Progress in Neuro-Psychopharmacology & Biological Psychiatry 42 (2013) 71–91
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Progress in Neuro-Psychopharmacology & Biological
Psychiatry
journal homepage: www.elsevier.com/locate/pnp
Updating the mild encephalitis hypothesis of schizophrenia
K. Bechter ⁎
Ulm University, Clinic for Psychiatry and Psychotherapy II, Ludwig-Heilmeyer-Str. 2, D-89312 Günzburg, Germany
a r t i c l e
i n f o
Article history:
Received 25 January 2012
Received in revised form 11 June 2012
Accepted 25 June 2012
Available online 3 July 2012
Keywords:
Autoimmunity
Gene–environment–immune interactions
Low-level neuroinflammation
Mild encephalitis hypothesis
Psychoneuroimmunology
Schizophrenia
a b s t r a c t
Schizophrenia seems to be a heterogeneous disorder. Emerging evidence indicates that low level neuroinflammation (LLNI) may not occur infrequently. Many infectious agents with low overall pathogenicity
are risk factors for psychoses including schizophrenia and for autoimmune disorders. According to the mild
encephalitis (ME) hypothesis, LLNI represents the core pathogenetic mechanism in a schizophrenia subgroup
that has syndromal overlap with other psychiatric disorders. ME may be triggered by infections, autoimmunity, toxicity, or trauma. A ‘late hit’ and gene–environment interaction are required to explain major findings
about schizophrenia, and both aspects would be consistent with the ME hypothesis. Schizophrenia risk genes
stay rather constant within populations despite a resulting low number of progeny; this may result from advantages associated with risk genes, e.g., an improved immune response, which may act protectively within
changing environments, although they are associated with the disadvantage of increased susceptibility to
psychotic disorders. Specific schizophrenic symptoms may arise with instances of LLNI when certain brain
functional systems are involved, in addition to being shaped by pre-existing liability factors. Prodrome
phase and the transition to a diseased status may be related to LLNI processes emerging and varying over
time. The variability in the course of schizophrenia resembles the varying courses of autoimmune disorders,
which result from three required factors: genes, the environment, and the immune system. Preliminary
criteria for subgrouping neurodevelopmental, genetic, ME, and other types of schizophrenias are provided.
A rare example of ME schizophrenia may be observed in Borna disease virus infection. Neurodevelopmental
schizophrenia due to early infections has been estimated by others to explain approximately 30% of cases, but
the underlying pathomechanisms of transition to disease remain in question. LLNI (e.g. from reactivation
related to persistent infection) may be involved and other pathomechanisms including dysfunction of the
blood–brain barrier or the blood–CSF barrier, CNS-endogenous immunity and the volume transmission
mode balancing wiring transmission (the latter represented mainly by synaptic transmission, which is
often described as being disturbed in schizophrenia). Volume transmission is linked to CSF signaling; and
together could represent a common pathogenetic link for the distributed brain dysfunction, dysconnectivity,
and brain structural abnormalities observed in schizophrenia. In addition, CSF signaling may extend into
peripheral tissues via the CSF outflow pathway along brain nerves and peripheral nerves, and it may explain
the peripheral topology of neuronal dysfunctions found, like in olfactory dysfunction, dysautonomia, and
even in peripheral tissues, i.e., the muscle lesions that were found in 50% of cases. Modulating factors in
schizophrenia, such as stress, hormones, and diet, are also modulating factors in the immune response. Considering recent investigations of CSF, the ME schizophrenia subgroup may constitute approximately 40% of
cases.
© 2012 Elsevier Inc. All rights reserved.
1. Introduction
Since the first version of the mild encephalitis (ME) hypothesis
was proposed (Bechter, 2001), many new findings and further
hypotheses have been published that fit in with or support the ME
hypothesis. The ME hypothesis characterized a subgroup of severe
psychiatric disorders, mainly on the affective and schizophrenic spectra, in which low level neuroinflammation (LLNI) causally underlies
the disorder as the core pathogenetic mechanism. Other underlying
⁎ Tel.: +49 8221 96 2540/96 00; fax: +49 8221 96 2736.
E-mail address: [email protected].
0278-5846/$ – see front matter © 2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.pnpbp.2012.06.019
causes of schizophrenia that have been proposed include a Th1–
Th2-imbalance and other immune abnormalities (Muller and Schwarz,
2010), cytokine abnormalities (Licinio and Wong, 1999, Maes, 1997),
the two-hit-hypothesis (Bayer et al., 1999), the genetic inflammatory
hypothesis (Hanson and Gottesman, 2005), the neuroprotective hypothesis (Lang et al., 2004), and the imbalance of kynurenic pathways related
to neuroinflammation and neurodegeneration (Myint and Kim, 2003,
Myint et al., 2011). The ME hypothesis assumed that LLNI prevailed
and was important during critical time periods of disease and, although
it overlaps with several psychiatric diagnostic categories, it was thought
to be especially relevant in affective and schizophrenic disorders. The etiologies proposed to be involved in LLNI are varied, including infections,
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K. Bechter / Progress in Neuro-Psychopharmacology & Biological Psychiatry 42 (2013) 71–91
autoimmunity, infection-triggered autoimmunity, toxicity (also including endogenous toxicity or disturbed protective capacity, e.g. caused by
hunger), and trauma. LLNI pathomechanisms may be influenced by or
even depend on pre-existing genetic factors and liabilities, including
immune and inflammatory response-related genes, and the final clinical
outcome may be influenced by independent factors at different pathogenetic levels, possibly relevant at multiple times over the course of the
inflammation. A complex etiopathogenetic scenario is the rule rather
than the exception, as demonstrated by recent insights into the infectious determinants involved in chronic CNS diseases (O'Connor et al.,
2006).
