora of about 20% adults and >75% healthy
children. It is the MOST COMMON cause of bacterial meningitis after 3 months of age. It
is highest cause of infantile meningitis. Mortality rate for pneumococcal meningitis is
~25%. Neurological sequelae is ~50%
In elderly, it may follow pneumonia, middle ear infections and sinusitis.

Pathogenesis (Braun et al.2002; J. Clin. Invest., 109:19-27)

Pneumolysin; a pore forming toxin and a potent neurotoxin which can trigger cellular
apoptosis
Hydrogen peroxide: Due to absence of catalase, large amounts of H2O2 accumulate
and enhance apoptosis.
Another mechanism of pathogenesis is provided by (Guikel et al., 2003, PNAS.
100:14363-14367).
–– In mouse models, invasion can occur through nasopharynx (not hematogenous).
–– Teichoic and lipoteichoic acids of cell wall mediate binding to the gangliosides
expressed on the neurons.
–– Subsequent travel is then via retrograde axonal transport along olfactory neurons.

Haemophilus influenzae

Gram negative, fastidious encapsulated pleomorphic organisms. Spread via blood from
respiratory tract to the brain. Infection opportunity is between 4 months to 3 years.
Pose greater risk of permanent neurologic damage than any other bacterial meningitis.
Vaccines are made with type B capsular polysaccharide.
 Enterobacteriaceae
Escherichia coli K1
These are Gram negative, lactose fermenting facultative anaerobes. During pregnancy
there is an increased vaginal colonization of K1 strain of E.coli with an approximately 8%
mortality. The bacteria spread from nasopharynx to the meninges.
Symptoms
–– <1 month old- irritability, lethargy, vomiting, lack of appetite and seizures
–– 4-18 months- nuchal rigidity, tense fontanels, and fever
–– Older children & adults- headache, vomiting, confusion, lethargy, seizures and
fever

Klebsiella pneumoniae
Gram negative rods
High incidence in cockroach infested areas
Early onset- <3 days- 2nd only to Gr. B Strep, causing Leukopenia and neutropenia
Late onset- 8-28 days-2nd only to Staphylococcus causing leukocytosis and
neutrophilia
Symptoms
Symptoms include lethargy, poor feeding, little cry, fever and sclerema.
Bacteria may be cultured from blood, CSF and urine.
Patient serum is C-reactive protein positive.

Listeria monocytogenes

Gram positive non spore forming aerobic motile rods.

Epidemiology
Infections may come from different sources such as Foods (dairy and deli), Soil, Water
and decaying vegetation. Human intestines may be a reservoir, as 2-12% humans carry
the organism. Can be transmitted to the baby during delivery (may cause spontaneous
abortions)
Pathogenesis
Grows in macrophages
Releases “Internalin”- as a cell attachment molecule which triggers entry
Listeriolysin- protein that helps in movement within the cell
Hemolysin- It is pore-forming toxin which allows escape from phagosome to the
phagosole.
Uses host cell actin to move to the new cells
Diagnosis
Intracellular gram positive rods in macrophages and neutrophils
CSF culture- looks like ȕ-Strep, but catalase + , and ““tumble””

Spirochetes Infections of CNS

Treponema pallidum
Early stages are infectious but without CNS involvement.
It takes about 10 years or longer for non treated cases to develop into Neurosyphilis.
Neurosyphilis is the Tertiary stage of the disease and is no longer infectious.
Delayed hypersensitivity is part of the pathologic mechanism of tissue damage.
Commonly found in different tissues of the body as ““Gummas””
Infection of CNS is via meningovascular route
Symptoms
Degenerative changes in CNS result in mental changes. Patients may develop frank
psychosis and/or a shuffling gait ““tabes dorsalis””
Diagnosis
Spinal fluid may be helpful by observing elevated WBCs and protein.
VDRL positive.

