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the lecture :
CNS infection 1
DR: INTISAR ALNAGI
Objectives
• Discuss the characteristics, pathogenesis,
clinical features, diagnosis, treatment and
prevention of poliovirus.
• Discuss the characteristics, pathogenesis,
clinical features, diagnosis, treatment and
prevention of Rabies virus
• Discuss the pathogenesis of prion diseases and
other infection-related causes of
encephalopathy such PML and SSPE

• Poliovirus Disease This virus causes
poliomyelitis.
• Important Properties :
The host range is limited to primates (i.e.,
humans and non-human primates such as apes
and monkeys).
This limitation is due to the binding of the viral
capsid protein to a receptor found only on
primate cell membranes.
• There are three serologic
(antigenic) types.
Transmission
• Transmitted by the fecal–oral route.
 It replicates in the oropharynx and intestinal
tract in human.
Pathogenesis & Immunity
• After replicating in the oropharynx and small
intestine, especially in lymphoid tissue, the virus
spreads through the bloodstream to the central
nervous system where replicate in motor
neurons located in anterior horn of spinal cord .
• It can also spread
retrograde along nerve
axons.
• Death of these cells results
in paralysis of the muscles
innervated by those
neurons.
• The virus also affects the
brainstem, leading to
“bulbar” poliomyelitis (with
respiratory paralysis), but
rarely damages the
cerebral cortex.
• In infected individuals, the immune response
consists of both intestinal IgA and humoral IgG
to the specific sero-type.
• Infection provides lifelong type-specific
immunity.
Clinical Findings
• The incubation period is usually 10 to 14 days.
• The range of responses to poliovirus infection includes:
 (1) in apparent, asymptomatic infection. common
 (2) abortive poliomyelitis.
mild, febrile illness characterized by headache, sore
throat, nausea, and vomiting. Most patients recover
spontaneously.
 (3) nonparalytic poliomyelitis.
manifests as aseptic meningitis with fever, headache, and
a stiff neck. This also usually resolves spontaneously.
 (4) paralytic poliomyelitis.
• flaccid paralysis , brainstem involvement can
lead to life-threatening respiratory paralysis.
• Painful muscle spasms.
 The motor nerve damage is permanent, but
some recovery of muscle function occurs as
other nerve cells take over.
• In paralytic polio, both the meninges and the
brain parenchyma (meningoencephalitis).
 If the spinal cord is also involved, the term
meningomyeloencephalitis.

• A postpolio syndrome that occurs many years
after the acute illness.
 Marked deterioration of the residual function of
the affected muscles occurs many years after the
acute phase.
• The cause of this deterioration is unknown.
• No permanent carrier state,
but virus excretion in the feces can occur for
several months.
Laboratory Diagnosis
• The diagnosis is made either by:
✔ isolation of the virus
✔ rise in antibody titer.
✔ Virus can be recovered from the throat, stool,
or spinal fluid by inoculation of cell cultures.
The virus causes a cytopathic effect (CPE) and
can be identified by neutralization of the CPE
with specific antisera.
Treatment
• There is no antiviral therapy.
• Treatment is limited to symptomatic relief and
respiratory support, if needed.
• Physiotherapy for the affected muscles is
important.
Prevention
• Poliomyelitis can be prevented by
1- killed vaccine (Salk vaccine,
inactivated vaccine, IPV).
2- live, attenuated vaccine (Sabin
vaccine, oral vaccine, OPV).
• Both vaccines induce humoral
antibodies, which neutralize virus
entering the blood and prevent CNS
infection and disease.
• Both contain all three serotypes.
• The current version of the
inactivated vaccine is called
enhanced polio vaccine, or eIPV.
 It has a higher seroconversion rate
and induces a higher titer of antibody
than the previous IPV.
• eIPV also induces some mucosal
immunity IgA, making it capable of
interrupting transmission, but the
amount of secretory IgA induced by
eIPV is significantly less than the
amount induced by OPV.
• OPV is therefore preferred for
eradication efforts.
• The live vaccine was preferred
in for two main reasons:
 (1) It interrupts fecal–oral
transmission by inducing
secretory IgA in the
gastrointestinal tract.
 (2) It is given orally and so is
more readily accepted.
(3)The duration of immunity is longer with the
live.
booster dose is recommended with both.
• The currently approved vaccine schedule
consists of four doses administered at 2
months, 4 months, 6 to 18 months, and upon
entry to school at 4 to 6 years.
 One booster (lifetime) is recommended for
adults who travel to endemic areas.
• Passive immunization with immune serum
globulin is available for protection of
unimmunized individuals known to have been
exposed.
Disadvantages of live vaccine:
 (1) Rarely, reversion of the attenuated virus to
virulence will occur, and disease may ensue
(especially for the type 3 virus).
(2) It can cause disease in immunodeficient
persons and therefore should not be given to
them.
(3) It must be kept refrigerated to prevent heat
inactivation of the live virus.


