- Arthropod-Borne Viral Encephalitis
- Herpes Simplex Virus Type 1
- Herpes Simplex Virus Type 2
- Varicella-Zoster Virus (Herpes Zoster)
- Human Immunodeficiency Virus
- Progressive Multifocal Leukoencephalopathy
- Subacute Sclerosing Panencephalitis
What is Viral encephalitis?
It is a parenchymal infection of the brain almost invariably associated with
meningeal inflammation (meningoencephalitis) and sometimes with simultaneous involvement of
the spinal cord (encephalomyelitis).
Some viruses tend to infect the nervous system.
Such neural tropism takes several forms:
- some viruses infect specific cell types (such as oligodendrocytes),
- while others preferentially involve particular areas of the brain (such as medial temporal lobes or the limbic system).
What __________y is an
important facet of several viral infections of the CNS (e.g., herpes zoster, progressive multifocal
What viruses exhibit latency?
Systemic viral infections in the absence of direct evidence of viral penetration into the CNS may be followed by an __________ (see “Acute Disseminated Encephalomyelitis and _______________.
immune-mediated disease, such as perivenous
and Acute Necrotizing Hemorrhagic
Intrauterine viral infection may cause congenital malformations, as occurs
A slowly progressive degenerative disease syndrome may follow many years after
a viral illness; an example is____________ after the 1918 viral influenza pandemic.
____________ are an important cause of epidemic encephalitis, especially in tropical regions of
the world, and they are capable of causing serious morbidity and high mortality.
In the Western
hemisphere the most important types are :
- Eastern and Western equine,
- West Nile,
- St. Louis, and La Crosse;
- elsewhere in the world, pathogenic arboviruses include Japanese B (Far East),
- Murray Valley (Australia and New Guinea),
- and tick-borne (Russia and Eastern Europe).
All have animal hosts and mosquito vectors, except for the ________________
What is the clinical manifestation of viral neurological diseases?
- affected individuals develop generalized neurologic deficits, such as:
- and stupor or coma
- , and often focal signs,
- such as reflex asymmetry and
- ocular palsies.
- and stupor or coma
- , and often focal signs,
- such as reflex asymmetry and
- ocular palsies.
Involvement of the spinal cord in ____________ can lead to a polio-like syndrome with paralysis.
West Nile encephalitis
What is the appearance of arthropod-borne Viral Encephalitis?
The CSF is usually :
- but with a slightly elevated pressure and,
- initially, a neutrophilic pleocytosis that rapidly converts to lymphocytes;
- the protein concentration is elevated,
- but glucose content is normal.
The encephalitides caused by various arboviruses differ in ____________but the histopathologic picture is similar, except for variations in the severity and
extent of the lesions within the CNS.
What is the characteristic of encephalitis caused by arbovirus? ,
- there is a lymphocytic meningoencephalitis (sometimes with neutrophils),
- and a tendency for inflammatory cells to
accumulate perivascularly ( Fig. 28-23A ).
- Multiple foci of necrosis of gray and white matter
- are found;
- in particular, there is evidence of single-cell neuronal necrosis with phagocytosis of
- the debris (neuronophagia).
Microglial cells form small aggregates around foci of necrosis, called microglial nodules ( Fig. 28-23B ).
In severe cases in encephalitis caused by arbovirus there may be a ________________
- necrotizing vasculitis with associated focal hemorrhages.
- While some viruses reveal their presence by inclusion bodies
the identification of viral pathogens is most often by a combination of
- and molecular methods.
______________) encephalitis is most common in children and young adults.
Herpes simplex virus type 1 (HSV-1
Only about ____________ of the affected individuals have a history of prior herpes.
The most commonly
observed clinical presenting symptoms in herpes encephalitis are___________
- alterations in mood,
- and behavior.
_____________ for virus detection in CSF
samples have increased the ease of diagnosis and the recognition of a subset of patients with
less severe disease.
Polymerase chain reaction (PCR)–based methods
Antiviral agents now provide effective treatment in many cases, with a
significant reduction in the mortality rate.
In some individuals, HSV-1 encephalitis follows a
subacute course with clinical manifestations (weakness, lethargy, ataxia, seizures) that evolve
during a more protracted period (4 to 6 weeks).
