Preface

This document is a response to ideas presented at a conference about Neuroimmune
Dysfunctions Syndromes, focusing upon biomedical aspects of ADHD, chronic
fatigue syndrome (CFS), and autism -- a conference reflecting the work of
Michael J. Goldberg, MD, and some of his professional colleagues from around the
world. My intention with this document is to present citations establishing that
a possible basis for hypofunction and/or hyperfunction in affected brain areas
may derive from pathogens which have established a chronic infection within
endothelial cells of the blood brain barrier. This document is not intended as
a reporter's review of the NIDS conference; instead, 'tis a researcher's first
steps in going forwards with the fine information presented at the conference.

A highlight of the NIDS Conference (19) was Dr. Ismael Mena's presentation of
SPECT-scan data indicating hypoperfusion and (in some cases) hyperperfusion in
brain regions associated with a child's autism-spectrum traits, as summarized
in a paper by Goldberg, Mena, and Miller. These findings prompt the question: 

          What might be causing the variations in blood-flow and
          nutrient access along the blood-brain barrier (bbb)? 

Dr. Hyde's conference lecture provided a clue, in a slide about vascular
inflammation in brain tissue taken from an deceased person who had had chronic
fatigue syndrome. Similarly, in some of these kids, a chronic active endothelial
infection along the blood brain barrier may be contributing to the child's
autism-spectrum traits, for the focal inflammation caused by such an infection
would seem able to minimize arterial blood flow into and/or to constrain venous
outflow from a brain-region adjoining the endothelial infection.

The possibility of viral bbb participation prompted an initial Medline search
that produced citations reporting that various viruses and other pathogens can
infect endothelial tissue (eg, 2-3), including endothelial tissues of the blood
brain barrier, wherein inflammation and viral shedding into the CNS can occur
(eg, 13). 
     That there may be an autism-spectrum link to chronic active (seemingly
subclinical) viral infections within portions of the bbb is consistent (i) with
my research into chronic active infections of autism-spectrum children, and (ii)
with Dr. Goldberg's treatment protocols that, for some kids, include specific
antivirals such as acyclovir or Valtrex, in response to which some kids improve
dramatically. One parent at the conference shared two anecdotes. 
     She and her child had visited a number of doctors, some of whom had tried
mild alternative therapies, but the mother felt that more aggressive diagnostics
and treatment were needed. She found her way to Michael Goldberg, MD, who
treated her son with an antiviral, and he began to improve dramatically and
lastingly. She also told of a younger child showing many of the same early
symptoms and traits that her son had manifested. This second Mom took her child
to Dr. Goldberg at an earlier age and sooner in the progression of autism-
spectrum symptoms. That child too was treated with an appropriate antiviral and
has resumed a neurotypical life. 
     Importantly, not all kids will be helped by an antiviral pharmaceutical.
However, that *some* kids profoundly benefit ought change early diagnostic
evaluations for all autism-spectrum kids -- especially since many pathogens can
exist as long-term, chronic, subclinical infections, and some such pathogens and
infections respond to appropriate medications. In other words, identifying or
ruling out subclinical infections affecting CNS function ought be a mandatory
part of autism-spectrum diagnostics and ought occur early in the child's
presentation to physicians, psychologists, or other clinicians who participate
in autism-spectrum diagnostics. And chronic active infection of the bbb may be
etiologically significant in some autism-spectrum children.

          {Hearing personal testimonies from parents at the NIDS
          conference was revelatory, even as a few parents there
          reported that the antivirals and complex diagnostics had
          not yet worked -- which is not surprising in a syndrome
          with as many etiologies as are present within the autism
          spectrum. Nonetheless, ruling out or identifying such
          infections is important in autism-spectrum diagnostics and
          treatment.}

          {A major goal of Goldberg, Pliopys, Hyde, Galpin, NIDS and
          MAT is to share the SPECT results and the immune-related
          diagnostics with parents and physicians around the world.}

Keeping in mind that viral etiologies do not apply in *all* autism spectrum
kids, let us return to a preliminary exploration of viruses and other pathogens
that can affect the blood-brain barrier and thus that might induce hypoperfusion
or hyperperfusion in a subgroup of autism-spectrum children, depending upon the
pathogen and its location of chronic active infection.
     What follows is a *preliminary* sketch of pathogens that can infect
endothelial tissues, ie, cells as can be found along the blood-brain barrier.
The notions are augmented by citations and are offered as a way to accelerate
research efforts and parental understandings. Some of the data are from studies
of endothelial tissues not within the bbb, and some of the studies focus upon
endothelia of the blood brain barrier.

One early study's abstract summarizes findings indicating that some viruses
favor venous cells whereas others favor arterial cells (2), suggesting
mechanisms by which hypoperfusion (from arterial-endothelial infection?) or
hyperperfusion (from venous-endothelial infection?) might occur. Importantly,
the 1981 study could not use PCR and reported that CMV did not grow in the
endothelial cultures (2), but subsequent studies have shown that CMV can reside
within endothelial tissue and can establish persistent infection (3-5, 6, 29-
30).

Measles virus can infect endothelial cells, including those of the blood brain
barrier, and a vaccine-strain of measles was shown to be permissive for
infections with HSV and mumps (2,7,8). Aspects of measles-related pathology
include altered cytokines patterns and changes in coagulation-related processes
(9-10); and for at least some strains of CNS-related measles infection and
inflammation within endothelial tissues of the bbb: "The degree of inflammation
corresponded well with antibody titer." (11)
     Diane E. Griffin and colleagues at Johns Hopkins have shown that both wild-
type and vaccinal measles impair immunity. Citation 8 here, along with Griffin's
work, provides a possible mechanism by which a small autism-spectrum subgroup
would deteriorate after an MMR, eg, if the child was already carrying a small
quantity of endothelial mumps virus and/or HSV as the MMR was given; and, along
with the immune permissiveness induced by the MMR, additional tendencies towards
endothelial inflammation and possible viral spread would be augmented by MMR's
production of interferon gamma and sequelae therefrom (12).
     Some of the autism-spectrum immune-panels I've perused document impaired
immunity against mumps, varicella, or other pathogens, and we note that mumps
and varicella are pathogens that can establish chronic infection in endothelial
tissues (eg, 2, 26), an infection that might be more likely to ensue if the
child has impaired immunity against that pathogen.

The thymus has endothelial cells that can be infected by measles virus (14); and
there is molecular mimicry among HSV, measles, and a neurofilament protein (15),
suggesting an additional mechanism by which CNS-autoimmune processes could be
initiated, eg, if a child had acquired a persistent, atypical measles infection
co-occurring with HSV along the endothelial tissues of the bbb.