RHABDOVIRUSES
 RABIES VIRUS
• This virus causes rabies, an encephalitis.
• Important Properties:
 Rhabdovirus family.
single-stranded RNA.
 bullet-shaped capsid surrounded by a lipoprotein
envelope.
 Because the genome RNA has negative polarity, the
virion contains an RNA-dependent RNA polymerase.
Rabies virus has a single antigenic type.
The antigenicity resides in the envelope
glycoprotein spikes.
 Rabies virus has a broad host range: It can
infect all mammals, but only certain mammals
are important sources of infection for humans
Transmission
• transmitted by the bite of a rabid
animal( bats; dogs and cats).
• The virus is in the saliva of the
rabid animal.
• “nonbite” exposures, the most
important example is exposure to
aerosols of bat secretions
containing rabies virus.
• Another rare example is
transmission in transplants of
corneas taken from patients who
died of undiagnosed rabies
Pathogenesis
1- The virus multiplies locally at the bite site.
2- infects the sensory neurons, and moves by axonal
transport to the central nervous system
3- The virus multiplies in the central nervous system
and then travels down the peripheral nerves to the
salivary glands and other organs.
 From the salivary glands, it enters the saliva to be
transmitted by the bite.
There is no viremic stage.
• Within the central nervous system,
encephalitis develops, with the death of
neurons and demyelination.
• Infected neurons contain an eosinophilic
cytoplasmic inclusion called a Negri body,
which is important in laboratory diagnosis of
rabies.
Clinical Findings
• The incubation period varies, according to the
location of the bite, from as short as 2 weeks
to 16 weeks or longer.
- nonspecific symptoms such as fever, anorexia,
paresthesias at site of bit .
 After the prodrome, rabies manifests as either
of two forms: (encephalitic) or (paralytic).
 encephalitic
agitation, delirium, seizures, and hydrophobia
occur. Hydrophobia is an aversion to swallowing
water because of painful spasm of the
pharyngeal muscles.
paralytic, the symptoms do not occur. Rather,
the spinal cord is primarily involved, and an
ascending paralysis occurs.
Laboratory Diagnosis
• Rapid diagnosis of rabies infection in the
animal is usually made by:
1- examination of brain tissue by using either
PCR assay.
2- fluorescent antibody to rabies virus.
3- histologic staining of Negri bodies in the
cytoplasm of neurons .
• Rabies in humans:
1- PCR assay.
2- fluorescent antibody staining.
3- isolation of the virus from sources such as
saliva, spinal fluid, and brain tissue.
4- rise in titer of antibody to the virus.
5- Negri bodies can be demonstrated in corneal
scrapings and in autopsy specimens of the brain.
Prevention
• rabies vaccine contains inactivated virus
grown in human diploid cells.
human diploid cell vaccine (HDCV).
There are two approaches to
prevention of rabies in humans:
preexposure and postexposure immunization.
Preexposure immunization with rabies vaccine
should be given to individuals in high-risk
groups, such as veterinarians, zookeepers, and
travelers to areas of hyperendemic infection.
• Postexposure immunization
use of both the vaccine (The
long incubation period of the
disease allows the virus in the
vaccine sufficient time to
induce protective immunity)
and human rabies immune
globulin (RIG, obtained from
hyperimmunized persons)
plus immediate cleaning of
the wound.
• Five doses of HDCV are given (on days 0, 3, 7,
14, and 28), but RIG is given only once with
the first dose of HDCV (at a different site).
• HDCV and RIG are given at different sites to
prevent neutralization of the virus in the
vaccine by the antibody in the RIG.
• RIG is given into the bite site, and the
remainder is given intramuscularly.

