VIRAL INFECTIONS OF THE NERVOUS

SYSTEM
Dr. Rosalina Picar
Neurology

5. Hematogenous spread is
by far the most important

VIRUSES WITH PROCLIVITY TO INVADE

THE NERVOUS SYSTEM
1. Human
immunodeficiency virus
(HIV-1, HIV-2)
2. Herpes simplex virus
(HSV-1, HSV-2)
3. Epstein-Barr virus (EBV)
4. Cytomegalovirus (CMV)
5. Poliovirus, rabies
6. Arthropod-borne viruses

PATHWAYS OF INFECTION
1. Respiratory passages:
mumps, measles and
varicella
2. Oral-intestinal route:
poliovirus, enteroviruses
3. Oral-genital route: herpes
simplex virus
4. Inoculation (animal
bites): rabies or
mosquitoes (arboviruses)

PATHWAYS OF INFECTION
1. Following entry into the
body, the virus multiplies
locally and in secondary
sites and usually gives
rise to viremia
2. Viral particles are cleared
from the body by the
reticuloendothelial
system but if the viremia
is massive and other
conditions are favorable,
viruses invade the CNS
via the cerebral
capillaries and the
choroid plexuses
3. Along peripheral nerves:
(Herpes simplex, varicella
zoster, rabies viruse)
4. Trigeminal nerve and
gasserian ganglion

MECHANISMS OF VIRAL
INFECTIONS
1. To be susceptible to a
viral infection, the host
cell must have specific
receptor sites on its
cytoplasm to which the
virus attaches
2. Some infections are
confined to meningeal
cells (viral meningitis):
enteroviruses
3. Others will involve
particular classes of
neurons of the brain
(encephalitis) or spinal
cord (poliomyelitis)
4. The virus or its
nucleocapsid penetrates
the cell mainly by
endocytosis
5. For virus reproduction to
occur, the cell must have
the metabolic capacity to
transcribe and translate
virus-coated proteins,
replicate viral nucleic
acid and under the
direction of the viruss
genome, to assemble
viruses

1. ASEPTIC MENINGITIS

Clinical syndrome consists of

fever, headache, signs of
meningeal irritation and a
predominantly lymphocytic
pleocytosis and normal CSF
glucose
Acute onset; T 38-40 C;
headache is the most frequent
symptom
Variable degree of lethargy,
irritability and drowsiness;
confusion, stupor and coma are
rare
1

Photophobia and pain on

movement of the eyes are
common complaints
Accompanying neurologic signs
are mild and fleeting:
paresthesias in an extremity,
isolated diplopia, slight
inequality of reflexes or a
wavering Babinski sign
CAUSES
1. Enteroviruses: most
common (echovirus,
cocksackie)
2. Mumps: 2nd most
common
3. Herpes simplex virus-2
4. Lymphocytic
choriomeningitis
5. Adenoviruses
6. Epstein-Barr virus
(infectious
mononucleosis)
7. Leptospirosis
8. Influenza virus
MANAGEMENT
Repeated lumbar
punctures for CSF culture
and cytology
MRI of the brain and
spinal cord
If increased CSF pressure,
treatment with steroids
should be tried
Trial of antiviral agents
and broad-spectrum
antimicrobials seems
reasonable
Biopsy of the meninges
(for febrile meningitis for
more than several weeks)
may yield a diagnosis in
5-25%

2.ACUTE ENCEPHALITIS
Syndrome consists of an acute
febrile illness with evidence of

meningeal involvement added

to which are the following:
1. Convulsions, delirium,
confusion, stupor or coma
2. Aphasia or mutism
3. Hemiparesis with
asymmetry of tendon
reflexes and Babinski
signs
4. Involuntary movement,
ataxia and myoclonic
jerks
5. Nystagmus, ocular
palsies and facial
weakness
Spinal fluid shows a cellular
reaction; protein is slightly
elevated
Imaging may show brain edema
or enhancement of the cortex,
and infrequently, subcortical
and deep nuclear involvement
2 Forms:
1. Direct invasion of the
brain and meninges (true
viral encephalitis: more
common)
2. Postinfectious
encephalomyelitis: an
autoimmune reaction to
the systemic viral
infection but in which the
virus is not present in
neural tissue