In 1979, Rapp and Fisher noted that "Maintenance of persistent infection may
involve both the presence of virus variants and a defect in the ability of the
infected cell to replicate the virus efficiently." (16), and I wonder: are some
cases of autism-spectrum hypoperfusion and CNS-hypofunction induced by a viral
variant that prevented the virus from replicating efficiently, thereby leading
to chronically infected cells? 
     Rapp and Fisher were studying a vaccine-related measles virus, which may
be instructive regarding the facts (i) that many parents report atypical
elevations of anti-measles antibodies, and (ii) that I see atypical elevations
of anti-measles antibodies in several of the autism-spectrum, thorough immune-
panels I've perused. Although the subject of interpreting antibodies titres is
complex, we might keep in mind that for at least some strains of CNS-related
measles infection with inflammation, "The degree of inflammation corresponded
well with antibody titer.", as reported in a study focusing upon measles
infection of endothelial tissues of the bbb (11).

Modified varicella-like syndrome (MVLS) occurs in a goodly percentage of
children vaccinated against varicella if and as the child is exposed to an actual
varicella infection. "Children with MVLS are frequently asymptomatic, and their
disease is characterized by having fewer lesions, less fever, and lasting fewer
days than natural varicella." (35) 
     When an autism-spectrum child's immune panel shows reference range values
for all vaccinal antigens except varicella, then that child's overall immune
response against varicella is atypical in ways that would seem to predispose the
child to chronic active varicella infection in susceptible tissues, eg, the
endothelial cells of the blood-brain barrier (24, 26-27). 
     Perhaps parents and physicians attending such a child ought not rest
content thinking that the lack of anti-varicella antibodies is not just a fluke
to be dismissed as yet another medical oddity but instead might consider that
varicella may be etiologically significant in a child with no anti-varicella
antibodies. Of course, there are other mechanisms by which immunity can be
impaired (eg, T cell anergy), thus having "no anti-varicella antibodies" would
not be a necessary pre-condition for MVLS-like disease processes to occur. 
     Dr. Clements writes that MVLS sequelae "such as secondary bacterial
infection, cerebellar ataxia, encephalitis, and pneumonia occur infrequently"
(35), and the possibility arises that between the extremes of asymptomatic MVLS
and encephalitic MVLS, there may well be intermediate cases of chronic active
varicella infections within endothelial tissues of the blood-brain barrier.

These various citations suggest, at least theoretically, that children with no
anti-mumps antibodies would seem similarly susceptible to chronic active
infection of blood-brain barrier endothelia. Again, several of the autism-
spectrum charts I've perused document no anti-mumps antibodies in a child whose
other vaccinal antibodies are within normal ranges.

The following list is derived from the citations presented here and is not
intended to be a comprehensive. Viruses that can establish endothelial
infections include: Herpes simplex virus type 1, adenovirus type 7, measles
virus, parainfluenza virus type 3, mumps virus, poliovirus type 1, echovirus
type 9, coxsackievirus B4 (2, 31), HHV6 (20, 25), parasites (17), EBV (21-23),
varicella (24, 26-27), Chlamydia (28), and cytomegalovirus (3, 28, 29), which
(along with other herpes class viruses) has an ability to hide from immune
surveillance (eg, 30) by downregulating cell-surface presentation of MHC
molecules (citations not presented here). Processes such as these may account
for vascular injury (32) leading to the hypoperfusion seen in many autism-
spectrum kids' SPECT images, and even to the hyperperfusion seen in some such
SPECTs (by blocking of venous outflow along a portion of the bbb).

Increasingly, viruses and other pathogens are implicated in vascular injuries
(eg, 31-32); but traditional lab-test results must be interpreted carefully,
because they do not necessarily reveal blood-brain barrier problems that can
occur in cases of subtle CNS infections (32). Furthermore, as weeks turn to
months subsequent to the initiation of a CNS-related viral infection, SPECT
images may change, even as they indicate subsequent perfusion atypicality (33-
34).

The NIDS conference represents a step forward in diagnosing and treating
children with autism-spectrum disorders. That some children improve dramatically
in response to anti-viral pharmaceuticals ought not be ignored. The new and
still being refined immune-related diagnostic algorithm shall help some of the
children and their families as they seek to rule out or identify and treat
chronic active infections that are etiologically significant in some autism-
spectrum children.
     In my opinion as a non-MD researcher, a thorough immune panel (i) appears
to be the only way to determine whether or not chronic active infectious
processes are occurring in an autism spectrum child, and (ii) ought become a
mandatory, insurance-paid aspect of autism-spectrum diagnostics and treatments.

Teresa Binstock
Researcher in Developmental and Behavioral Neuroanatomy
June 16, 1999

A series of autism-spectrum research monographs are available by links on a web
page: http://www.jorsm.com/~binstock/index.htm

References

1. Goldberg M, Mena I, Miller B. Frontal and temporal lobe dysfunction in autism
and other related disorders: ADHS and OCD. Latin American Journal of Nuclear
Medicine, July 1999. http://www.alasbimnjournal.cl

2. Friedman HM et al. Virus infection of endothelial cells. J Infect Dis 1981
Feb;143(2):266-73.
     ab: Endothelial injury is important in the pathogenesis of thrombosis,
atherosclerosis, disseminated intravascular coagulation, and vasculitis. The
ability of several common human viruses to infect cultures of endothelial cells
obtained from human umbilical veins or bovine thoracic aorta was demonstrated.
Indicators of infection included cytopathology, viral growth curves, and
antigen detection by immunofluorescence. Herpes simplex virus type 1,
adenovirus type 7, measles virus, and parainfluenza virus type 3 infected both
human venous and bovine aorta endothelium. Mumps virus, poliovirus type 1, and
echovirus type 9 grew only in human venous cells; coxsackievirus B4 infected
only bovine arterial cultures; and cytomegalovirus, influenza A/Victoria/75
(H3N2) virus, and respiratory syncytial virus failed to grow in either cell
culture. During replication some viruses caused acute lytic changes; some
produced chronic, less destructive alterations; and other induced no apparent
cytopathology. The results suggest that viral replication within endothelium
may be important in the pathogenesis of viral disease of initiation of
vessel-wall injury.

