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Artículo original
Evidencia directa del virus Herpes Simplex Hominis Tipo I
en el lóbulo temporal de pacientes esquizofrénicos, en su
descendencia y en animales experimentales
Direct evidence of Herpes Simplex Hominis Type I virus in the temporal lobe of schizophrenic patients, their offspring
and in experimental animals
Segundo Mesa Castillo
Resumen
De acuerdo con nuestros previos reportes los avances obtenidos en el conocimiento de las
infecciones virales del sistema nervioso, hacen de los virus candidatos etiológicos atractivos para
el origen prenatal de la esquizofrenia. Entre estos candidatos está el virus Herpes Simplex
Hominis tipo I [VHS-1] debido a su capacidad de permanecer latente con reactivaciones
periódicas, su afinidad por el sistema límbico, la región del cerebro implicada en la
esquizofrenia, su reactivación por los cambios endocrinos, el estrés, las radiaciones y las
alteraciones inmunológicas y por su relación con la predisposición genética. La presunción de
evidencia para una etiología viral requiere la demostración de un virus, de su antígeno o de
anticuerpos virales. Nuestras observaciones electro e inmuno-electromicroscópicas de partículas
virales y antígeno del VHS-1 en el lóbulo temporal del cerebro de pacientes esquizofrénicos
adultos fallecidos, en fetos abortados de madres esquizofrénicas y en animales inoculados con
líquido céfalo raquídeo [LCR] de pacientes esquizofrénicos nos hace considerar este virus como
un agente etiológico ya que los postulados de Koch han sido parcialmente cumplidos. En este
trabajo presentamos los resultados obtenidos durante 33 años usando técnicas de microscopía
electrónica en el estudio de la etiología de la esquizofrenia.
Palabras claves: Esquizofrenia, virus, microscopía electrónica, herpes, origen prenatal.
Abstract
In agreement with our previous reports the advances obtained in understanding central nervous
system (CNS) viral infections make viruses attractive etiological candidates for the prenatal
origin of schizophrenia. Among these candidates is Herpes Simplex Hominis type I Virus (HSV1) due its capacity to remain latent with periodic reactivation, its affinity for the limbic system,
the region of the brain involved in schizophrenia, its reactivation by endocrine changes, stress,
radiation and immune alterations and for its relation to genetic predisposition. Presumptive
evidence for a viral etiology requires the demonstration of a virus, antigen or viral antibody. Our
electron and immuno-electronmicroscopic observations of viral particles and HSV-1 antigen in
the temporal lobe of the brain of dead adults schizophrenic patients, of aborted fetuses from
schizophrenic mothers and in experimental animals inoculated with cerebrospinal fluid [CSF]
from schizophrenic patients made us to consider this virus as an etiological agent since Koch
postulates have been partially fulfilled. In this work we present the result obtained for 33 years
using electron microscopic techniques on the study of the etiology of schizophrenia.
Keywords: Schizophrenia, virus, electron microscopy, herpes, prenatal origin.
Psiquiatria.com ISSN: 1137-3148
© 2011 Mesa Castillo S.
Mesa Castillo S. Psiquiatria.com. 2011; 15:32.
http://hdl.handle.net/10401/4348
Recibido: 25/10/2010 Aceptado: 04/11/2011 Publicado: 05/09/2011
* Correspondencia: segundo@infomed.sld.cu
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Background
Karl Menninger wrote in 1922: "I am persuaded that dementia praecox (schizophrenia) is at
least in most instances a somato-psychosis; the psychic manifestations of an encephalitis. The
acuteness or chronicity, the benign or malignant nature of the encephalitis perhaps determines
the degree of reversibility of the schizophrenia" [1]. By 1930 the cerebrospinal fluid and
nasopharyngeal washings from schizophrenic patients were being injected into rabbit brains in
attempts to produce sepsis in the brain [2].
