Emily
Editor, Senior Moderator
There are several full text articles about central nervous system pathogens included in the 77 page PDF file. Swine influenza viruses are mentioned as zoonotic viruses associated with encephalitis.
This is the introductory editorial.
This is the introductory editorial.
SAGE-Hindawi Access to Research
Pathology Research International
Volume 2011, Article ID 878263, 4 pages
doi:10.4061/2011/878263
Editorial
Pathology and Diagnosis of Central Nervous System Infections
C. Sundaram,1 S. K. Shankar,2 Wong KumThong,3 and Carlos A. Pardo-Villamizar4
1Department of Pathology, Nizam’s Institute of Medical Sciences, Hyderabad, India
2Department of Neuropathology, National Institute of Mental Health and Neurosciences, Hosur Road, Karnataka,
Bangalore 560029, India
3Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
4Department of Pathology, The Johns Hopkins Hospital Baltimore, MD, USA
Correspondence should be addressed to C. Sundaram, challa sundaram@yahoo.com
Received 23 November 2011; Accepted 23 November 2011
Copyright © 2011 C. Sundaram et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Infections of the central nervous system (CNS) are important
because of the many pathogens, the emerging and reemerging
of new infections, and the heavy burden they impose
on health care system. The most formidable challenge is
the increasing number of people at risk of developing CNS
infections due to acquired immunodeficiency syndrome
(AIDS) and the recipients of hemopoietic and solid organ
transplantation and other causes of immunosuppression.
There have been significant developments in the last few
decades in understanding the biology of disease process by
the application of new technologies. Advancements in brain
imaging and newer diagnostic modalities have achieved early
diagnosis helping patient management with new therapies.
The pathogenetic factors contributing to neurovirulence of
the pathogens have been elucidated by the use of molecular
biological techniques.
The infections are caused by wide variety of organisms
including bacteria, parasites, fungi, and viruses. The clinical
course may be acute, subacute, or chronic depending on
the pathogen, location, and immune status of the host. The
clinical manifestations are protean.
The normal brain is a highly complex and specialized
organ. It is protected by bony encasement of skull and thick
dura mater. However, this encasement limits its capacity to
swell in case of inflammation. Another important defense
for brain is in the form of blood brain barrier (BBB), made
up of a system of tight junctions in capillaries that resist
the entry of the inflammatory cells, pathogens, and macromolecules
into the subarachnoid space. The brain has a
rudimentary lymphatic system. The microglia and perivascular
macrophages have much lower expression of major
histocompatibility complex (MHC) molecules. This helps
the pathogen by poor antigen presentation to body’s immune
system and greater survival.
The exact mechanisms to breach the BBB by certain
pathogens are poorly understood, for example, rabies virus
and herpes simplex virus travel within peripheral nerves to
enter CNS, whereas encapsulated bacteria and fungi enter
from the blood stream and possess surface components
that allow them to traverse the capillary tight junctions.
The natural CNS parasites (Naegleria fowleri) infiltrate and
infect the CNS of healthy host by targeted attacking of the
BBB’s endothelial cells. The opportunistic CNS parasites
(Toxoplasma gondii) infect the CNS in immunocompromised
patients when the body is unable to effectively resolve inflammation
of the BBB’s endothelial cells, increase the permeability
of the BBB, and allow large molecules and parasites to
cross BBB and enter the brain.
Owing to the limited space and involvement of vital areas,
CNS infections are associated with high morbidity and mortality.
Rapid diagnosis and emergent interventions are necessary
to improve outcomes of these patients. The laboratory
diagnosis of CNS infection is essential for optimal therapy.
However, it is most challenging and appropriate that the use
and selection of laboratory tests requires close interaction
between clinician and laboratory personnel. A timely cerebrospinal
fluid (CSF) examination can give wealth of information.
Apart from cell count, the CSF can be subjected to
Gram’s stain, fungal stains and culture of bacteria, fungi, and
mycobacteria. Moreover, viral meningitis and encephalitis
can be diagnosed by CSF serology, viral DNA markers, and
polymerase chain reaction (PCR). Tissue diagnosis depends
upon location of the infectious focus and possibility of a
biopsy from the site. Histopathology almost always gives
a clue to the underlying infectious agent with the help of
special and immunohistochemical stains for various types of
organisms. The diagnostic yield can be further improved by
the application of PCR and other molecular techniques.