3. Smiley ML et al. Cytomegalovirus infection and viral-induced transformation
of human endothelial cells. J Med Virol 1988 Jun;25(2):213-26.
          Department of Medicine, School of Medicine, University of
          North Carolina, Chapel Hill 27514.
ab: Human cytomegalovirus (CMV) has been associated with vascular pathology. In
vivo, CMV is present in vessel wall cells during acute and chronic infections
as well as in atherosclerotic lesions. CMV nucleic acids and proteins have also
been detected within Kaposi's sarcoma lesions. Because of these associations,
we studied the interaction of CMV with human endothelial cells with particular
attention to its oncogenicity in this cell type. Our data demonstrate that
human endothelial cells are permissive to viral replication but that the viral
replication cycle is delayed compared with fibroblast cells. Persistent
infections can result with minimal cytopathology. CMV can transform these cells
to anchorage-independent growth, and noninfectious virus is still capable of
inducing this transforming event. Our results demonstrate that productive or
persistent CMV infection of endothelial cells and viral-induced transformation
can occur, thus providing an in vitro correlate of in vivo events.

4. Bruggeman CA et al. Cytomegalovirus infection of rat endothelial cells in
vitro. Arch Virol 1986;87(3-4):265-72.
     ab: Rat endothelial cells were productively infected with rat
cytomegalovirus in vitro. A typical CMV-like cytopathic effect resulting in a
lytic infection was observed. Intracytoplasmic and intranuclear virus and viral
antigens were detected by fluorescence and electron microscopy. Receptors for
the Fc region of IgG in the cytoplasm and on the cell membrane were observed.
Infectious virus was released in the supernatant of the infected cell cultures.

5. Waldman WJ et al. Preservation of natural endothelial cytopathogenicity of
cytomegalovirus by propagation in endothelial cells. Arch Virol
1991;117(3-4):143-64.
          Department of Pathology, Ohio State University, Columbus.
ab: Cytomegalovirus (CMV) is a source of major complications in immunosuppressed
individuals, and endothelial involvement in CMV infection is well documented.
Traditionally the virus has been propagated in fibroblasts, however this
process may alter CMV's characteristics, thereby limiting the fibroblast
model's utility as a research tool. In our efforts to develop a more accurate
in vitro model of CMV/endothelial cell interaction, we have propagated a recent
isolate (CMV VHL) through multiple passages in human umbilical vein endothelial
cells (HUVE) and, collaterally in neonatal human dermal fibroblasts (NHDF).
Infection of HUVE inoculated with either sub-strain of the virus was confirmed
by CMV-specific in situ hybridization and by immunocytochemical staining for
CMV antigens. Whereas infection of HUVE by substrain VHL/E (endothelial-raised)
was accompanied by dramatic cytopathology resembling that observed clinically,
the endothelial cytopathic potential of VHL/F (fibroblast-raised) was lost by
its 20th passage in NHDF. Similarly, the ability of VHL/F to initiate sustained
productive infection in HUVE was severely attenuated; plaque assay of culture
supernatants and infected cell fractions, as well as virus-specific DNA
polymerase assay of cell lysates, demonstrated progressive viral reproductive
activity in VHL/E-inoculated HUVE, whereas VHL/F reproduction was barely
detectable. Since properties of VHL/F bear strong resemblance to those of the
fibroblast-raised AD169, these studies suggest that while the fibroblast
adaptation process commonly employed in the propagation of CMV restricts the
host range of the virus and attenuates its spectrum of cytopathic potential,
endothelial-based propagation preserves the natural endothelial
cytopathogenicity of the original isolate.

6. Ogura T et al. Human cytomegalovirus persistent infection in a human central
nervous system cell line: production of a variant virus with different growth
characteristics. J Gen Virol 1986 Dec;67 ( Pt 12):2605-16. 
     ab: The susceptibility of human central nervous system cell lines to human
cytomegalovirus (HCMV) and the fate of infected cultures were studied.
Significant amounts of infectious progeny virus were produced in 118MGC glioma
and IMR-32 neuroblastoma, but not in KGC oligodendroglioma cells when the
cultures were infected with wild-type virus (HCMVwt) at an m.o.i. of 10 p.f.u.
per cell. 
**   Further passage of infected 118MGC cells resulted in the
     establishment of a long-term persistent infection. This infection,
     designated 118MGC/Towne, continuously produced infectious virus... 
     maintenance of the persistent infection seemed to be due to a balance
     between the release of infectious virus and the growth of uninfected
     cells. 
The HCMVpi produced in long-term persistently infected
cultures was shown to be different from the HCMVwt originally used to infect by
the following characteristics: HCMVpi replicated slowly and yielded lower
amounts of progeny virus than HCMVwt; HCMVpi induced a 73,000 mol. wt.
immediate early protein that was not synthesized in HCMVwt-infected cells;
HCMVpi had a different DNA structure from that of HCMVwt. These results suggest
that HCMVpi is a slower growing variant of HCMVwt and probably plays an
important role in the maintenance of the persistent infection.

7. Friedman HM et al. Susceptibility of endothelial cells derived from different
blood vessels to common viruses. In Vitro Cell Dev Biol 1986 Jul;22(7):397-401.
     ab: We examined whether endothelial cells derived from different blood
vessels vary in their susceptibility to viral infection. Five common viral
pathogens of humans (herpes simplex 1, measles, mumps, echo 9, and coxsackie B4
viruses) were evaluated for growth in endothelial cells derived from bovine
fetal pulmonary artery, thoracic aorta, and vena cava. All five viruses
replicated in each type of endothelial cell. There were apparent differences in
the quantities of measles and mumps viruses produced in pulmonary artery
endothelium compared with thoracic aorta and vena cava when endothelial cells
were obtained from different animals. However, when pulmonary artery
endothelial cells were compared with vena cava cells from the same animal,
growth of each virus was similar in the two cell types. Four of the viruses
replicated in the various endothelial cells without producing appreciable
changes in cell morphology. These results indicate that endothelial cells from
different blood vessels are equally susceptible to the human viruses evaluated,
and that viral replication can occur without major alterations in cell
morphology. Endothelial cells could serve as permissive cells permitting
viruses to leave the circulation and initiate infection in adjacent tissues,
including subendothelial smooth muscle cells.

8. Koptiaeva IB, Bogomolova NN. [Chronic infection of HEp-2 cells with the L-16
vaccinal strain of the measles virus]. [Article in Russian] Vopr Virusol 1982
May-Jun;27(3):362-5.
     ab: Chronic infection of HEp-2 cells with the vaccine L-16 strain of
measles virus was produced. HEp-2 culture infected with the measles virus (HEp-2
MV) is characterized by the presence of the virus-specific antigen in 95% of the
cells, adsorption of simian erythrocytes on all cells in the culture and the
absence of infectious virus in the medium. The infectious virus is detected in
the culture fluid only after destruction of the cells in the chronically
infected culture. HEp-2 MV is resistant to infection with measles virus but
susceptible to infection with mumps and herpes simplex viruses. The expression
of virus-specific antigen in cells of chronically infected culture was found to
be temperature-dependent.