Direct evidence of viral infection
Direct testing of a viral hypothesis of serious mental illnesses began in the 1950s. Utilizing the
technology that was then available, Morozov [3] and his colleagues in the Soviet Union claimed
to have microscopically seen "virus-like corpuscles" in the CSF and nasal secretions of many
patients with schizophrenia. In Italy, Mastrogiovanni and Scarlato [4] inoculated CSF from
patients with schizophrenia into chicken embryos and also claimed to have microscopically
visualized "virus like particles". Since that time, the only researches who have claimed to have
found virus particles in patients with serious mental illnesses have been Castillo and his
colleagues in Havana, Cuba. They have described intracytoplasmic encapsulated structures
similar to herpesviruses in freshly obtained postmortem brain tissue from patients with
schizophrenia [5] and also in brain tissue from aborted fetuses from mothers with schizophrenia
[6]. Cited by Fuller Torrey [7].
Viral genome
Studies of viral genome in postmortem brain tissue from individuals with schizophrenia started
in 1979. Sequiera et al. found HSV-1 positive genome by solution and in situ hybridization in a
patient with schizophrenia [8]. Taylor et al. in 1985 obtained negative results to HSV-1 studying
the temporal lobe by dot blot hybridization [9]. Carter et al in 1987 also obtained negative
results studying samples from caudate, putamen, hippocampus, temporal cortex and frontal
cortex by dot blot hybridization to HSV-1 [10]. Hayward et al. also reported negative results to
HSV-1 in temporal cortex by Southern blot hybridization. Cited by Torrey [11]. Rajcani et al. [12]
found positive genome results for HSV-1 by blot hybridization studying amygdala samples from
schizophrenic patients in 1991. Alexander et al. found negative results in temporal cortex by
PCR in 1992 [13]. Taller et al. studying temporal cortex samples from 63 schizophrenics and 7
controls by PCR found negative results except 1 HSV-1. It is interesting to highlight the positive
results in samples obtained from the amygdala in the study done by Rajcani in 3 of 18 patients
(17%) and in 4 of 26 controls (15%) which relate the amygdala to herpes simplex hominis type I
virus. The negative results may indicate that HSV-1 is not present in other brain regions apart
of the region of interest [ROIs] obtained by imagenology.
Material and method
The method of control and patient selection, diagnosis and procedure have been previously
described [5,6,14].
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Results
In previous works we have published in independent form the results obtained of each one of
the three exposed investigations in the present work [5,6,14]. The obtained results were similar
in the studies carried out in the samples of the left temporal lobe in adults dead schizophrenic
patients, in aborted fetuses from schizophrenic mothers and in animals experimentally
inoculated with cerebrospinal fluid from schizophrenic patients. They consisted on all in nuclear
bodies, membrane alterations and particles with viral morphology which reacted in a positive
form with antiherpes simplex hominis type I antibody [Fig.1].
Fig.1
Adults dead schizophrenic patients. Particles with viral morphology were observed in the three
ROIs temporal lobe brain samples. Some of them as budding like particles within the nuclear
envelope of neurons, mainly in the amygdala-hippocampus complex. Intranuclear spherical
viral particles with a central core and an envelope related to membrane structures were also
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observed. The central core measure was 80 to 90 nanometers. When comparing the images of
the obtained particles with those described in the literature of herpes simplex hominis type I
virus in experimental conditions a similarity was observed Fig.2 (a,b,c,d).
Fig. 2
In the immuno-electron microscopic studies of the samples a positive reaction to herpes simplex
hominis type I virus as its relation to membrane structures (out and within the nuclei) was
observed when peroxidase conjugated antiherpes antibody was used. Fig. 2 (e,f,g,h).
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Fig. 2
Aborted fetuses. In the studied foetuses it was observed within the nucleus of neurons the
presence of spherical empty particles of 100 nm occupying the centre of an electron-lucid area.
