Transcript Viral Infections of the Central Nervous System

Viral Infections of the Central
Nervous System
Introduction
• Anatomic considerations are important in
infections of the CNS.
- the brain and spinal cord are protected by bone
and meningeal coverings that compartmentalize
infection.
- they are divided by barriers from the systemic
circulation.
- they lack an intrinsic immune system
- they have a unique compact structure.
Natural Defenses of the CNS
 Skull
and vertebrae
 Microglial
cells and macrophages
 Restricted
entry into brain (blood-brain barrier)
for:
 microorganisms
 medications, including antibiotics
 immune system
• The blood-brain barrier largely prevents
macromolecules from entering the brain
parenchyma.
• The space between cells in the brain parenchyma
is too small to permit passage even of a virus.
• However, tetanus toxin and some viruses travel
through the CNS by axoplasmic flow.
• Most agents invade from blood.
• Bacteria grow rapidly in cerebrospinal fluid; viruses
infect meningeal and ependymal cells.
Immune System
• Levels of IgG and IgA in the CSF are
approximately 0.2 to 0.4 percent of the serum
levels. IgM is present at even lower levels.
• There is also no lymphatic system in the usual
sense, and few phagocytic cells.
• Complement is also largely excluded.
• When trauma or inflammation disrupts the
blood-brain barrier, antibody molecules
passively leak into the CNS along with other
serum proteins.
• When an inflammatory reaction has been
mounted against an infection, B cells from the
peripheral circulation can move into the
perivascular spaces of the CNS and generate
immunoglobulins intrathecally.
• Types of CNS infections include; meningitis,
encephalitis, myelitis, and meningoencephalitis
or meningoencephalomyelitis
Meningitis
• Meningitis is an infection which causes
inflammation of the membranes covering the brain
and spinal cord.
• Bacterial meningitis may be referred to as ‘purulent
meningitis’. Non-bacterial meningitis is often
referred to as ‘aseptic meningitis’ – eg. viral
meningitis
• Causes and risks
- The most common causes of meningitis are viral
infections that usually resolve without treatment.
- Bacterial infections of the meninges are extremely
serious illnesses, and may result in death or brain
damage even if treated.
Aseptic Meningitis
Aseptic Meningitis
• Definition: A syndrome characterized by acute onset
of meningeal symptoms, fever, and cerebrospinal fluid
pleocytosis, with bacteriologically sterile cultures.
• Laboratory criteria for diagnosis:
- CSF showing ≥ 5 WBC/cu mm and elevated protein
- No evidence of bacterial or fungal meningitis.
• Confirmed case: a clinically compatible illness
diagnosed by a physician as aseptic meningitis, with
no laboratory evidence of bacterial or fungal
meningitis
• Viral meningitis is more common than bacterial
meningitis and it is often less severe than
bacterial meningitis.
• Recovery is almost always complete, since only
meningeal and ependymal cells are involved.
• The disease is benign and tends to be
seasonal.
Aseptic meningitis syndrome
• Acute onset of fever, headache, neck pain/stiffness,
vomiting, and meningeal irritation signs
• No confusion/stupor
• CSF:
  WBC
  protein
 normal glucose
• Negative bacterial culture of CSF
Clinical Manifestations
• Manifestations vary depending on age; below 2 years
and above 2 years.
• In older children and adults: main
manifestations of
meningitis are headache, fever, and nuchal rigidity.
• Flexion of the neck may also cause reflex flexion of the
legs (Brudzinski sign), and meningeal irritation may
limit extension of the leg when flexed at the knee
(Kerning sign).
• Meningeal inflammation may also cause some degree
of obtundation (reduced consciousness), and seizures
are common in children.
Brudzinski’s Neck Sign
Kernig’s Sign
Symptoms of meningitis
Adults and children
Babies, neonates and the elderly often present atypically
.
• Systemic clinical signs sometimes suggest the
agent (e.g., the rash or herpangina of
enterovirus infections and the parotitis of
mumps).
• Examination of the CSF provides the most
important diagnostic information.
• In general, viruses produce a modest
mononuclear cell response, and although the
CSF protein may be elevated, CSF sugar is
normal or only mildly depressed.
Causative Agents of Aseptic Meningitis
• Viruses
•
 Enteroviruses
 Herpesviruses (HSV- 1, HSV- 2, EBV, HHV- 6, VZV)
 HIV
 Lymphocytic choriomeningitis
 Mumps
 Arboviruses
 West Nile virus
Numerous other causes e.g., Lyme disease,
leptospirosis, 2º syphilis, partially-treated bacterial
meningitis, TB, Cryptococcus, autoimmune disease,
and medications
• Enteroviruses (echoviruses and Coxsackie's
viruses) are the most common cause, and they
cause disease primarily in the late summer and
early fall.
• Mumps virus is the second most common
cause in unvaccinated communities and it
spreads predominantly in the spring.