9. Gerson SL et al. Viral infection of vascular endothelial cells alters
production of colony-stimulating activity. J Clin Invest 1985 Oct;76(4):1382-90.
     ab: Viral infections in humans are frequently associated with
granulocytopenia and/or granulocytosis. Such changes in myelopoiesis could
result from infection of the granulocyte-macrophage colony-forming cell (CFC-GM)
or changes in the production of colony-stimulating activity (CSA). Endothelial
cells are a known source of CSA and may be transiently or persistently infected
during a number of viral infections, including infection with herpes simplex
virus type I (HSV-I) and measles virus. Therefore, we examined the effect of
endothelial cell infection with these two viruses on the production of CSA.
Uninfected passaged endothelial cells produce CSA when stimulated by the
continual presence of a factor present in medium conditioned by peripheral blood
monocytes (MCM). Within 4 h of infection with HSV-I, endothelial cells no longer
produced CSA in response to MCM. In contrast, measles virus infection induced
CSA production by passaged endothelial cells even in the absence of MCM. Measles
virus-induced CSA production was maximal at 24 h and required the presence of
live virus within the endothelial cells. The effects of HSV-I and measles virus
on CSA production were not dependent on alterations in the production of alpha-
or gamma-interferon by the infected endothelial cells. Infection with HSV-I did
not stimulate endothelial cells to release any detectable interferon. In
contrast, the supernatants of the measles-infected cells contained only
beta-interferon, a known inhibitor of CFC-GM development. These studies suggest
that CSA production by endothelial cells is directly altered by infection with
HSV-I and measles virus. An alteration in CSA production might contribute to
changes in myelopoiesis that frequently accompany viral infection in humans.

10. Mazure G... Wakefield AJ. Measles virus induction of human endothelial cell
tissue factor procoagulant activity in vitro. J Gen Virol 1994 Nov;75 ( Pt
11):2863-71.
          Inflammatory Bowel Disease Study Group, Royal Free Hospital
          School of Medicine, London, U.K.
ab: Measles virus infection of microvascular endothelium in vivo and ensuing
endothelial cell activation may be important in the pathogenesis of subsequent
inflammation in target organs. This study investigated the capacity of measles
virus to induce procoagulant activity, in vitro, in endothelial cells isolated
from human umbilical cord veins. Endothelial cells were infected with a
clinical isolate of measles virus propagated in Vero cells. Cells were also
incubated with bacterial lipopolysaccharide (10 micrograms/ml), herpes simplex
virus type 1, cytomegalovirus or culture medium alone as positive and negative
controls, respectively. Endothelial cell procoagulant activity was measured in
a one-stage clotting assay. Measles virus stimulated both a time and
dose-dependent endothelial cell procoagulant response by the induction of
tissue factor synthesis, confirmed by both immunocytochemistry and its
dependence on factor VII for activity. This activity was reduced by
u.v.-irradiation of the virus. Infected cells were analysed by double
immunofluorescent staining for both tissue factor and measles virus N-protein,
and examined using confocal scanning laser microscopy. Cells expressing tissue
factor were also positive for the measles virus N-protein. Low levels of
interleukin-1 were detected in some viral inocula derived from measles
virus-infected Vero cells, however neutralising antibody to interleukin-1
failed to inhibit the endothelial cell procoagulant response to measles virus,
whereas it significantly reduced procoagulant activity induced in endothelial
cells by recombinant interleukin-1. The capacity of measles virus to induce
endothelial tissue factor in vitro, may be relevant to the thrombotic
vasculopathy associated with measles virus infection in vivo.

11. Wisniewski HM et al. Pathogenesis of viral encephalitis: demonstration of
viral antigen(s) in the brain endothelium. Acta Neuropathol (Berl)
1983;60(1-2):107-12.

     ab: One of the enigmas in the pathogenesis of inflammation is why the white
cells adhere to the endothelium. In trying to define the pathogenic mechanism,
we carried out experiments on ferrets infected with an SSPE strain of measles
virus. Using immunoperoxidase labeling techniques, viral antigens were
demonstrated on the luminal surface and in the cytoplasm of endothelial cells,
irrespective of the presence or absence of inflammatory changes. The degree of
inflammation corresponded well with antibody titer.  These data suggest that the
viral antigen in the endothelial cells is the site of interaction between these
cells and sensitized lymphoid cells.

12. http://www.jorsm.com/~binstock/mmr-v-g.htm

13. Cosby SL, Brankin B. Measles virus infection of cerebral endothelial cells
and effect on their adhesive properties. Vet Microbiol 1995 May;44(2-4):135-9. 
          Division of Molecular Biology, School of Biology and
          Biochemistry, Queen's University of Belfast, UK.
ab: Measles virus (MV) RNA is present in endothelial cells (Ec) in brain tissue
from cases of subacute sclerosing panencephalitis (SSPE) and relatively high
titres of infectious virus are produced in human cerebral Ec in vitro.
Infection of Ec at the blood-brain barrier could therefore provide the
opportunity for entry of virus to the CNS. Adhesion of syngeneic splenocytes to
MV infected murine (Balb/c) cerebral Ec is found to be upregulated. Increased
expression of endothelial adhesion molecules, following virus infection at the
blood-brain-barrier, may be an important mechanism in inducing inflammatory
infiltration of the CNS in SSPE.
Publication Types:  Review  Review, tutorial

14. Numazaki K et al. Replication of measles virus in cultured human thymic
epithelial cells. J Med Virol 1989 Jan;27(1):52-8.
          Department of Microbiology, McGill University, Montreal,
          Children's Hospital Research Institute, Canada.
ab: Measles virus can replicate in cultures of both infantile and fetal human
thymic epithelial cells. Virus-induced cytopathology including syncytium
formation was first evident around 24 hr after viral inoculation of these
cultures. At the same time, the cultures began to lose their characteristic
thymus-like organizational structure. Viral antigens were detected in infected
cells by indirect immunofluorescence, and the presence of progeny virions was
demonstrated in culture fluids.