prion diseases
✔ Prions are
protein-containing particles
with no detectable nucleic
acid that are highly resistant
to inactivation by heat,
formaldehyde, and
ultraviolet light .
✔ Pathogenic prion proteins is
misfolded proteins
• These misfolded proteins cause
Creutzfeldt-Jakob disease [CJD] in humans and
“mad cow” disease in cattle.
• In humans, the “slow” agents cause central
nervous system diseases characterized by:
long incubation period.
 gradual onset.
 progressive, invariably fatal course.
There is no antimicrobial therapy for these
diseases.
• The human prion-mediated
diseases (e.g., kuru and CJD)
are called transmissible
spongiform
encephalopathies (TSE).
The term spongiform refers to
the spongy, Swiss cheese–like
holes seen in the brain
parenchyma that are caused
by the death of the neurons.
• No virus particles are seen
in the brain.
Transmission &Pathogenesis
• both kuru and CJD (and bovine spongiform
encephalopathy [BSE]—“mad cow” disease)
are acquired by ingestion.
• In this route, the prion protein must survive
digestion in the intestinal tract and then
penetrate the gut mucosa.
• The prion protein is then amplified
within follicle dendritic cells in lymphatic
tissue, such as Peyer’s patches.
• Prions then spread to the spleen, carried
by migrating dendritic cells.
• From the spleen, prions spread to the
central nervous system probably via the
sympathetic nerves.
• It is also possible that
prions reach the brain
within lymphocytes as
there is a documented case
of CJD that was acquired by
transfused blood.
• CJD has been transmitted
iatrogenically ( corneal
transplants, dura mater
grafts, implanted brain
electrodes, and growth
hormone extracts made
from human pituitary
glands).
Subacute Sclerosing Panencephalitis
(SSPE)
• It is a slowly progressive disease characterized
by inflammatory lesions in many areas of the
brain.
• The disease may develop due to reactivation
of the measles virus or an inappropriate
immune response to the measles virus.
• SSPE begins with mild changes in personality
and ends with dementia and death.
• SSPE is a persistent infection by a variant of
measles virus that cannot complete its
replication.

• The evidence for this is as follows:
 (1) Inclusion bodies containing helical
nucleocapsids, which react with antibody to
measles virus, are seen in the affected neurons.
(2) A virus very similar to measles virus.
 (3) Patients have high titers of measles antibody
in the blood and spinal fluid.
(4) SSPE has virtually disappeared by
immunization with measles vaccine.

Progressive multifocal
leukoencephalopathy (PML)
• PML is caused by JC virus, nonenveloped viruses with
a circular, double-stranded DNA genome.
• JC virus infects and kills oligodendroglia, causing
demyelination.
• Neurons are unaffected.
• Antibodies to JC virus are found in approximately
75% of normal human sera, indicating that infection
is widespread.
• Disease occurs when latent JC virus is activated in an
immunocompromised patient.
• The virus persists in the kidney and is excreted in the
urine.
Progressive multifocal
leukoencephalopathy (PML)
• It is a fatal demyelinating disease of the white matter
(i.e., leukoencephalopathy) and involves multiple areas
of the brain (i.e., multifocal).
• The clinical picture:
 visual field defects.
 mental status changes.
 weakness.
• The disease rapidly progresses to blindness, dementia,
and coma, and most patients die within 6 months.

summary 1:

### CNS Infection Summary: Poliovirus, Rabies, and Prion Diseases

**1. Poliovirus**
   - **Characteristics & Transmission**: Poliovirus, which causes poliomyelitis, is exclusive to primates and spreads via the fecal-oral route.
   - **Pathogenesis**: Initially replicates in the oropharynx and intestines, then spreads to the CNS, primarily targeting motor neurons in the spinal cord. Damage to these cells can result in paralysis.
   - **Clinical Forms**:
      - **Asymptomatic** to **abortive** (mild illness).
      - **Nonparalytic**: Aseptic meningitis with fever, headache, and stiff neck.
      - **Paralytic**: Flaccid paralysis, possibly life-threatening if respiratory muscles are involved.
      - **Post-Polio Syndrome**: Late-stage muscle deterioration years after recovery.
   - **Diagnosis**: Viral isolation from throat, stool, or spinal fluid; antibody titers.
   - **Prevention**: **Vaccines**—either IPV (inactivated) or OPV (live attenuated)—are critical, with OPV preferred in eradication due to stronger mucosal immunity. Booster doses are recommended for travelers to endemic areas.

**2. Rabies Virus**
   - **Transmission**: Spread through the bite or saliva of infected animals (e.g., bats, dogs).
   - **Pathogenesis**: After local replication at the bite site, the virus travels via nerves to the CNS, where it causes encephalitis and may lead to death.
   - **Clinical Presentation**:
      - **Prodrome**: Fever, anorexia, and tingling at the bite site.
      - **Two Forms**:
         - **Encephalitic**: Delirium, hydrophobia, seizures.
         - **Paralytic**: Ascending paralysis affecting motor functions.
   - **Diagnosis**: PCR, fluorescent antibody testing, and detection of Negri bodies in neurons.
   - **Prevention**:
      - **Post-Exposure Prophylaxis (PEP)**: Rabies immune globulin (RIG) and vaccine (HDCV) to induce immunity.
      - **Pre-Exposure Vaccination** for high-risk groups.

**3. Prion Diseases**
   - **Characteristics**: Prions are misfolded proteins without nucleic acid that cause transmissible spongiform encephalopathies, such as CJD (Creutzfeldt-Jakob disease) in humans, leading to a spongy appearance in the brain.
   - **Pathogenesis**: Prions enter via ingestion, replicate in lymphatic tissues, and spread to the CNS, causing progressive neurodegeneration.
   - **Transmission**: Can occur through contaminated surgical tools or infected tissue (e.g., dura mater grafts).
   - **Clinical Course**: Long incubation, gradual onset, fatal outcome; no effective treatment.

**4. Other Infection-Related Encephalopathies**
   - **Subacute Sclerosing Panencephalitis (SSPE)**: Linked to measles virus reactivation; causes progressive neurological deterioration leading to dementia and death.
   - **Progressive Multifocal Leukoencephalopathy (PML)**: Caused by JC virus in immunocompromised individuals; characterized by fatal demyelination of brain white matter, leading to visual deficits, mental changes, and paralysis.

summary 2 :
# CNS Infections Part 1

## Poliovirus Disease (Poliomyelitis)

### Characteristics
- Infects only primates (humans and some non-human primates) due to specific cell receptors.
- Three serotypes (antigenic types).

### Transmission
- **Fecal-oral route**.
- Replicates in the **oropharynx** and **intestinal tract**.

### Pathogenesis
- After replicating in the **oropharynx** and **small intestine** (especially in lymphoid tissues), the virus spreads to the **central nervous system (CNS)** via the bloodstream.
- It primarily infects **motor neurons in the spinal cord’s anterior horn**, leading to **muscle paralysis**.
- May also infect the **brainstem** (causing bulbar poliomyelitis with respiratory paralysis).
- Immune response includes **intestinal IgA** and **humoral IgG** against the serotype, granting **lifelong immunity**.

### Clinical Findings
- **Incubation period**: 10–14 days.
- **Types of infection**:
  1. **Asymptomatic** (most common).
  2. **Abortive poliomyelitis**: Mild febrile illness.
  3. **Nonparalytic poliomyelitis**: Aseptic meningitis.
  4. **Paralytic poliomyelitis**: Flaccid paralysis; brainstem involvement may lead to **respiratory failure**.
- **Post-polio syndrome**: Late deterioration in affected muscles, years after initial infection.