The inclusions with particles appeared in number from 2 to 8 per nucleus, with great incidence
in their appearance. In the immuno-electronmicroscopic study a positive reaction against
herpes simplex hominis type I virus was observed. The viral particles were not observed in the
control, as in the rest of the cells of the nervous system neither the immune-reaction. A digital
analysis of the particles was done. Fig. 3 (a,b,c,d).
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Fig. 3
Experimental animals. The obtained results are similar to those observed in previous studies of
brains from adults' dead schizophrenic patients and in the brain of aborted fetuses from
schizophrenic mothers. These results are related to the presence of particles, a phenomenon of
abnormal replication of membranes and the presence of herpes simplex hominis type I virus
(HSV-1) antigen in particles and membrane structures in the left temporal lobe of the
experimental animals -chicken embryos and rats- inoculated with the cerebrospinal fluid of
schizophrenic patients. Fig. 4 (a,b,c,d).
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Discussion
The viral hypothesis of schizophrenia has been considered by several elements: the seasonality
of birth with a modest excess - related to population control -about 8% of spring and winter
births among individuals who become schizophrenics [15-17]. This seasonality relation suggests
an association with the well known increased occurrence of viral epidemics in spring and winter
and therefore of viral replication. Increased of viral antibodies particularly of the herpes class,
have been elevated in schizophrenic patients [18-20]. Viral isolation and Transmission of illness
[21-26]. Immunological measures. Initial evidence from several sources indicates abnormal
functioning of the immune system [27-33]. Brain pathology related to the imaging observations.
A significant proportion of schizophrenic patients have evidence of structural brain
abnormalities [34-39] that may be consistent with a viral etiology. Gene and virus. A viral
hypothesis can coexist with the clear evidence for genetic factors in schizophrenia since viruses
can integrate into the genome and be transmitted to offspring as genetic material or could
interact with cells in events occurring prenatally, perinatally or later during puberty due to
hormone endocrine changes at this stage of life that facilitates virus replication. Viruses may
remain latent and transmitted from generation to generation in a pattern that would make it
appear to be a genetic disease. The concept of latent viral infections with periodic reactivation is
now well established. Among the viruses that have this property are many of the herpes family.
The presence of virus like particle in the studied fetuses from schizophrenic mothers favors the
possibility of virus insult to the brain at crucial times in the growth and differentiation of areas
of limbic regions: amygdala e hippocampus. It is interesting the observation that the changes
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observed in the amygdala-hippocampus volume start with the psychotic symptomatology.
Medial temporal structural changes are not seen until after the onset of a psychotic illness [40].
Nevertheless other authors have observed these changes even in the prodromic stage, observing
that some of the grey-matter abnormalities associated with psychotic disorders predate the
onset of frank symptoms, whereas others appear in association with their first expression
[41,42]. This aspect could be related to the neurobiology of slow virus infections affecting the
ROIs after a period of latency starting their replication under stress u hormonal changes at
puberty. A delay between transmission in the perinatal period and symptom onset in late
adolescence is compatible with chronic, latent, slow, or persistent viral infection and with the
neurodevelopment hypothesis of schizophrenia with involvement of the regions of the limbic
system mainly in the left temporal lobe. These areas that at present have been called regions of
interest (ROIs) in macroscopic examination of the brain were stalking since the use of the
imaging techniques that started to develop in the 70s and 80s. As one observed said: "such
approaches give us a broad sense of how the brain looks anatomically and how it functions
physiologically. To understand how genes affect the brain in a way that puts it at risk, we need to
examine in a much more finely detailed way the actual cells of the brain. We can do this with
living brain tissue to some degree, and we can do this with postmortem brain tissue to a much
greater degree" cited by Weinberger DR [43]. Viruses may selectively attack specific cells types
or locations in the CNS and alter their chemical functions. It is reasonable to postulate specific
viruses that may selectively alter only one enzyme system of one cell type or one area of the
brain. It has been shown that HSV infection alters the dopamine system in animal models.