15. Fujinami RS et al. Molecular mimicry in virus infection: crossreaction of
measles virus phosphoprotein or of herpes simplex virus protein with human
intermediate filaments. Proc Natl Acad Sci U S A 1983 Apr;80(8):2346-50.
     ab: Using monoclonal antibodies, we demonstrate that the phosphoprotein of
measles virus and a protein of herpes simplex virus type 1 crossreact with an
intermediate filament protein of human cells. This intermediate filament
protein, probably vimentin, has a molecular weight of 52,000, whereas the
molecular weights of the measles viral phosphoprotein and the herpes virus
protein are 70,000 and 146,000, respectively. Crossreactivity was shown by
immunofluorescent staining of infected and uninfected cells and by
immunoblotting. The monoclonal antibody against measles virus phosphoprotein
did not react with herpes simplex virus protein and vice versa, indicating that
these monoclonal antibodies recognize different antigenic determinants on the
intermediate filament molecule. The significance of these results in explaining
the appearance of autoantibodies during virus infections in humans is
discussed.

16. Fisher LE, Rapp F. Role of virus variants and cells in maintenance of
persistent infection by measles virus. J Virol 1979 Apr;30(1):64-8.
     ab: Hamster embryo fibroblasts persistently infected with a derivative of
the Schwarz vaccine strain of measles virus spontaneously released virus
particles with an average buoyant density considerably lower than that of the
parental virus. The released virus contained all of the measles virus structural
proteins and interfered with replication of standard virus. All of the virus
structural proteins were associated with a membrane-free cytoplasmic extract
from the persistently infected cells. Membrane-free cytoplasmic extracts
prepared from Vero cells lytically infected with Schwarz strain measles
contained little or no virus envelope structural protein. Maintenance of
persistent infection may involve both the presence of virus variants and a
defect in the ability of the infected cell to replicate the virus efficiently.

17. Morsy TA et al. Endothelial tissue pathological alterations demonstrated in
mice naturally infected with Sarcocystis. J Egypt Soc Parasitol 1994
Dec;24(3):569-77.
          Department of Parasitology, Faculty of Medicine, Ain Shams
          University, Cairo, Egypt.
ab: Comparative electron microscopical study showed a spectrum of
cytopathological changes ranging from exudative to obstructive inflammation of
the vascular endothelium in mice naturally infected with Sarcocystis. The
endothelial cells changes were characteristic of necrotizing vasculitis and
ischaemic injury indicating loss of metabolic integrity and impaired perfusion.
Signs of chronic inflammation and reflecting macrophage-lymphocyte interaction
were also evident. The fact that the endothelial affection was not a consistent
feature in all infected mice, indicates that such cytopathological alterations
may often be temporary and repairable or more likely they are genetically
predisposed.

18. Binstock, T. Perusal of thorough immune panels and other med-history and lab
data from autism-spectrum children (n<15), 1997-1999. *Most* of the immune
panels have revealed one or several atypically elevated antibodies, alterations
in CD4/CD8 counts and ratios, altered NK cell count and/or function, and in some
cases missing antibodies for common antigens -- such as mumps, varicella,
tetanus, etc. 

19. NIDS conference. Neuroimmune Dysfunction Syndromes: redefining
Autism/ADHD/CFS. Presented by The Medical Society of the State of New York and
by Medicine for Autism Today (aka MAT).
                             http://www.nids.com
                             http://www.mat.org

20. Wu CA, Shanley JD. Chronic infection of human umbilical vein endothelial
cells by human herpesvirus-6. J Gen Virol 1998 May;79 ( Pt 5):1247-56.
          Division of Infectious Diseases, Department of Medicine,
          University of Connecticut Health Center, Farmington
          06030-3212, USA. CaWu@nso1.uchc.edu
ab: Human herpesvirus-6 (HHV-6) exhibits a predominant tropism for CD4+
T-lymphocytes, but can infect other components of the blood as well as
surrounding tissue and organs. To understand the role of the endothelium in the
transmission and haematogenous spread of this virus, human umbilical vein
endothelial cells (HUVEC) were infected with HHV-6 and monitored for viral gene
expression. The presence of both early and late viral antigens was demonstrated
by indirect immunofluorescence in 37.6 and 6.5%, respectively, of HUVEC.
However, attempts to detect the release of infectious virus were not
successful, indicating infection is semipermissive in nature. Upon continued
passage of infected HUVEC monolayers, HHV-6 antigen-positive cells persisted up
to 27 days post-infection. Furthermore, the virus could be recovered from HUVEC
monolayers that contained fewer than 1% antigen-positive cells by
co-cultivation with peripheral blood mononuclear cells. Together, these
findings suggest that endothelial cells may serve as a reservoir for harbouring
HHV-6.

21. Teruya-Feldstein J et al. The role of Mig, the monokine induced by
interferon-gamma, and IP-10, the interferon-gamma-inducible protein-10, in
tissue necrosis and vascular damage associated with Epstein-Barr virus-positive
lymphoproliferative disease. Blood 1997 Nov 15;90(10):4099-105.
          Laboratory of Pathology, Hematopathology Section, National
          Cancer Institute, National Institutes of Health, Bethesda,
          MD 20892-1500, USA.
ab: The mechanisms of tissue necrosis and vascular damage characteristics of
certain Epstein-Barr virus (EBV)-associated lymphoproliferative disorders are
unknown. The CXC chemokines interferon-gamma-inducible protein-10 (IP-10) and
the monokine induced by interferon-gamma (Mig) caused tissue necrosis and
vascular damage in Burkitt's lymphoma tumors established in nude mice. We
report higher levels of IP-10 and Mig gene expression in tissues with necrosis
and vascular damage from EBV-positive lymphomatoid granulomatosis and nasal or
nasal-type T/natural killer (NK)-cell lymphomas compared with tissues with
lymphoid hyperplasia, which lacked tissue necrosis and vascular damage. By
immunohistochemistry, Mig and IP-10 proteins localized with similar patterns in
viable tissue surrounding dead tissue, mostly within endothelial cells,
monocyte/macrophages, and lymphocytes. Circulating levels of IP-10 were
abnormally elevated in patients with EBV-positive lymphomatoid granulomatosis
and nasal or nasal-type T/NK-cell lymphomas. These experiments provide the
first description of the presence of Mig in any human normal or diseased tissue
and the first description of IP-10 in certain lymphoproliferative lesions.
These data suggest that Mig and IP-10 play an important role in the
pathogenesis of tissue necrosis and vascular damage associated with certain
EBV-positive lymphoproliferative processes.