Brain abscess is a focal suppurative process within the
brain parenchyma, commonly caused by bacterial, fungal,
and parasitic pathogens. Despite advances in diagnostic and
surgical methods and advent of new antibiotics, brain abscess
continues to be a serious medical problem. The predisposing
factors vary in different parts of the world. Because of
improvements in the treatment of ear, sinus, and orofacial
infections over the last 50 years, there is decreasing incidence
of brain abscess due to otogenic infections in developed
countries when compared to developing countries. However
the frequency of brain abscess increased in patients with
AIDS and in patients using broad spectrum antibiotics,
corticosteroids, or immunosuppressive agents.
V. Lakshmi et al. in a review of 352 brain abscess samples
in 24 years from a developing country like India observed
that otogenic infections and sinus infections by contiguous
spread constitute the commonest source for brain abscess.
There were only 4 patients who were immune suppressed,
and two of them had mycotic abscesses. Cryptogenic brain
abscesses constituted 23.3% of abscesses. Staphylococcus
aureus was the most common isolate. The authors observed
a change in the trend of the causative organisms in the
later half of the study period when unusual organisms like
Burkholderia pseudomallei, Salmonella typhi, Nocardia spp,
Cladosporium bantiana, Fonsecaea pedrosoi, Entamoeba histolytica,
and Acanthamoeba were isolated. There were 8 brain
abscesses due to mycobacterium tuberculosis, 3 Nocardia spp
and 5 mycotic organisms and 2 amoebic abscesses. The diagnosis
of these group of brain abscess was complemented by
histological studies. Tuberculous brain abscess is essentially
a histological diagnosis wherein the wall of the abscess lacks
granulomas, and the central necrotic material contains acid
fast bacilli.
The factors for a favorable outcome for brain abscess include
being male, having a Glasgow corna scale score >1.2,
and being sepsis-free and having positive culture. Identification
of microorganisms in the aspirated material depends on
the prompt examination of smear and appropriate culture
techniques. The mortality and morbidity and long-term
sequelae of brain abscess are due to persistent release of
proinflammatory mediators by activated microglia, astrocytes,
and infiltrating inflammatory cells along with disruption
of BBB. Anti-inflammatory drugs along with specific
antimicrobial agents help in minimizing damage to the adjacent
brain parenchyma.
Most protozoal infections except cerebral malaria are uncommon
and are restricted to particular geographical regions.
Because of increasing international travel, parasites
that were previously limited to tropical regions pose an
increasing infectious threat to populations at risk for acquiring
opportunistic infection, especially people with human
immunodeficiency virus (HIV) infection or individuals who
have received a solid organ or bone marrow transplantation.
Though CNS is an immunologically privileged site, the parasites
try and gain access to the CNS due to a variety of factors
which include easy access to nutrition and the ability to avoid
much of the body’s normal immune response. Though CNS
may be one of the many systems involved, CNS involvement
indicates a poor prognosis in the protozoal infections.
Though only a relatively limited number of parasites can
penetrate and infect the CNS, the parasites employ a variety
of techniques to evade and suppress immunity and exploit
themilieu for survival.Understanding the host parasite interactions
and pathogenesis helps develop efficacious treatment
strategies. Detailed neuropathological studies with application
of molecular biological methods helps in this direction.
The awareness of endemicity and geographical distribution
of parasites is necessary for proper planning of the laboratory
tests. Serological tests, culture and molecular methods,
are very useful in the diagnosis of parasitic infections. L.
Chimelli in her paper stressed the importance ofmorphology
of the parasites on tissue in establishing the diagnosis. She
stressed the changing patterns of some protozoal infections
of CNS after the institution of highly active antiretroviral
therapy (HAART). The diagnosis remains a problem in many
patients despite all the available tests and examination of
brain at autopsy may become inevitable in making a diagnosis.
Fungal infections of CNS are being increasingly reported
in the last few decades due to increase in the number of
immunosuppressed individuals. A variety of fungi cause
infections of CNS either an acute or chronic meningitis
or space occupying lesion. Yeast fungi predominantly cause
meningitis, and mycelial fungi cause mass lesions of brain.