Leptospira interogans
Animals are reservoirs. The bacteria spread through animal urine contaminated
water and food (the bacteria can survive for weeks in water). No body of water in the
US is free from it (approximately 100 cases/year are reported in US). Bacteria are
Sensitive to Acid pH, drying and soap.
Sewer workers, miners, veterinarians and meat packers are at risk.
Symptoms
Incubation is from 7-13 days (range 5 days - 4 weeks)
Bacteremic phase- influenza like symptoms and fever (bacteria NOW enter the
CNS)
2nd Phase- ~3+weeks
Headache with ““aseptic”” meningitis
Sometimes hemodynamic collapse is also observed.
Diagnosis
Blood culture
CSF analysis and culture
Rise in antibody between acute and convalescent stages

Borrelia burgdorferi
These are large spirochetes- 0.2x10-30 µm carried by ticks. Nearly 15% of the
patients show neurologic abnormalities. The disease is rarely fatal.
Symptoms
Classic ““bull’’s eye”” rash, fever, joint pain, meningeal irritation
2nd Stage- dissemination system wide
3rd Stage- mild neurologic or frank encephalitis
Diagnosis
Loose irregular spirals, Silver or immunoflourescent stain
Difficult to culture
CDC recommends antibody screen using ELISA

Fungal Infections of CNS

Disseminate hematogenously from a remote site of infection usually in the oropharynx or
lung. Create multiple areas (cause abscesses ) of infection within brain and other organs
Meningoencephalitis occurs early by vascular invasion of the fungus.
Secondary thrombosis, cerebral infarction and hemorrhages may also b e observed.
Common fungi
–– Candida albicans
–– Cryptococcus neoformans
–– Histoplasma capsulatum
–– Aspergillus fumigatus
Diagnosis
Antibody studies
CXR
Candida- forms granulomatus reaction. Yeast forms seen with silver stain
Cryptococcus-fungi appear like encapsulated spheres. Capsules can be seen by
mucicarmine stain
Histoplasma- CT scan
Aspergillus- branching hyphae; classical appearance
•• Please revisit your notes on Respiratory fungal infections by Dr. Lennon

Transmissible Spongiform Encephalopathies

Prion is an abnormal isomer of normal host protein
NO NUCLEIC ACID present
Replicate without provoking antibody or inflammatory response
Are resistant to some inactivation methods used for bacteria and viruses (70% alcohol,
X-rays and UV light etc)
Sensitive to autoclaving and bleach
Disease confined to the CNS and may take decades to manifest
Prion can be inherited in about 15% of cases.

Pathogenesis
Normal PrPc- glycoprotein with secondary structures dominated by Alpha helix
Prion protein PrPSc- glycoprotein with secondary structures dominated by Beta-pleats
When PrPSc molecules comes in contact with the normal PrPc molecule, the normal
PrPc changes into the abnormal PrPSc
Modified protein aggregates in neurons as myeloid plaques
Spongy appearance of cerebrum is due to the formation of vacuoles in the cortex
and cerebellum

Spread of Prions
Sporadic- no apparent cause
Inherited- through autosomal dominant trait
Ingestion- infected food, cannibalism

Kuru- incubation period is about 20 years. Symptoms include progressive trunchal

shaking and unsteady gait. Death occurs within 3-24 months. Medical events- can also
spread the disease (Iatrogenic) through surgery, organs etc

Creutzfeld Jekob Disease (CJD)

Most common prion human disease with a peak incidence at 55-65 years, but can affect
teenagers also.
No treatment
Symptoms
Symptoms include insidious mental deterioration with early cerebellar and visual
problems followed by severe dementia within 6 months involving brain and lower motor
neurons.
Cases of CJD have been due to;
Use of infected corneal transplants,
Using nonsterilized surgical equipment.
Pituitary hormone injections derived from cadavers.
Accidental cuts suffered during autopsies or surgeries.

Bovine Variant of CJD

BSE re-emerged in 1996 with progressive neurodegenerative disease resulting in patient
death. It is normally a bovine infection but crossed to humans as Mad Cow Disease.
Diagnosis
Biopsy of Brain to look for Spongiform encephalopathy and accumulation of abnormally
folded protein.
It is a sporadic disease.
CSF- no cells are found in the CSF.

This was by no means a complete inventory of infectious agents involved

There are many more; however, we discussed ONLY the very common and
frequent infections.