What is the characteristic of HSV encephalitis?
This encephalitis starts in, and most severely involves, the inferior and medial
regions of the temporal lobes and the orbital gyri of the frontal lobes ( Fig. 28-24 ).
infection is necrotizing and often hemorrhagic in the most severely affected regions.
What is the inclusion body seen in HSV-1?
Perivascular inflammatory infiltrates are usually present, and Cowdry type A intranuclear viral
inclusion bodies may be found in both neurons and glia.
In individuals with slowly evolving
HSV-1 encephalitis, there is more diffuse involvement of the brain.
____________also infects the nervous system;
in adults it causes
meningitis, but as many as 50% of neonates born by vaginal delivery to women with active
primary HSV genital infections acquire the infection during passage through the birth canal and
develop severe encephalitis.
Herpes simplex virus type 2 (HSV-2)
In the face of active HIV infection, HSV-2 may cause an____________-
- necrotizing encephalitis
Primary varicella infection presents as one of the childhood _____________, ordinarily
without any evidence of neurologic involvement.
What is the pathophysio of Varicella Zoster Virus?
Following the cutaneous infection, the virus
enters a latent phase within sensory neurons of the dorsal root or trigeminal ganglia.
Reactivation of infection in adults (“shingles”) usually manifests as a painful, vesicular skin
eruption in a single or limited dermatomal distribution.
Herpes zoster reactivation is usually a self-limited process, but there may be a persistent postherpetic neuralgia syndrome particularly
after age 60, including both persistent pain as well as painful sensation following nonpainful
Overt CNS involvement with herpes zoster is much rarer but can be severe.
Herpes zoster has
been associated with a g___________; immunocytochemical and electron microscopic
evidence of viral involvement has been obtained in a few of these cases.
individuals, herpes zoster may cause acute encephalitis with ____________
numerous sharply circumscribed
lesions characterized by demyelination followed by necrosis.
CMV infection of the nervous system occurs in____________individuals.
fetuses and immunosuppressed individuals
What is the
outcome of CMV infection in utero is ____________
periventricular necrosis that produces severe brain destruction
followed later by microcephaly and periventricular calcification.
CMV is a common opportunistic
viral pathogen in individuals with _________, with CNS involvement being common in this setting.
In CMV infection of the immunosuppressed individual, the most common pattern of involvement
is that of a ______________
subacute encephalitis, which may be associated with CMV inclusion-bearing cells
(see Fig. 8-15 ).
Although any type of cell within the CNS (neurons, glia, ependyma,
endothelium) can be infected by CMV, there is a tendency for the virus to localize in the
____________of the brain. This results in a severe hemorrhagic
necrotizing ventriculoencephalitis and a choroid plexitis.
paraventricular subependymal regions
CMV virus can also attack the lower
spinal cord and roots, producing a ____________
Prominent cytomegalic cells with
intranuclear and intracytoplasmic inclusions can be readily identified by ______________
microscopy and confirmed as CMV by immunohistochemistry.
While _____________ has been effectively eradicated by vaccination in many parts of the
world, there are still regions where it remains a problem.
In nonimmunized individuals poliovirus
infection causes a subclinical or mild gastroenteritis, similar to that caused by other members of
the picorna group of enteroviruses. In a small fraction of the vulnerable population, however, it
secondarily invades the nervous system.
In Acute cases of Poliomyelitis show _____________
mononuclear cell perivascular cuffs and neuronophagia of
the anterior-horn motor neurons of the spinal cord.
The inflammatory reaction in Poliomyelitis is
usually confined to the__________ but may extend into the posterior horns, and the
damage is occasionally severe enough to produce cavitation.
In situ reverse transcriptase
–PCR has shown poliovirus RNA in anterior-horn cell motor neurons.
The cranial motor
nuclei are sometimes involved.
Postmortem examination in long-term survivors of
symptomatic poliomyelitis shows loss of neurons and gliosis in the affected anterior horns of
the spinal cord, some residual inflammation, atrophy of the anterior (motor) spinal roots, and
neurogenic atrophy of denervated muscle.