The type of pathology and clinical syndrome is determined
by the morphology and size of the fungus and the host
immune status. In the patients with intracranialmass lesions,
direct extension from colonized paranasal sinuses or ear
canal is more common than by hematogenous dissemination
from lung, gastrointestinal tract (GIT), or skin. Aspergillus
sp is the most common agent to cause intracerebral granuloma
or abscess.
C. Sundaram and J. M. K. Murthy reviewed intracranial
aspergillus granulomas and observed that most of the reported
large series are from countries with temperate climate
like India, Pakistan, Sudan, and Saudi Arabia. The spread
is often from paranasal sinuses by direct extension and in
immune competent hosts. The lesions are often extracerebral
granulomas, characterized by dense fibrosis. Rare intraparenchymal
granulomas were reported. The importance of
histochemical stains like Gomori methenamine silver in the
diagnosis is stressed. Environmental factors like temperate
climate humidity favor the growth of the fungus. The
aerolized spores during ploughing or construction activity
are colonized in the sinuses or lungs. Dissemination to CNS
occurs due to local altered immunity and mucosal invasion.
The dense fibrosis does not allow effective penetration of
antifungal agents thus necessitating radical surgery.
Following HIV infection, especially with HIV encephalitis,
variable degree of demyelination is found in the brain,
especially the subcortical whitematter of the frontal and temporal
lobes. This is further accentuated by coinfection with
JC virus causing progressive multifocal leucoencephalopathy,
involving the white matter fiber tracts, basically infecting the
oligodendroglia. S. Surendran et al. in their earlier molecular
studies showed the presence of human aspartoacylase in
oligodendroglia taking part in myelin synthesis. Altered levels
of aspartoacylase/aminoacylase (ASPA) and abnormality
in the metabolic pathway have been found to induce oxidative
damage and participate in the evolution of Canavan’s
disease and Parkinson’s disease. In a brief report in this
issue, they described depletion of immune labeling for ASPA
protein in the white matter in cases of HIV encephalitis. This
indicates that an aberration in ASPA pathway participates
in the demyelinating pathology seen in cases of HIV. More
in depth study with larger autopsy sample size is needed to
further validate the observations and suggest a pathogenetic
role.
With transformation of the world into a global village
with primitive to advanced modes of transport, old infective
conditions are emerging in new places, and same diseases
are manifesting with varied clinical features confounding
the infectious disease specialist and the laboratories. Many
of them are turning out to be zoonoses of well-recognized
or newly discovered viral infections, jumping the species
barrier and infecting the human beings. This is further
facilitated by the economic necessity of close proximity of the
domesticated animals and the human beings, afforestation
leading to migration of the animals into human habitat. K.
T. Wong and K. C. Ong have provided a brief review of an
encephalitis, glomerulonephritis, bronchitis, and bronchiolitis
caused by Hendra virus and Nipah virus originating in
the Eastern World. The viral infection has spread to humans
essentially by contaminated oropharyngeal secretions and
urine from infected domestic animals. The intermediate host
is essentially determined by the proximity to the human
habitat and domestic animal rearing habit of the villages
involved. The person-to-person transmission in Bangladesh
and India by the henipaviruses reflects high human density in
a restricted area and aerosol spread like the recent mutated
influenza virus epidemic. The clinical features of Hendra
virus has not been well characterized while Nipah viral
infection is very well studied and recorded.
With henipavirus infection, probably viral persistence
is responsible for recurrent and recrudescent encephalitis,
similar to a few of the arboviral infections. The site of latency
of the virus is not clear. The pathology of henipavirus is
diffuse parenchymal vasculopathy, endothelial cell syncytia,
and encephalitis. In Nipah virus infection CNS vasculopathy
is more prominent, thus highlighting variable pathologies in
henipavirus group of infections. Similarly the susceptibility
of the experimental animals is also variable, modulating the
spread of infection in the natural habitat. Curiously in case
of Nipah viral infection, role of peripheral nerves in the viral
transmission to CNS had been suggested only in pigs.