22. Jones K et al. Infection of human endothelial cells with Epstein-Barr virus.
J Exp Med 1995 Nov 1;182(5):1213-21.
          Division of Hematologic Products, Food and Drug
          Administration, Bethesda, Maryland, USA.
ab: Interleukin-6 (IL-6) promotes growth and tumorigenicity of Epstein-Barr
virus (EBV)-immortalized B cells, and is abnormally elevated in the serum of
solid organ transplant recipients who develop EBV-positive posttransplant
lymphoproliferative disease (PTLD), but not in control transplant recipients.
Endothelial cells derived from PTLD lesions were found to secrete spontaneously
high levels of IL-6 in vitro for up to 4 mo. We examined possible mechanisms
for sustained IL-6 production by endothelial cells. Here, we show that EBV can
infect endothelial cells in vitro. After 3-4 wk incubation with lethally
irradiated EBV-positive, but not EBV-negative cell lines, a proportion of human
umbilical cord-derived endothelial cells (HUVECs) expressed in situ the
EBV-encoded small RNAs (EBER). Southern blot analysis after polymerase chain
reaction showed EBV DNA in HUVEC that had been incubated with lethally
irradiated EBV-positive cells, but not in the controls. Exposure of HUVECs to
lethally irradiated EBV-positive but not EBV-negative cell lines induced IL-6
production that was sustained for up to 120 d of culture. These studies
identify endothelial cells as targets for EBV infection and raise the
possibility that this infection may be important in the life cycle and
pathology of EBV.

23. Morgello S.  Pathogenesis and classification of primary central nervous
system lymphoma: an update. Brain Pathol 1995 Oct;5(4):383-93.
          Department of Pathology, Mount Sinai Medical Center, New
          York City, NY 10029, USA.
ab: Primary central nervous system lymphoma has undergone a remarkable increase
in incidence over the last decade, both in immunosuppressed and immunocompetent
individuals. Its clinicopathologic evaluation requires knowledge of current
hematopathologic systems for lymphoma classification, as well as specific
understanding of unique central nervous system determinants. In
immunocompromised individuals, the tumor has a constant association with
Epstein-Barr virus. The form of Epstein-Barr virus in these tumors appears to
be predominantly latent, however, the precise mechanism relating virus to tumor
pathogenesis is still unclear. In immunocompetent patients, risk factors and
oncogenic associations are completely unknown. Critical to the formation of
these tumors is the trafficking of B-cells, whether pre- or
post-transformation, across the blood-brain barrier. These B-cell migrations
may require perturbations to the barrier that originate in or around neural
parenchyma, such as localized injury or infection.

24. Bredlich RO et al. [Meningeal irritation--a complication of herpes zoster].
[Article in German] Dtsch Med Wochenschr 1998 Sep 4;123(36):1035-8.
          Abteilung Dermatologie, Klinikums der Universitat Ulm.
HISTORY AND CLINICAL FINDINGS: A previously healthy 26-year-old man complained
of gradually increasing headache after an attack of flu. After 4 days an
erythema with papules but no blisters was noted in the area of distribution of
the left 10th thoracic nerve. As a child he had varicella (chickenpox) without
complications. INVESTIGATIONS: Lymphocytic pleocytosis and evidence of an
abnormal blood-brain barrier were noted in cerebrospinal fluid (CSF). Serology
for varicella zoster virus revealed an IgG titre of > 7400 IU/l in serum and 21
IU/l in CSF. The corresponding IgM titres were negative. TREATMENT AND COURSE:
The headaches and cutaneous changes regressed under i.v. treatment with
acyclovir, 10 mg/kg body weight, 3 x daily for 10 days. Repeat CSF examination
after 10 days showed merely minimal residual changes of inflammation.
CONCLUSION: This case illustrates the risk of severe neurological complications
of herpes zoster infection. A seemingly minor rash with headache must be
correctly diagnosed and immediate high-dosage acyclovir treatment instituted to
prevent life-threatening and severe complications of herpes zoster meningitis
or encephalitis.

25. Ueda T et al. Distribution of human herpesvirus 6 and varicella-zoster virus
in organs of a fatal case with exanthem subitum and varicella. Acta Paediatr Jpn
1996 Dec;38(6):590-5.
          Department of Pediatrics, Kagawa Prefectural Central
          Hospital, Japan.
ab: The distribution of human herpesvirus 6 (HHV-6) and varicella-zoster virus
(VZV) was examined in autopsy samples from a fatal case with both virus
infections. A 9-month-old boy developed convulsive seizures followed by macular
skin rashes, rapidly progressed to brain death, and died 15 days after the
onset, when signs of varicella were noted... Among the findings for the
distribution of virus antigens, it was noteworthy that HHV-6 antigen was
demonstrated in the endothelial cells of small vessels in the frontal lobe of
the brain... 

26. Erhard H et al. Atypical varicella-zoster virus infection in an
immunocompromised patient: result of a virus-induced vasculitis. J Am Acad
Dermatol 1995 May;32(5 Pt 2):908-11.
          Department of Dermatology, University of Wurzburg, Germany.
ab: We describe a patient with cutaneous T-cell lymphoma in whom persistent,
painless, ecthymatous nodules developed as a result of a varicella-zoster virus
infection. The localized infection occurred without a vesicular stage.
Ultrastructural studies revealed a lack of epidermal involvement and massive
varicella-zoster virus replication within endothelial cells, leading to an
obliterative vasculitis. This suggests direct infection of dermal vessels from
adjacent nerves, bypassing the epidermis, which is usually infected first in
the classic infectious pathway during varicella-zoster virus reactivation from
sensory nerves.

27. Nikkels AF et al. Comparative immunohistochemical study of herpes simplex
and varicella-zoster infections. Virchows Arch A Pathol Anat Histopathol
1993;422(2):121-6.
          Department of Dermatopathology, University of Liege,
          Belgium.
ab: Herpes simplex (HSV) and varicella-zoster (VZV) skin infections share so
many histological similarities that distinguishing between them may prove to be
impossible. We developed and characterized a new monoclonal antibody, VL8, IgG
kappa isotype, directed to the VZV envelope glycoprotein gpI.
Immunohistochemistry with VL8 appeared highly sensitive and specific on
formalin-fixed paraffin-embedded biopsies and a clear-cut distinction between
HSV and VZV infections was possible. The pattern of VL8 immunolabelling in VZV
infections was strikingly different from that found in HSV infections studied
with polyclonal antibodies to HSV I and II. Double immunolabelling revealed the
VL8 positivity of sebaceous cells, endothelial cells, Mac 387- and
CD68-positive monocyte-macrophages, and factor XIIIa-positive perivascular,
perineural and interstitial dendrocytes. Intracytoplasmic VL8 labelling of
endothelial cells and perivascular dendrocytes was found at the site of
leukocytoclastic vasculitis.