Several lines of evidence have been cited suggesting that schizophrenia might begin as an in
utero infection. In spite of that commented it should be kept in mind that a virus presence in
any illness can be the result of the succession of biological events that happen for that illness
and not to be related specifically with the etiology of the same one. Nevertheless the fact that
the present investigation is the only one carried out in the calls regions of interest in the
temporal lobe of the brain in schizophrenia (ROIs) using a higher resolution power technique
and of being the reported findings to be able to be related with the viral etiology, the necessity is
imposed of replying these studies in other populations with different ethnical, cultural and socio
economic conditions in order to discarding other coincident factors that could alter the obtained
results. Then, the presence of a virus does not always mean that it is etiologically related to the
disease under study specially related to HSV-1 as many normal persons carry this virus in their
brain, but the observation of similar neuropathological findings in the brain of schizophrenic
adults, fetuses from schizophrenic mothers and in experimental animals inoculated with
cerebrospinal fluid [CSF] from schizophrenic patients made us to consider this virus as an
etiological agent since Koch postulates had been partially fulfilled. Another important aspect of
these results is those related to the effect of these findings, especially in the studied fetuses on
the prenatal origin of schizophrenia and neurodevelopment. There are increasing evidences that
favour the prenatal beginning of schizophrenia [44-48]. These evidences point toward intrauterine environmental factors that act specifically during the second pregnancy trimester
producing a direct damage of the brain of the fetus. The current available technology doesn't
allow observing what it is happening at cellular level since the human brain it is not exposed to a
direct analysis in that stage of the life. Most of the techniques that have accumulated evidences
of prenatal cerebral damage have been of little resolution power and by means of indirect
methods. It is necessary a technique with high resolution power that allows obtaining the
necessary information of the brain of the fetus and of the environmental factors that surround
him. As an author comments in his article on epigenetic mediation of environmental influences
in major psychotic disorders: "of particular note is the high degree of discordance between
monozygotic (MZ) twins for both disorders. Such phenotypic discordance between MZ twins is
often attributed to nonshared environmental factors, although the empirical evidence for such a
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large environmental contribution to either disorder is still lacking, with nospecific
environmental risk factors being conclusively linked to etiology. The mechanism through which
these environmental factors act upon molecular and cellular biological machineries in the
human brain and ultimately giverise to psychosis-related phenotypes and pathology remains
poorly understood", cited by Rutten [49]. Our findings of HSV-1 particles in the brain of fetuses
from schizophrenic mothers could be the answer to this query considering also de discordance
of infection in monozygotic twins [50]. These are the first direct evidence that demonstrate the
presence of virus particles in the central nervous system of foetuses from schizophrenic mothers
in the critical period of the second trimester of foetal development. These findings make us to
consider the following hypothesis related to the possible explanation of the biological events in
schizophrenia. [Fig. 5]
Our work hypothesis would be:
1. The existence of the illness (virus latency) in the mother or the father.
2. The viral transmission or viral activation of the illness to the fetus especially during the
second pregnancy trimester.
3. The infection of the brain of the fetus and of the placenta for the virus.
4. The presence of the viral infection in the free cells of the amniotic fluid those that will present
similar alterations to those observed in the brain of the studied fetuses of schizophrenic mothers
and in the placenta [51].
5. To study these free cells by means of similar electron microscopic techniques or DNA viral
identification.
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Fig. 5
Conclusion
The importance of these findings can have practical applications in the prevention of the illness
keeping in mind their direct relation to the aetiology and physiopathology of schizophrenia. The
possibility to study the amniotic fluid cells by means of virological or electron microscopic
techniques is suggested in women at risk of having a schizophrenia offspring with the objective
of applying preventive measures, pregnancy interruption or early antiviral treatment, if a viral
infection is demonstrated in early neurodevelopment stages in the amniotic fluid cells.
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Cite este artículo de la siguiente forma (estilo de Vancouver):
Mesa Castillo S. Evidencia directa del virus Herpes Simplex Hominis Tipo I en el lóbulo
temporal de pacientes esquizofrénicos, en su descendencia y en animales experimentales.
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