2A.HERPES SIMPLEX ENCEPHALITIS

The commonest and gravest

form of acute encephalitis
Between 30-70% are fatal;
majority of patients who survive
are left with serious neurologic
abnormalities
Almost always due to HSV-1
(also the cause of common
herpetic lesions of the oral
mucosa)
Type 2 virus encephalitis:
usually in neonates (genital
herpetic infection in the mother)
2

Type 2 infection in the adult:

aseptic meningitis,
polyradiculitis or myelitis in
association with a recent genital
herpes infection
CLINICAL FEATURES
Fever, headache,
seizures, confusion,
stupor and coma
Predilection for the
infero-medial frontal and
temporal lobes: olfactory
or gustatory
hallucinations, anosmia,
temporal lobe seizures,
personality changes,
bizarre or psychotic
behavior or delirium,
aphasia and hemiparesis
CSF is under increased
pressure with pleocytosis
(mainly lymphocytes) and
red cells (reflect
hemorrhagic nature of
the lesions); increased
protein
PATHOLOGY
Intense hemorrhagic
necrosis of the inferior
and medial parts of the
temporal lobes and the
medial-orbital parts of
the frontal lobes
Intranuclear eosinophilic
inclusions found in
neurons and glial cells
Unique localization
possibly explained by the
viruss route of entry into
the CNS
The virus is
thought to be
latent in the
trigeminal ganglion
and with
reactivation,

infects the nose

and the olfactory
tract
Alternatively, the
infection may
spread along fibers
that innervate the
leptomeninges of
the anterior and
middle fossa

HERPES SIMPLEX VIRUS 1

HERPES SIMPLEX ENCEPHALITIS

DIAGNOSIS
1. EEG: lateralized periodic
high voltage sharp waves
2-3/second (PLEDS)
2. CT scan and MRI:
scattered areas of
hemorrhage
3. Detection of HSV antigen
in the CSF by polymerase
chain reaction (PCR);

positive in the first 3

weeks of illness
4. Fluorescent antibody
study and by viral culture
of cerebral tissue
obtained by brain biopsy

1. Practically all cases are

the result of transdermal
viral inoculation by an
animal bite (dogs,
raccoons, skunks, foxes,
bats and cats)
2. Virus spreads along
peripheral nerves to
reach the central nervous
system

TREATMENT
Within the first 4 days: good
outcome, survival rate is > 90%
1. Acyclovir: 30 mg/kg/day
IV for 10-14 days
2. Corticosteroids for brain
edema
3. Anticonvulsants
NEUROLOGIC SEQUELAE
1. Korsakoff amnesic defect
2. Global dementia
3. Seizures
4. Aphasia

2B. RABIES
Almost invariably fatal once the
clinical features appear
ETIOLOGY

CLINICAL FEATURES
1. Incubation period usually
10-20 days but may be as
short as 14 days (in
multiple deep bites
around the face and
neck)
2. Tingling or numbness at
the site of the bite even
after the wound has
healed (inflammatory
response when the virus
reaches the sensory
ganglion)
3. 2-4 day prodromal period
of fever, headache and
malaise
4. Severe apprehension,
dysarthria, psychomotor
overactivity
5. 5. Dysphagia, salivation
and frothing at the mouth
6. 6. Spasms of throat
muscles induced by
attempts to swallow
water or in rare cases, by
the mere sight of water
(hydrophobia)
7. 7. Generalized seizures,
confusional psychosis
and agitation
8. 8. Coma gradually follows
the acute encephalitic
symptoms and death
within 4-10 days or
longer

4.

5.