Several reviews of the accumulated findings on neuropsychoimmunology in schizophrenia have been published in the past two
decades (Bahn and Schwarz, 2011, Licinio and Wong, 1999, Maes,
1997, Muller and Schwarz, 2010, Myint et al., 2011). The previous
ME view that the diagnostic spectrum overlapped with other severe
psychiatric disorders was supported by the results of large genetic
studies (see below) and is consistent with longstanding knowledge
about the lack of syndromal-specific etiologies in psychiatric disorders (Bechter, 2001, Gross and Huber, 2007). The ME hypothesis
has recently been supported by results from epidemiological studies
involving a number of infectious agents as risk factors (Benros et al.,
2011, Brown et al., 2001, 2004, Dalman et al., 2008, Niebuhr et al.,
2008, Yolken and Torrey, 2008) and from a large milestone study
showing an additive effect of severe infections and autoimmune disorders over time (Benros et al., 2011). Findings from studies relying
on newly introduced research methods such as proteomics (Holmes
et al., 2006, Schwarz et al., 2012) and immune cell blood analysis
(Drexhage et al., 2010a), as well as from CSF investigations (Bechter
et al., 2010a, Maxeiner et al., 2009), support the view that LLNI may
prevail in a considerable number of schizophrenic patients; specifically in CSF investigations, LLNI is involved in approximately 40% of
cases. In this article, the ME concept is updated, and an ME subgroup
comprising heterogeneous subtypes of schizophrenia is discussed. To
understand the complexity of the questions involved, the definitions
of inflammation must first be discussed.
2. Definitions of inflammation
The preliminary definition of ME included the possibility that
over short time periods, small (classical) inflammatory lesions (of
microscopic size) within the CNS might prevail and might remain
undetected in clinical cases due to the limitations of the methods
available in the clinical approach (Table 1). LLNI pathomechanisms
should generally involve brain cells, immune cells and solutes, as
well as the respective exchanges between three important bodily
compartments: the blood, the CSF and the CNS plus its extracellular
fluid. The immune-inflammatory mediators and cells involved in
LLNI may vary over time and may shape the psychiatric syndromes
associated with LLNI.
In the meantime, inflammation was generally redefined (see
Table 2) to include a large number of possible factors on the cellular
and humoral levels, the full ranges of which are only partly applicable
in clinical situations. In vivo assessment and thus definition of both
systemic inflammation and especially CNS inflammation remain generally limited, as the CNS is well-protected and difficult to access.
Nevertheless, low-degree inflammation appears to be frequent in
clinical settings, and there is little reason to assume that inflammation in the CNS occurs with any less frequency (and perhaps with
greater frequency) than it does in other organs; immune regulation
within the CNS is both more complex and more separated than it is
in other organs, constituting an endogenous CNS immune response
system (McGeer and McGeer, 1995).
The roles of CSF cells were redefined in experimental neuroimmunology as playing prominent and highly active roles in the
immune surveillance of the CNS during both health and disease
(Schwartz and Shechter, 2010). Moreover, the CSF interacts with extracellular CNS fluid (ECF), and together, the CSF and the ECF provide
signaling functions formulated in the volume transmission mode concept (Fuxe et al., 2010). These insights are corroborated by knowledge gained in the field of clinical neurology, which suggests that
the investigation of the CSF is of outstanding importance for the diagnosis and thus for the pathogenesis of CNS inflammation.
2.1. Interaction between central and peripheral immunity
Based on recent insights, the BBB was redefined as having two
locally differing exchange components: solutes and cells (Bechmann
et al., 2007). The BCB was anatomically defined as involving the choroid plexus and the circumventricular organ (Wolburg and Paulus,
2010). The choroid plexus secretes CSF and signaling molecules and
is a site of active cell trafficking between the blood and the CSF
(Engelhardt and Sorokin, 2009, Marques et al., 2009, Ransohoff,
2009). Modern CSF analyses have been validated by broad experience
with neurological and especially neuroinflammatory disorders, leading to sophisticated rules (Reiber and Peter, 2001). However, such
advanced versions of CSF analysis have only rarely been applied in
psychiatric disorders thus far, and one should keep in mind that systemic inflammation and CNS-specific inflammation must be assessed
in parallel.