Poliomyelitis CNS infection manifests initially with _____________.
meningeal irritation and a CSF picture of aseptic meningitis
What is the clinical feature of Poliomyelitis?
The disease may progress no further or advance to involve the spinal cord.
When the disease
affects the motor neurons of the spinal cord, it produces a flaccid paralysis with muscle wasting
and hyporeflexia in the corresponding region of the body—the permanent neurologic residue of
In the acute disease, death can occur from paralysis of the respiratory muscles,
and a myocarditis sometimes complicates the clinical course. Because of the destruction of
motor neurons, paresis or paralysis follows; when it involves the innervation of the diaphragm and intercostal muscles, severe respiratory compromise may occur and cause long-term
Post-polio syndrome can develop in patients 25 to 35 years after the resolution of the
initial illness. It is characterized by ______________
progressive weakness associated with decreased muscle
mass and pain, and has an unclear pathogenesis.
Rabies is a severe encephalitis transmitted to humans by the bite of a rabid animal, usually a
dog or various wild mammals that form natural reservoirs. Exposure to certain species of bats,
even without a known bite, can also lead to rabies.
What is the mcroscopic appearance of Rabies the brain shows____________.
intense edema and vascular
What is the microscopic appearance of Rabies?
there is widespread neuronal degeneration and an
inflammatory reaction that is most severe in the brainstem. The basal ganglia, spinal cbord,
and dorsal root ganglia may also be involved.
In Rabies, the involvement of ____________ is mostly severe?
What is the__________, pathognomonic microscopic
finding in Rabies?
What are Negri bodies?
- round to oval,
- eosinophilic inclusions
Negri bodies are found in the?
pyramidal neurons of the hippocampus and Purkinje cells of the cerebellum, sites usually devoid of inflammation ( Fig. 28-25 ).
The presence of rabies virus can be detected within Negri bodies
ultrastructural and immunohistochemical examination
The diagnostic histologic finding in Rabies is the eosinophilic Negri body, as
seen here in a Purkinje cell
Since the virus enters the CNS by ascending along the peripheral nerves from the wound site,
the incuba tion period (commonly between _________) depends on the distance between
the wound and the brain.
1 and 3 months
What is the clinical feature of Rabies?
The disease begins with nonspecific symptoms of malaise, headache, and fever, but the conjunction of these symptoms with local paresthesias around the wound is
What is the diagnostic feature of Rabies?
the conjunction of nonspecific symptoms with local paresthesias around the wound is
What happens as the Rabies infection advances, the affected individual exhibits?
exhibits extraordinary CNS
the slightest touch is painful, with violent motor responses progressing to
Contracture of the pharyngeal musculature on swallowing produces foaming at the
mouth, which may create an aversion to swallowing even water (hydrophobia).
meningismus and, as the disease progresses, flaccid paralysis. Periods of alternating mania
and stupor progress to coma and death from respiratory center failure.
In the period before the availability of effective anti-retroviral therapy, neuropathologic changes
were demonstrated at postmortem examination in as many as 80% to 90% of cases of AIDS.
These included _______________.
Since the early days, there has been a decrease in the frequency of
these secondary effects of HIV infection, in those who receive intensive multidrug anti-retroviral
direct effects of virus on the nervous system, opportunistic infections, and
primary CNS lymphoma.
HIV aseptic meningitis occurs within____________ of seroconversion in about 10% of patients;
antibodies to HIV can be demonstrated and the virus can be isolated from the CSF.
1 to 2 weeks
neuropathologic studies of the early and acute phases of symptomatic or asymptomatic HIV
invasion of the nervous system have shown a ___________, ___________ and _________
- mild lymphocytic meningitis,
- perivascular inflammation,
- and some myelin loss in the hemispheres.
Among the cell types of the CNS, only
_________- have the appropriate combination of CD4 and a chemokine receptor (CCR5 or
CXCR4) to allow for efficient infection by HIV. 
During the chronic phase, an HIV encephalitis
is commonly found when symptomatic individuals come to autopsy.
HIV encephalitis is best characterized microscopically as a _____________- Fig. 28-26 ).