PATHOLOGIC FEATURES
1. Presence of cytoplasmic
inclusions: negri bodies
(prominent in the
pyramidal cells of the
hippocampus and the
Purkinje cells)
2. Widespread perivascular
cuffing and meningeal
infiltration with
lymphocytes and
mononuclear cells and
small foci of
inflammatory necrosis
3. Inflammatory reaction is
most intense in the
brainstem
4. Focal collections of
microglia: Babes nodules

Negri Bodies

6.

7.
8.

the animal for a 10-day

period
Should signs of illness
appear in the animal, it
should be killed and the
brain is sent for
investigation
5. If the patient is bitten
by an animal which
escaped, give
postexposure prophylaxis
Human rabies immune
globulin (HRIG): 20 u/kg,
infiltrated around the
wound and
intramuscular
Deck embryo vaccine
(DEV): 23 doses
Human diploid cell
vaccine (HDCV): 5 doses;
1 ml injections on the day
of exposure and then on
days 3,7,14,28 after the
first dose

2C. HERPES ZOSTER (SHINGLES)

Becomes increasingly common
with advancing age; distinctly
rare in childhood
An inflammatory reaction in one
or more dorsal root or cranial
nerve ganglia, in the affected
root or nerve itself and in the
CSF
Characterized clinically by
radicular pain, a vesicular
cutaneous eruption and less
often by segmental sensory and
motor loss

TREATMENT
1. Wash wound thoroughly
with soap and water
2. Cleanse with benzyl
ammonium chloride
(zephiran)
3. After a bite by a
seemingly healthy
animal, surveillance of
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pain and speeds the healing of the

vesicles

Agent is a varicella or varicella

zoster (VZ) virus
Common in patients with
lymphoma, following regional
chemotherapy
CLINICAL FEATURES
1. Initially, a burning or
stabbing pain in the
involved dermatome
followed by the
development of a
vesicular erythematous
rash
2. Pain and dysesthesia may
persist for many months
(postherpetic neuralgia)
3. Superficial sensation
often impaired in the
affected dermatome;
focal weakness and
atrophy may occur
4. Most commonly involved
sites are the thoracic dermatomes and
trigeminal nerve
5. Facial nerve palsy occurring
in association with a herpetic eruption
in the ear, palate and pharynx:
RAMSAY HUNT SYNDROME
TREATMENT
Acute stage: analgesics, drying
and soothing lotions
Acyclovir (800 mg, 5X/day for 7
days) shortens the duration of acute

TREATMENT
Postherpetic Neuralgia
1. Amitryptiline 50-125
mg/day
2. Addition of
carbamazepine,
gabapentin or valproic
acid may further
moderate the pain
3. Capsaicin ointment can
be applied
4. Two aspirin tablets,
crushed and mixed with
cold cream or chloroform
(15 ml) and spread on the
painful skin
5. Post herpetic neuralgia
eventually subsides even
in the most severe and
persistent cases

PATHOLOGY
Pathologic changes consist of
one or more of the following:
1. An inflammatory reaction
in several unilateral
adjacent sensory ganglia
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of the spinal or cranial

nerves
2. An inflammatory reaction
in the spinal roots and
peripheral nerves
contiguous with the
involved ganglia
3. A poliomyelitis closely
resembling anterior polio
but is unilateral,
segmentally localized
with greater involvement
of dorsal horn, root and
ganglia
4. Relatively mild
leptomeningitis (limited
to the involved spinal or
cranial segments and
nerve roots)

PATHOGENESIS
Represents a spontaneous
reactivation of VZ virus
infection, which becomes latent
in the sensory ganglion
following a primary infection
with chickenpox
Chicken pox is highly
contagious, has a wellmarked seasonal
incidence and tends to
occur in epidemics
Zoster is not
communicable except to
a person who has not had
chickenpox, occurs
sporadically throughout
the year and shows no
increase in incidence
during epidemics of
chickenpox

PATHOGENESIS
Once activated, it progresses
down the axon to the skin
Viral multiplication in epidermal
cells causes swelling,
vacuolation and lysis of cell
boundaries, leading to the
formation of vesicles