The formation of neuronal syncytia indicates the activity
of fusion viral protein, a feature of paramyxoviruses. Sharing
the same viral receptor on the cell membrane of both humans
and animals (ephrin B2 and ephrin B3), especially the
vascular endothelium explains the evolution of clinicopathological
features and CNS involvement. With changing
ecology following the expansion of human habitat and associated
domesticated animals, disturbing the environment
and homes of pteroid bats in developing countries, future
outbreaks of henipavirus can be anticipated. This calls for
evolving treatment strategies and vaccination policies.
In Asian countries rabies viral infection continues to be a
public health problem with no reliable cure in sight. WHO
estimates 50,000 deaths every year worldwide, nearly 60%
of them occurring in India alone. Humans and canines, the
common mammals infected, acquire the disease following
the bite of a rabid animal. On entering the nervous system
by a receptor-mediated mechanism, the virus replicates and
spreads widely in the CNS with a fatal end. Clinically rabies
infection manifests either as furious (encephalitis) or paralytic
form, two thirds of the subjects suffering from the
aggressive, hydrophobic, and furious form. Most of the
studies evaluating the pathogenesis of rabies have been
carried out in laboratory animals using laboratory-adopted
virus strain (CVS), while the natural infection by the nonattenuated
“street virus” in humans and canines is not well
worked out.
In addition to cytopathic effect of the viruses, altered
neurotransmitter activity resulting in deleterious CNS physiology
have been incriminated as the cause for acute morbidity
and mortality following infection with neurotropic
viruses like rabies. Apoptosis, which is essential for the programmed
cell death and embryogenesis, has been observed
in a multitude of viral infections, and the number of correlations
between viral pathogenesis and apoptosis continues
to grow. Some of the viruses promote noninflammatory
apoptotic mechanism to induce cell death and escape into
the interstitium to infect another healthy cell. On the
other hand, other viruses cleverly exploit the high regulated
apoptotic pathway by blocking it within the cells they reside,
thus evading the host surveillance mechanism and promote
their survival. RNA viruses multiply rapidly to produce
many virions before the host mounts effective immune
surveillance to contain them. Observation of apoptosis
in mouse neuroblastoma cells when infected with highly
neurotropic challenge virus standard (CVS) of rabies virus
leads to the impression that neuronal damage and loss in
rabies is mediated by apoptosis. Subsequent workers as well,
using the laboratory passaged CVS strain and animal models,
have suggested that apoptotic neuronal cell loss was an early
event correlating with disease severity. Though apoptosis is
well recognized in animals infected with laboratory-adoptedrabies
virus, whether the same mechanism is operative in
natural infection by rabies virus present in nature remained
a moot point.
The neuronal apoptosis following rabies infection is
found to be age dependent, being evidence in suckling mice
infected with CVS strain, but not in weanling and adult mice.
In the present issue, in an original study, M. S. Suja et al.
evaluated the role of apoptosis in rabies encephalitis in humans,
canines, and rodents infected with wild-type street
virus and compared with a rodent model infected with
laboratory-passage and -attenuated rabies virus, inoculated
by different routes. They also studied the age-dependent
expression of apoptosis in mice when infected with CVS
strain. Rabies viral load and encephalitic pathology were
more evident in the human and canine brain in contrast to
rodents infected with wild type of virus, but absence of neuronal
apoptosis was common. On the contrary, as observed
by other researchers, apoptosis was recorded in suckling
mice infected with CVS strain, more evident by intracerebral
inoculation and rarely in wild-type street virus-inoculated
rodents. Interestingly the apoptotic cell signal was noted only
in inflammatory cells, but was distinctly absent in neurons
and glia. It is suggested that apoptotic cell loss only in inflammatory
cells but not in neurons, could be a natural adoptive
mechanism by the rabies virus to facilitate the survival of the
virus, its propagation in stable population of neurons. It is
also evident that the apoptotic cell damage is not responsible
for the evolution of clinical features and terminal mortality
following rabies infection. This also could account for long
incubation period and long-term survival of the rabies virus
in the host. It is not yet clear in which of the neuroanatomical