28. Visseren FL, Erkelens DW. [Atherosclerosis as an infectious disease].
[Article in Dutch] Ned Tijdschr Geneeskd 1999 Feb 6;143(6):291-5.
          Academisch Ziekenhuis, afd. Inwendige Geneeskunde, Utrecht.
ab: According to several published studies micro-organisms may be involved in
atherogenesis. An association is described between cytomegalovirus or Chlamydia
pneumoniae and an increased risk of vascular events. The micro-organisms are
able to infect endothelial cells and smooth muscle cells in vivo and in vitro,
evoking to pathophysiological reactions of these cells which may lead to
atherosclerosis, arterial thrombosis and plaque rupture. In two small secondary
prevention trials, macrolide treatment proved successful in preventing second
myocardial infarctions. At this moment, however, it is too early for treatment
with antimicrobial agents to prevent vascular diseases in daily clinical
practice.

29. Kas-Deelen AM et al. A sensitive method for quantifying cytomegalic
endothelial cells in peripheral blood from cytomegalovirus-infected patients.
Clin Diagn Lab Immunol 1998 Sep;5(5):622-6. 
          Department of Clinical Immunology, University Hospital
          Groningen, Groningen, The Netherlands.
          A.M.Deelen@med.rug.nl
ab: A sensitive method has been developed for the quantification of cytomegalic
endothelial cells (CEC) in peripheral blood (PB) of patients with active
cytomegalovirus (CMV) infections. The three subsequent key steps of this method
are density centrifugation to enrich endothelial cells (EC) in the mononuclear
cell (MNC) fraction, EC-specific staining, and fluorescence-activated cell
sorting (FACS) of EC onto adhesion slides. The FACS method was compared with
the conventional method of cytocentrifugation of the MNC fraction onto slides,
followed by EC-specific staining. The main advantage of the additional steps
for the isolation and quantification of CEC in PB by FACS is a 10-times-greater
sensitivity than by cytocentrifugation of the MNC fraction alone. The recovery
percentages of EC from whole blood were comparable for both methods. Recoveries
of EC obtained after FACS were 53% +/- 16.5%, (mean +/- standard deviation),
and recoveries of EC obtained after cytocentrifugation of the MNC fraction were
43% +/- 4.3%. In patients with active CMV infection, 5 to 72 CEC were detected
by FACS, equivalent to 0.8 to 9.0 CEC/ml of blood. With this method for
isolation and quantification, the characterization of CEC in PB of patients
with CMV-associated clinical symptoms, as well as the quantification of EC in
PB of patients with pathophysiological manifestations involving endothelial
damage that are different from those caused by CMV infections, can be
performed.

30. Waldman WJ et al. Cytolytic activity against allogeneic human endothelia:
resistance of cytomegalovirus-infected cells and virally activated lysis of
uninfected cells. Transplantation 1998 Jul 15;66(1):67-77.
          Department of Pathology, Ohio State University College of
          Medicine, Columbus 43210, USA. waldman.1@osu.edu
BACKGROUND: Cytomegalovirus (CMV) has been implicated as an exacerbating agent
in the development of transplant vascular sclerosis; however, specific
etiologic mechanisms remain unresolved. Based upon our previous observations
that CMV-infected endothelial cells (ECs) stimulate proliferation and cytokine
production by allogeneic T cells, we now test the hypothesis that CMV-driven
cytolytic activity may contribute to graft endothelial injury. METHODS:
Limiting dilutions of CMV-seropositive or -seronegative donor-derived T cells
were stimulated with CMV-infected or uninfected allogeneic ECs in the presence
of interleukin-2. T-cell proliferation was monitored by assay of [3H]thymidine
incorporation and stimulated T cells were tested for lytic activity against
CMV-infected or uninfected radiolabeled EC targets by 51Cr release assay.
Natural killer (NK) cell activity was examined by incubating freshly isolated
peripheral blood mononuclear cells with 51Cr-labeled targets, followed by assay
of radiolabel release. RESULTS: CMV-infected ECs were resistant to T cell- and
NK-mediated cytolysis regardless of donor serostatus, nature of stimulation, or
level of T-cell proliferation. In contrast, although uninfected ECs were
unharmed by NK cells, these targets experienced significant lysis by T cells
stimulated with either uninfected or CMV-infected ECs. CONCLUSIONS: These
results implicate CMV-infected graft endothelium as a persistent source of
infectious virus, a chronic stimulus for potentially destructive host
inflammatory activity, and a potential trigger for the generation of lytic
injury to uninfected bystander endothelia, suggesting multiple mechanisms by
which this virus might perturb equilibrium at the graft/host interface.

31. Robertson AL Jr et al. Viral genomes and arterial disease. Ann N Y Acad Sci
1995 Jan 17;748:57-72; discussion 72-3 
          Department of Pathology, University of Illinois, College of
          Medicine, Chicago.
ab: Recent studies suggest that the initial stages of human atherogenesis may
be defined as inordinate inflammatory-proliferative responses of intimal
arterial cells, interacting with circulating lymphocytes and
monocyte/macrophages, to multiple focal stimuli. The latter include
transmembrane signal transductions induced by cytokines and growth factors as
well as by activated immune cells releasing vasoregulatory molecules affecting
local transarterial lipoprotein transport and metabolism. The observed
discriminating cell proliferation and characteristic focal eccentric intimal
thickening of spontaneous atheroma may thus result from the phenotypic
expression of transformed cell clones with selective proliferative advantages
and yet unaffected by tissue immune responses. A suggested mechanism for such
cell transformation is the partial expression of widely distributed herpesvirus
genomes, resulting in the induction of clonal expansion and enhancement of
selective cell growth in transfected host cells. Major obstacles for the
unambiguous laboratory demonstration of a direct cause/effect relationship
between herpes induced cellular transformation and early human atheroma are (1)
potential loss of recognizable viral transforming sequences in the host cell
genome by the "hit and run" mechanism originally proposed by Skinner in 1976 and
(2) irreversible cytopathic effects induced by these viruses in experimentally
infected human cells in vitro, preventing any long-term proliferative or
metabolic studies. The observation that immortalized cultured rabbit arterial
cells retain for many generations marked mitogenic activity and accelerated
lipoprotein uptake after herpesvirus transfection suggested to us the
possibility of developing a reproducible in vivo laboratory model in inbred
rabbits. To that end, discrete intraarterial injections of fragments of HSV-1
or HSV-2 genomes were made via specially designed catheters in temporarily
isolated arterial segments of Watanabe heritable hyperlipemic rabbits. While
normolipemic heterozygous animals developed segmental, highly localized,
proliferative intimal tumors, containing over 95% HHF35 (+) smooth muscle cells
with RAM 11 (+) macrophages and platelets attached to the endothelial surface
in 30-60 days, no lesions were found in placebo-injected controls. When
hyperlipemic homozygous rabbits were similarly tested, they manifested at
injected loci larger intimal lesions containing abundant lipid-laden macrophages
and smooth muscle cells before typical rabbit fatty streaks developed elsewhere.
These findings suggest that selective transfection with viral genome sequences
may indeed induce specific growth promoters for intimal arterial smooth muscle
cells and thus play an important role during the initial stages of
atherogenesis.