Reactivation of the virus is

attributed to waning immunity

2D. ARBOVIRAL ENCEPHALITIS

Alternating cycles of viral
infection in mosquitoes and
vertebrate hosts
The mosquito becomes infected
by taking a blood meal from a
viremic host (horse or bird) and
injects virus into the host
(humans)
Antiviral IgM can be detected
and quantified
CLINICAL MANIFESTATIONS
Fever and convulsions
Headaches, dizziness,
nausea and vomiting
Photophobia, diffuse
myalgia, tremors
Reflex asymmetry,
hemiparesis, myoclonus,
chorea and sucking and
grasping reflexes may
occur
PATHOLOGIC CHANGES
Widespread degeneration
of nerve cells, scattered
foci of inflammatory
necrosis involving both
gray and white matter
Brainstem is relatively
spared
SEQUELAE
Eastern equine
encephalitis: the most
serious of the arboviruses
but also the least
frequent
Mental retardation,
emotional disorders,
recurrent seizures,
blindness, deafness,
speech disorders (e.g.,
eastern equine virus)
Mortality rate among
arbovirus infections: 212%
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3. ACUTE POLIOMYELITIS
Still a frequent illness in regions
of the world where vaccines are
not available
ETIOLOGY AND
EPIDEMIOLOGY
1. Caused by small RNA
viruses that are members
of the enterovirus group
of the picornavirus family
2. Highly communicable
3. Main reservoir of
infection is the human
intestinal tract; main
route is fecal-oral
4. Virus multiplies in the
pharynx and intestinal
tract
5. Incubation period: 1-3
weeks
6. Between 95-99% of
infected patients are
asymptomatic (carrier)
and are most important
in the spread of the virus
from one person to
another

POLIO VIRUS

- Sore throat in the

absence of respiratory tract infection,
anorexia, nausea and vomiting
- Tenderness and pain in
the muscles, tightness of the
hamstrings
- Kernig and Brudzinskis
signs
- Characteristic CSF
finding: aseptic meningitis
- Symptoms may
constitute the entire illness,
alternatively, the preparalytic
symptoms may be followed by
paralytic ones
CLINICAL FEATURES (2
FORMS)
2. PARALYTIC
- Muscle weakness may
develop rapidly with maximum
severity in 48 h
- No progression of
weakness after the temperature has
been normal for 48 h
- Tendon reflexes are
diminished; paralyzed muscles
become flaccid
- Objective sensory loss
seldom demonstrable
- Bulbar paralysis more
common in young adults: muscles of
deglutition, reflecting involvement of
the nucleus ambiguus
- Disturbances of
respiration and vasomotor control:
hiccough, shallowness and progressive
slowing of respiration, cyanosis

CLINICAL FEATURES (2
FORMS)
1. NONPARALYTIC OR
PREPARALYTIC
- Listlessness,
generalized nonthrobbing headache,
fever, stiffness and aching of the
muscles

PATHOLOGY
Lesions found in the
precentral gyrus of the
brain, brainstem and
spinal cord
Brunt of the disease
borne by the
hypothalamus, thalamus,
motor nuclei of the
brainstem and
surrounding reticular
formation, vestibular
nuclei and the
intermediolateral gray of
the spinal cord
Nerve cells are destroyed
and phagocytized by
microgliocytes
Nuclear or cytoplasmic
inclusion bodies are not
seen
Atrophic, areflexic
paralysis of muscles of
the trunk and limb relates
to destruction of neurons
in the anterior horns
TREATMENT

Careful observation of
swallowing function, vital
capacity, pulse and blood
pressure
With paralysis of limb
muscles: foot boards,
hand and arm splints
Respiratory support and
tracheostomy in
respiratory failure
No known systematic
study on the potency of
antiviral agents in
poliomyelitis

PREVENTION (most
significant aspect of
treatment)
Sabin vaccine:
attenuated live virus,
given orally in 2 doses 8
weeks apart; boosters at
1 year old and before
starting school
PROGNOSIS
Mortality is between 510%, higher in the elderly
and very young
Paralysis of respiration
and deglutition usually
recovers completely
May also recover
completely from
muscular weakness:
return of muscle strength
in the first 3-4 months
4. SUBACUTE AND
CHRONIC VIRAL
INFECTIONS
SIMULATING
DEGENERATIVE
DISEASE