areas in the mammalian system the virus resides dormant
in latency to get activated in opportune moment. Further
studies on molecular, cytokine/chemokine pathways, and
neurotransmitter pathways coupled with investigating aberrant
neurophysiology may offer clues to bimodal clinical
manifestation and fatality from rabies virus. Among the
four types of Prion disease, Creutzfeldt-Jakob disease (CJD),
sporadic CJD (sCJD) is the commonest form arising from
random mutation or posttranslational modification of the
PrP gene. On the contrary, the new type of CJD, namely,
the variant CJD (vCJD) manifests in young (mean age of
23 yrs) has longer duration of illness (12–24 months), with
psychiatric presentation and absence of characteristic EEG
changes. This form of CJD is causally linked to oral ingestion
of meat from cattle infected with bovine spongiform
encephalopathy. Neuropathologically CJD is characterized
by spongiform change of cortical neuropil in cerebral cortex,
cerebellar molecular layer, diencephalic nuclear areas and
brainstem, neuronal loss, and reactive astrocytosis. Fairly
distinct differences in the pattern of prion protein distribution
recognized by immunohistochemistry are described. In
sCJD, the deposition of PrPSc occurs in a synaptic pattern,
distributed along the cortical ribbon and the neuropil of
nuclear areas reflecting diffuse degenerative change in the
presynaptic terminals and relative failure to aggregate. In the
case of vCJD, the PrPSc deposits take the form of classic
mature plaques of Alzheimer’s disease (AD) with dense
central core and less compacted halo of deposit around,
and diffuse deposits (fine feathery diffuse deposits akin to
immature plaques in AD) floridly.
These morphological variations appear to reflect differential
distribution of the prion protein in different anatomical
areas corresponding to the evolution of pathology
spreading along relatively distinct axonal pathways reaching
the cortical lamina and other nuclear areas. In other
neurodegenerative disorders (β amyloidopathies, taupathies,
and synucleinopathies) like in AD, Lewy body dementia,
Pick’s disease the density distribution of the pathological
change in cerebral cortical ribbon varies across the different
cortical lamina. This probably reflects laminar spread and
distribution of the pathological changes corresponding to
degeneration of specific anatomical pathways having their
neurons of origin or presynaptic axonal termination in
particular cortical lamina. To an extent, this laminar distribution
gives insight into neuroanatomical progression of
the proteinopathies in the cerebral cortex and corresponding
clinical cognitive and motor abnormalities during the disease
progression.
In this issue, R. A. Armstrong from Birmingham evaluated
the laminar distribution of the pathological changes
in sporadic and variant CJD by rigorous quantitative morphometry
in well-characterized samples. The cases of sCJD
were homozygous for methionine at codon 129 with Type
1 PrPSc (MIM1). All the cases of vCJD were also methionine/
methionine (M/M) homozygotes at codon 129. Thus,
the cases analyzed had relative genetic homogeneity to
compare. The cases of sCJD revealed diffuse spongy change
in the cortex affecting all the cortical lamina, more surviving
neurons in upper layers of the cortex and neuronal depletion
in lower layers, classical synaptic pattern of prion protein
deposition, and gliosis in the lower layers. On the contrary,
in cases of vCJD, the spongy change was more evident in
the upper layers corresponding to subpial spongy change
and presynaptic targeting axonal pathology. This was further
corroborated by florid and diffuse deposits of prion protein
in upper cortex. The astrocytosis in vCJD was essentially
similar to sCJD, more evident in the lower layers, probably
as a late event to neuronal and axonal degeneration. Similar
though labour intensive, study in some of the neuroanatomical
areas like cerebellum, brainstem, and diencephalic nuclei
leading to neo cortex probably can offer insight into temporal
evolution and neuroanatomical spread of prion pathology
and contrasting features with other protein misfolding
neurodegenerative disease.
In conclusion, the various articles in this issue address the
pathology, pathogenesis and diagnosis of infections of CNS.
C. Sundaram
S. K. Shankar
Wong Kum Thong
Carlos A. Pardo-Villamizar
Copyright © 2011 SAGE-Hindawi Access to Research. All rights reserved. This is a special issue published in volume 2011 of “Pathology Research nternational.” All articles are open access articles distributed under the Creative Commons Attribution License, which permits unrestricted use, istribution, and reproduction in any medium, provided the original work is properly cited.
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