• Lymphocytic choriomeningitis virus is more
common in winter, since this virus is acquired
from mice, which move indoors during cold
weather and increase human exposure.
• Most viruses invade the CNS from the blood, and the
risk of CNS invasion has been shown to be related to
the magnitude and duration of viremia.
• The virus may cross the BBB directly at the capillary
endothelial level or through natural defects such as
the area postrema and other sites that lack a BBB.
• Particles in the blood, including bacteria or viruses,
are normally cleared by the reticuloendothelial system,
and speed of removal is proportional to size.
• A variety of viruses elude clearance by replicating
within blood cells.
• Enteroviruses and some arboviruses are
cleared less effectively from blood because of
their small size.
• Some viruses enter the CNS by infecting
endothelial cells or choroid plexus epithelium.
• Indeed, in mumps virus meningitis, choroid
plexus cells containing viral nucleocapsids are
frequently found within the CSF.
Diagnostic test for meningitis :
lumbar puncture
•A lumbar puncture
collects cerebrospinal
fluid to check for the
presence of disease
or injury.
•A spinal needle is
inserted, usually
between the 3rd and
4th lumbar vertebrae
in the lower spine.
Typical CSF findings in Meningitis
Bacterial meningitis
1. Presence of neutrophils
in the CSF is associated
with infection by N.
meningitidis, S.
pneumoniae etc.
2. CSF protein level reflects
the degree of meningeal
inflammation:10 X in bacterial
infections
3. CSF glucose levels:very low in bacterial
infections
Viral meningitis
1. Presence of lymphocytes is
associated with infection by
viruses or mycobacteria.
Neutrophils increase in the
first 24-48 hours, then
replaced by lymphocytes.
2. CSF protein level reflects
the degree of meningeal
inflammation:2-3 X in viral CNS infection
3. CSF glucose levels:
normal with viral infections
Epidemiology
 Incidence
varies depending on age and
geography, ranging from 11-219 cases per
100,000 population.
 Incidence is highest in children aged 1-4 years
and it decreases with age
 Males are more commonly affected than
females.
 No specific racial predilection has been
identified.
 Mortality is low being less than 1%
Management
• Most cases of viral meningitis require only
symptomatic treatment.
• Since the disease is self-limited; the prime
management problem is to rule out nonviral,
treatable illnesses that can mimic acute viral
meningitis.
• Examples are; partially treated bacterial
meningitis, tuberculous or fungal meningitis,
syphilis, Lyme disease, etc.)
Enteroviral Meningitis
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Enteroviruses are thought to be the most common
cause of viral meningitis
Account for >50% of cases and approximately 90% of
cases in which a specific etiologic agent is identified.
Majority of cases are in children or adolescents, but
patients of any age can be affected.
Transmitted primarily by fecal-oral route, but can also
be spread by contact with infected respiratory
secretions.
The incidence is increased in the summer months, but
cases occur throughout the year.
Sporadic outbreaks are generally associated with
specific serotypes (eg, ECV-30), typically related to
introduction of new virus strain to a region.
Enterovirus Lab Findings

CSF- findings typical of viral meningitis
- Lymphocytic pleocytosis of generally <250 cells/mm3,
with modest protein elevation generally <150 mg/dl,
and normal glucose
- Viral cultures positive in 40-80% of cases but it usually
takes 4-12 days to become positive
- PCR is the most specific (close to 100%) and sensitive
(97-100%) test and is positive in more than 2/3 of
culture negative CSF in patients with aseptic
meningitis
Herpes Simplex Meningitis
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Generally caused by HSV-2 (as opposed to encephalitis
which is caused by HSV-1)
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Increasingly recognized as a cause of aseptic meningitis,
with improving diagnostic techniques and a continued
increase in the transmission of HSV-2
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Can be due to primary or recurrent HSV infection
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Between 13 and 36% of patients presenting with primary
genital herpes have clinical findings consistent with
meningeal involvement including headache, photophobia,
and meningismus.
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Occasionally patients present with more severe signs
including urinary retention, paresthesias, weakness of
upper or lower extremities, or ascending myelitis.
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The genital lesions are typically present (85% of the
time), and usually precede the CNS symptoms by
seven days.
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HSV meningitis can be recurrent, these patients may
not have clinically evident genital lesions.
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For patients with benign recurrent lymphocytic
meningitis, careful analysis has revealed that over
80% are due to HSV meningitis.
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It is also likely the cause of a large percentage of
patients with Mollaret’s meningitis, which is a form of
recurrent meningitis characterized by large monocytic/
macrophage lineage cells in the CSF.
HSV Diagnosis
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CSF- typical of a viral meningitis, with lymphocytic
pleocytosis, modest elevation in protein, and normal
glucose.
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Viral cultures are positive in about 80% of patients
with primary HSV meningitis, but less frequently
positive in patients with recurrent HSV meningitis.