4A. SUBACUTE SCLEROSING

PANENCEPHALITIS (SSPE)
Affects children and
adolescents for the most
9

part, rarely appearing

beyond 10 years old
Typically, a history of
primary measles infection
before 2 years old
followed by a 6-8 year
asymptomatic period

CLINICAL FEATURES
1. Decline in proficiency at
school, temper outbursts
and other changes in
personality, difficulty with
language and loss of
interest in usual activities
2. Severe and progressive
intellectual deterioration
with focal or generalized
seizures, widespread
myoclonus, ataxia
3. Rigidity, hyperactive
reflexes, Babinski signs,
progressive
unresponsiveness and
autonomic dysfunctions
4. Insensate, virtually
decorticate posture
5. Death in 1-3 years
DIAGNOSIS
1. EEG: periodic bursts of 23/second high-voltage
waves, followed by a
relatively flat pattern
2. CSF with few or no cells
but protein is increased
(CSF IgG)
3. Both the serum and CSF
have high concentrations
of measles antibody
TREATMENT
1. No effective treatment
available;
anticonvulsants:
clonazepam
2. Amantadine and inosiplex
may lead to improvement
and prolong survival

PATHOLOGY
1. Lesions involve the
cerebral cortex and white
matter of both
hemispheres and the
brainstem; cerebellum
usually spared
2. Destruction of nerve
cells, neuronophagia and
perivenous cuffing by
lymphocytes and
mononuclear cells
3. Eosinophillic inclusions
(hallmark of the disease)
in the cytoplasm and
nuclei of neurons and
glial cells
4. Delay in the development
of immune responses
during the initial infection
and later development of
immune responses that
are incapable of clearing
the suppressed infection

4B. SUBACUTE MEASLES

ENCEPHALITIS WITH
IMMUNOSUPPRESSION
In children and adults with
defective cell-mediated immune
responses; 1-6 months after
exposure to measles
Seizures, focal neurologic signs,
stupor and coma are the main
features
Lesions similar to SSPE
(eosinophilic inclusions in
neurons and glia) but no
inflammatory changes
An opportunistic infection of the
brain in an
immunocompromised patient:
short interval between exposure
and onset, rapid course, lack of
antibodies
4C. PROGRESSIVE RUBELLA
PANENCEPHALITIS
10

Either congenital or acquired

rubella syndromes
CLINICAL FEATURES
1. Deterioration in behavior
and school performance
2. Gait clumsiness, followed
by frank ataxia of the gait
and limb
3. Seizures, progressive
impairment in mental
functions
4. Pallor of the optic discs,
ophthalmoplegia, spastic
quadriplegia and mutism
CSF: mild increase in
lymphocytes, elevated protein,
marked increase in the
proportion of gamma globulin
Elevated CSF and serum
rubella-antibody titers
PATHOLOGY: widespread
progressive subacute
panencephalitis mainly affecting
the white matter; no inclusionbearing cells

4D. PROGRESSIVE MULTIFOCAL

LEUKOENCEPHALOPATHY (PML)
Widespread demyelinative
lesions in the cerebral
hemispheres, brainstem and
cerebellum
Distinct abnormalities of the
glial cells: gigantic and
deformed cells with bizarreshaped nuclei with mitotic
changes
At the periphery of the lesions,
the nuclei of oligodendrocytes
are greatly enlarged and
contain abnormal inclusions
Lacks vascular changes;
insignificant inflammatory
changes

CLINICAL FEATURES
1. Develops in a patient
with neoplasm or chronic
immunodeficiency states
2. Personality changes,
intellectual impairment
3. Hemiparesis, visual field
defects, cortical
blindness, aphasia,
ataxia, dysarthria,
dementia
4. Confusional states, coma
5. Death in 1-6 months
6. CSF is normal; CT scan
and MRI localize the
lesions with striking
clarity

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