### Diagnosis
- **Virus isolation** from throat, stool, or spinal fluid.
- **Antibody titer** rise.
- **Cytopathic effect (CPE)** in cell cultures confirmed with neutralization assays.

### Treatment
- No antiviral therapy; treatment is **symptomatic**.
- **Respiratory support** and **physiotherapy** as needed.

### Prevention
- **Vaccines**:
  1. **Inactivated (IPV)** – Salk vaccine.
  2. **Live attenuated (OPV)** – Sabin vaccine, oral administration.
  - Both vaccines include all three serotypes.
  - OPV is preferred for eradication due to its ability to stimulate **mucosal IgA** and interrupt fecal-oral transmission.
- **Vaccination schedule**: Four doses by school entry and a booster for travelers to endemic areas.
- **Passive immunization** available post-exposure for unvaccinated individuals.

---

## Rabies Virus (Rhabdovirus)

### Characteristics
- **Single-stranded RNA** with a bullet-shaped, lipoprotein-enveloped capsid.
- Broad host range, infecting all mammals.

### Transmission
- **Bite of a rabid animal** (e.g., bats, dogs, cats) or exposure to infected **saliva**.
- **Non-bite exposure**: Aerosols of infected bat secretions or transplants (e.g., cornea).

### Pathogenesis
1. Virus replicates at the bite site, infects sensory neurons, and migrates to the **CNS** via axonal transport.
2. Virus spreads to **salivary glands** and other organs, causing **encephalitis** with neuron death and **demyelination**.
3. **Negri bodies** in neurons are diagnostic.

### Clinical Findings
- **Incubation period**: 2–16 weeks.
- **Symptoms**: Fever, anorexia, paresthesias. Two forms:
  1. **Encephalitic rabies**: Delirium, seizures, **hydrophobia**.
  2. **Paralytic rabies**: Ascending paralysis without hydrophobia.

### Diagnosis
- **Animal testing**: PCR, fluorescent antibody, and Negri body staining.
- **Human diagnosis**: PCR, fluorescent antibody, virus isolation, antibody titers, and Negri bodies in tissues.

### Prevention
- **Rabies vaccine (HDCV)** for high-risk groups (e.g., veterinarians) and post-exposure.
- **Post-exposure immunization**: Vaccine and **rabies immune globulin (RIG)**.
  - Five doses of HDCV on days 0, 3, 7, 14, and 28; RIG on day 0 at the bite site.

---

## Prion Diseases and Encephalopathies

### Prion Diseases
- **Characteristics**: Prions are misfolded proteins causing **spongiform encephalopathy** (Swiss cheese-like holes in the brain).
- **Pathogenesis**: Transmitted by ingestion, resistant to heat and UV. Amplify in lymphoid tissues before spreading to the CNS.
- **Diseases**:
  - **Creutzfeldt-Jakob Disease (CJD)** in humans.
  - **Kuru** and **Bovine Spongiform Encephalopathy (BSE)** ("mad cow" disease).
- **Transmission**: Ingestion, iatrogenic (e.g., corneal transplants, dura grafts).
  
### Subacute Sclerosing Panencephalitis (SSPE)
- **Cause**: Persistent measles virus infection leading to inflammatory brain lesions.
- **Symptoms**: Progressive personality changes, dementia, leading to death.
- **Diagnosis**: Presence of helical nucleocapsid inclusion bodies, high measles antibody titers.
- Immunization with measles vaccine has virtually eliminated SSPE.

### Progressive Multifocal Leukoencephalopathy (PML)
- **Cause**: JC virus reactivation in immunocompromised patients, targeting **oligodendroglia** and causing **demyelination**.
- **Symptoms**: Visual defects, mental changes, weakness, progressing to blindness and coma.
- **Prognosis**: Rapid progression, typically fatal within 6 months.