- chronic inflammatory reaction
- with widely distributed infiltrates of microglial nodules,
- sometimes with associated foci of tissue necrosis and reactive gliosis (
HIV encephalitis. Note the microglial nodule and multinucleated giant cells.
In the microscopic finding HIV, The microglial nodules are also
found in the vicinity of small blood vessels, which show abnormally prominent endothelial cells
and perivascular foamy or pigment-laden macrophages. These changes occur especially in
the subcortical white matter, diencephalon, and brainstem.
An important component of the
microglial nodule is the ______________
In some cases there
is also a disorder of white matter characterized by multifocal or diffuse areas of myelin pallor,
axonal swelling and gliosis. HIV can be detected in CD4+ mononuclear and multinucleated
macrophages and microglia by immunoperoxidase and molecular methods.
macrophage-derived multinucleated giant cell.
Cognitive changes, both____________ enough to be termed HIV-associated dementia, appear
to have persisted into the era of effective anti-HIV treatment regimens
mild and florid
Rather than having a
specific pathologic lesion as its correlate, this disorder is most tightly related to the ____________, not all of which are necessarily HIV-infected. A wide range of
possible mechanisms for neuronal dysfunction and injury in this setting have been proposed,
including actions of cytokines and activation of an inflammatory cascade as well as a cavalcade
of toxic effects of HIV-derived proteins; in all probability, each of these pathways has a
contributory role in the pathogenesis of neural injury
activated microglia in the brain
Progressive multifocal leukoencephalopathy (PML) is a viral encephalitis caused by the ___________
Progressive multifocal leukoencephalopathy (PML) preferentially infects____________ demyelination is its
principal pathologic effect.
PML occurs almost exclusively in immunosuppressed
individuals in various clinical settings, including chronic lymphoproliferative or myeloproliferative
illnesses, immunosuppressive chemotherapy including monoclonal antibody therapy targeting
integrins, granulomatous diseases, and HIV/AIDS.
Although most people have serologic evidence of exposure to JC virus by the age of____________,
no clinical disease has been associated with primary infection by the virus.
It is thought that
PML results from the _______________.
reactivation of virus in the setting of immunosuppression
affected individuals develop _______________
- focal and relentlessly progressive neurologic symptoms and signs,
- and imaging studies show extensive,
- often multifocal, lesions in the hemispheric or cerebellar white matter.
What is the morphology of PML?
The lesions consist of patches of irregular, ill-defined destruction of the white
matter ranging in size from millimeters to extensive involvement of an entire lobe of the brain (
Fig. 28-27 ).
Wha the microscopic appearance of PML?
- the typical lesion consists of a patch of demyelination, most often in a subcortical location, in the center of which are scattered lipidladen
macrophages and a reduced number of axons.
- At the edge of the lesion are greatly enlarged oligodendrocyte nuclei with glassy amphophilic viral inclusions ( Fig. 28-27, inset ), which contain viral antigens by immunohistochemistry.
- Within the lesions, there may be bizarre giant astrocytes with one to several irregular, hyperchromatic nuclei mixed with more typical reactive astrocytes.
Progressive multifocal leukoencephalopathy.
Section stained for myelin
showing irregular, poorly defined areas of demyelination, which become confluent in
Inset, Enlarged oligodendrocyte nucleus represents the effect of viral infection.
What is Subacute sclerosing panencephalitis (SSPE)?
- rare progressive clinical syndrome
- characterized by cognitive decline, spasticity of limbs, and seizures.
- It occurs in children or young adults, months or years after an initial, early-age acute infection with measles.
SSPE is associated wit what viral infection?
persistent, but nonproductive, infection of the CNS by an altered measles virus;
changes in several viral genes have been associated with the disease.
What can you see on microscopic
examination in SSPE?,
- there are widespread gliosis and myelin degeneration;
viral inclusions, largely within the nuclei, of oligodendrocytes and neurons;
- variable inflammation of white and gray
- and neurofibrillary tangles
In the ultrastructural study of SSPE shows that the inclusions contain ____________
nucleocapsids characteristic of measles;
immunohistochemistry for measles virus antigen is
NOTE :The disease has largely disappeared with the spread of vaccination programs; however, there are still cases being reported from nonimmunized populations.