32. Vercellotti GM. Effects of viral activation of the vessel wall on
inflammation and thrombosis. Blood Coagul Fibrinolysis 1998 Apr;9 Suppl 2:S3-6.
          University of Minnesota Medical School, Minneapolis 55105,
          USA.
ab: Herpes simplex virus type 1 and cytomegalovirus alter the phenotype of the
endothelium in vitro from anticoagulant to procoagulant, thereby promoting the
adherence of neutrophils and platelets to the endothelium. Virus infection of
the endothelium induces the expression of viral glycoproteins and adhesion
molecules, which promote neutrophil and monocyte adhesion. Herpes simplex
infection of the endothelium promotes prothrombinase assembly, allowing more
efficient thrombin generation. Excess thrombin generation causes translocation
of P-selectin. Viral infection also induces the procoagulant molecule, tissue
factor, in endothelial cells. These enhanced procoagulant effects are
associated with the loss of anticoagulants, including thrombomodulin,
prostacyclin and tissue plasminogen activator. These studies support the
speculation that virus infection in vivo promotes vascular injury and
thrombosis, which may contribute to disease states such as atherosclerosis.

33. Kurokawa Y et al. [Serial changes of SPECT and MRI findings in a patient
with herpes simplex encephalitis]. [Article in Japanese] No To Shinkei 1996
Feb;49(2):163-9.
          Takahashi Neurosurgical Hospital, Sapporo, Japan.
ab: We report a case of herpes simplex encephalitis in which the patient was
repeatedly examined by magnetic resonance imaging (MRI) and single photon
emission computed tomography (SPECT). The patient was a 36 year-old woman who
had been transferred to our institution 6 days after the onset of symptoms with
mild consciousness disturbance, nuchal rigidity, and high fever. Cerebrospinal
fluid examination revealed an elevated mononuclear cell count with normal sugar
concentration. Intravenous aciclovir was started 7 days after the onset of
symptoms. The initial plain computed tomography (CT) scans did not reveal any
abnormal findings, but contrast enhanced CT the next day showed a slight
enhancement effect around the affected middle cerebral artery. Serial MRI
showed the initial high intensity lesion starting on the medial cortex of the
temporal lobe, then spreading to throughout the entire temporal lobe. During
this period SPECT showed a marked, broad hot spot in the temporal lobe. The
medial temporal lobe was high density on the CT 15 days after the onset. As the
encephalitic lesion spread more laterally, the hot spot on SPECT moved
laterally and then decreased in activity. Eleven weeks after the onset, the MRI
showed intracerebral vacuolization of the lesion and it appeared as a wide cold
spot on SPECT. The cause of the hot spot seen in the acute period was thought
to be vasoparalysis of the affected area rather than breakdown of the
blood-brain barrier, or impaired washout of the isotope, because the SPECT
images after acetazolamide administration showed the cold spot even in the
subacute phase.

34. Shinjo H et al. [A case of chronic encephalitis due to double infection with
herpes simplex and measles viruses]. [Article in Japanese] No To Shinkei 1997
Nov;49(11):1021-6.
          Department of Neuropsychiatry, Hyogo College of Medicine,
          Japan.
ab: In a healthy 49-year-old man, a decrease in job efficiency was noticed along
with bizarre behavior. On admission, he was euphoric, childish, superficial and
had increased libido. Neurological findings were normal. There were no abnormal
findings on routine blood tests, hematochemistry or urine analysis. MRI showed
no abnormal findings. However, single photon emission CT (SPECT) showed diffuse
hypoaccummulation of tracer from the temporal to frontal regions. Lumbar
puncture showed clear cerebrospinal fluid (CSF) with pleocytosis and an
elevated protein level. Moreover, antibody IgG titers to herpes simplex virus
(HSV) and measles virus were elevated, according to EIA [serum HSV -1,202.2x,
measles virus 47.1x: CSF HSV-116.1x, measles virus 9.9x]. The ratio of serum to
CSF antibody titers of HSV and measles virus were 12.5 and 4.75, respectively.
The antibody index values of HSV and measles virus IgG titers were 8.42 and
22.22. The ratio of albumin was 105.7. Chronic, progressive HSV encephalitis is
rare, and there have been very few reports of encephalitis due to double
infection by HSV and another virus. Our patient was diagnosed as having
encephalitis due to double infection with HSV and measles virus, because the
ratio of serum to CSF antibody titers was less than 20 and the antibody index
values were over 1.91. Moreover, since the IgG index was elevated and the ratio
of albumin was not low, it was suggested that the blood-brain-barrier had not
been disrupted, and antibodies were being produced chronically in the medullary
cavity. Hyperaccummulation of tracer on SPECT studies has been reported in the
early stages of HSV encephalitis. In our case, while CT and MRI showed no
abnormal findings, SPECT showed diffuse hypoaccummulation. SPECT appears to be
a useful tool in the diagnosis of this disorder. In case of chronic,
progressive personality change in middle-aged adults, we must be aware of
double virus infection of the brain as a possible causal factor.

35. Clements DA. Modified varicella-like syndrome. Infect Dis Clin North Am 1996
Sep;10(3):617-29 
          Division of General Pediatrics, Duke University Medical
          Center, Durham, North Carolina, USA.
ab: After incidental exposure to natural varicella, up to 18% of vaccinees
reported a breakthrough infection known as modified varicella-like syndrome
(MVLS) over up to 10 years of postvaccination follow-up, compared with natural
varicella occurring in similarly aged unvaccinated children at the rate of 9%
per year. Children with MVLS are frequently asymptomatic, and their disease is
characterized by having fewer lesions, less fever, and lasting fewer days than
natural varicella. When a case of MVLS occurs there are few secondary cases,
suggesting that it is infrequently transmitted. Sequelae such as secondary
bacterial infection, cerebellar ataxia, encephalitis, and pneumonia occur
infrequently.