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HSV PCR of the CSF is the single most useful test for
the evaluation of a patient with suspected HSV
meningitis.
HIV meningitis
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A subset of patients with primary HIV infection will
present with meningitis or meningoencephalitis,
manifested by headache, confusion, seizures or cranial
nerve abnormalities.
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HIV atypical meningitis is characterized by chronicity
and recurrence.
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Reports have suggested that as many as 5-10% of HIV
infections can be heralded by meningitis.
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Aside from the usual meningeal signs, HIV infections may also
cause global encephalopathy, seizures, and focal neurologic
deficits.
Diagnosis of HIV Meningitis
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Serum might reveal atypical lymphocytosis,
leukopenia, and elevated serum aminotransferases.
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Documentation of seroconversion or detection of HIV
plasma viremia by nucleic acid techniques can be
used for diagnosis.
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CSF- might show a lymphocytic pleocytosis, elevated
protein, and normal glucose.
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CSF cultures are often positive, but are not available
in most centers.
Lymphocytic Choriomeningitis Virus
• LCM is thought to be an underdiagnosed cause of viral
meningitis, in one review it was noted to be responsible for 1015% of cases.
• LCM is excreted in the urine and feces of rodents, including
mice, rats, and hamsters.
• It is transmitted to humans by either direct contact with infected
animals or environmental surfaces
• Transmission can occur by inhaling aerosolized particles of
rodent excrement, by ingesting food contaminated with the
virus or by direct contact of mucus membranes with infected
fluids (lab and pets).
• Infection occurs more commonly in the winter months.
• Incubation Period = 8 –13 days
• Symptoms:
Biphasic febrile illness.
 Initial phase: fever, malaise, headache, muscle
aches, anorexia, nausea and vomiting.
 Second phase: After a few days of remission,
symptoms of meningitis and rarely encephalitis.
• The mortality rate is <1%.
Most patients
recover completely
• Treatment:
Supportive care
LCM Diagnosis
 CSF-
typical of other viral meningitis causes
except that 20-30% of the time low glucose
levels are present, and cell counts of >
1000/mm3 are not unusual
 Diagnosis
is made by documentation of
seroconversion to the virus in paired serum
samples.
Mumps Meningitis
 Prior
to the introduction of the mumps vaccine
in 1967, it accounted for 10-20% of all cases of
viral meningitis.
 Even
now this virus causes a significant
minority of cases in unvaccinated adolescents
and adults.
 In
patients who do acquire mumps, CNS
infection occurs rather frequently, with CSF
pleocytosis detected in 40-60%.
 Males
aged 16-21 years are at highest risk of
developing this infection, with a 3:1 male/female
ratio.
 Clusters
of cases occur in schools and colleges
in the winter months.
 Concomitant
parotitis is a helpful clinical tool
but may be absent in as many as half of cases
with CNS involvement.
Mumps Diagnosis

CSF- similar to other viral causes, but like LCM it can
induce a lymphocytic pleocytosis with cell counts
>1000/mm3 or a decreased glucose <50mg/dl, can
isolate the virus from the CSF
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Can document seroconversion
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Clinical correlation is very helpful, especially if the
patient has parotitis or orchitis.
West Nile virus
• Most infected individuals develop WNV fever
• Time from mosquito bite to illness ranges from 3-14
days
• Fever, chills, headache, fatigue can be severe
• Nausea and vomiting can develop
• Rash, usually not itchy, lasting a few days, mainly on
chest, back, abdomen, and/or arms
• Persistent fatigue is common and may continue for
months, even among otherwise healthy persons
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In one study, “~96% of patients with WNF described postillness fatigue that lasted a median of 36 days” (Sejvar,
2007)
West Nile Virus
 Season:
summer
 Mosquito transmission (currently infects
43/ 174 different types of North American
mosquitoes)
 Other routes
 Placenta
 Lactation
 Transfusion
 Organ transplant
WNV
 Presenting
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symptoms
Headache, fever, mental status changes
CN findings, optic neuritis
Myoclonus
 Flaccid
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Paralysis
With or without encephalitis
Asymmetric weakness/paralysis, no
sensory loss
Anterior horn cells (polio like)
WNV
 Movement
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Disorders
Parkinsonian
Tremors
Bradykinesia
Cogwheel rigidity
Postural instability
Masked facies
80-100% will have rest or intention tremor
30% will have myoclonus
WNV: Predictors
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Admission diagnoses:
 30%: aseptic meningitis
 15%: fever
 18%: viral infection
 14%: UTI
 10% pneumonia
 7% : encephalitis
 5%: probable WNV (year 2001)
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Mortality rates highest with:
Initial diagnosis of encephalitis (35% of those who died),
No headache (50% had headache, 7% those that died had
headache), and
Initial mental status changes
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