2.2. Defining LLNI
In experimental studies, LLNI-related situations are now often
described (see, for example O'Callaghan et al., 2008), but a generally
accepted definition is pending. Several major aspects of LLNI are
briefly described here (see Table 3). The ME hypothesis (compared
Table 1
The mild encephalitis (ME) hypothesis updated.
• “ME is understood as a non-lethal, low grade cellular-infiltrative and/or humoral brain inflammation hypothetically underlying and basically explaining variable psychiatric symptoms/syndromes, especially a subgroup of schizophrenic or affective psychoses, possibly accompanied by neurological soft but not hard signs. Inflammatory cell infiltrates within
the brain are assumed to be small and short-lived, inflammation later characterized by humoral ‘inflammatory upregulation’, which remains to be exactly defined. ME may only rarely
be diagnosed by established clinical methods in the individual patient because of low sensitivity of methods” (Bechter, 2001, Neurol Psychiatry Brain Res 2001; 9:55–70)
• Low grade neuroinflammation (LLNI) as major pathogenetic aspect, difficult to detect by available diagnostic methods, but core and sufficient to induce brain dysfunction
resulting in psychiatric syndrome, as a diagnostic category termed ME.
• Various psychiatric symptoms may be related to ME, the LLNI process may change over time (compare changing symptomatology with emerging classical encephalitis)
• ME may become chronic for example in therapy-resistant affective and schizophrenic spectrum disorders
• Etiologies may differ: agents (viruses, bacteria, protozoa), autoimmune, toxic, possibly traumatic injuries (including ‘endogenous’ injuries, see interaction between brain and
systemic immunity)
• Contributive factors in infectious ME: genetic factors, type/strain of agent, immune status, additional environmental factors
• Independent liability factors: pre-existent factors (e.g. inborn, or neurodevelopmental, which may especially influence the type of syndromal outcome), changing environments, chance
• Note: Course variability of schizophrenic spectrum disorders (prodromes, phases, ‘Schübe’, progression) and change of diagnosis in early years of illness might associate with
emerging and changing LLNI process
K. Bechter / Progress in Neuro-Psychopharmacology & Biological Psychiatry 42 (2013) 71–91
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Table 2
Definitons of inflammation.
Classical inflammation (acc. to Celsus around AD): rubor, calor, dolor, tumor; functio laesa (last criterion added in medieval times)
Conventional histopathology/virology: inflammatory cellular infiltrates within tissue visible under the microscope
Recent definition (acc. to C. Nathan, 2002): “inflammation is a complex set of interactions among soluble factors and cells that can arise in any tissue in response to traumatic,
infectious, post-ischaemic, toxic or autoimmune injury”
Clinical definition: derived from above definitions with surprising weaknesses not least depending from diagnostic approaches applicable in vivo. Note: rather weak
clinico-pathological correlations between brain inflammation and symptoms evoked.
Low level neuroinflammation (LLNI) is often used as a term in experimental and now also in clinical publications (for example Keizman et al., 2009), but consensus criteria in
both fields are lacking. The common aspect in such publications was that classical inflammation was not found but molecular or cellular abnormalities of minor degree, like
may be found in beginning classical inflammation.
The definition of ME (Table 1) remains preliminary. ME hypothesis has to be probed in psychiatric disorders with yet unknown etiopathogenesis, or in psychiatric disorders
accompanying systemic inflammatory disorders, or in early or late stages of classical neuroinflammatory disorders. Recent studies in therapy-resistant affective and schizophrenic spectrum disorders performed with modern CSF analytic methods demonstrated subgroups presenting minor CSF abnormalities matching the LLNI concept (Bechter
et al., 2010a, 2010b).
Grading of diagnostic validity of ME: possible–probable–definite
The grading should follow the accepted rules in the diagnosis of neuroinflammatory disorders, especially the CSF diagnostics (compared with Reiber and Peter 2001;
Wildemann et al 2010) and neuroimaging (Osborn et al, 2010).
to Bechter, 2001) has yet to be generally accepted. Compromises between clinical and theoretical approaches seem inevitable; we recall
the difficulties and compromises involved in defining HIV encephalitis (HIVe). A diagnosis of HIVe required the detection of a minimum
of three inflammatory lesions within the post-mortem brain, which
matched well with the symptoms of clinical HIVe (Cherner et al.,
2007). However, this consensus definition was considerably flawed:
even one single inflammatory lesion detected under the microscope
should theoretically be termed encephalitis. In addition, considering
the technical details (the considerable distance in between the cuts
through the brain), one can infer that many more lesions would be
found in such a brain if it were studied more carefully. This compromise led to a definition that suffered from such extreme theoretical
flaws that one might ask why such a compromise was deemed necessary. It has long been known that the brain can be surprisingly tolerant to pathology, and this is certainly the case in HIVe: the high
cut-off required by the HIVe definition was apparently related to
the low clinical symptom load observed in cases with a low number
of classical inflammatory lesions; yet, this is not to say that there
was an absence of inflammation, if a more basic definition of inflammation is considered. Such an interpretation is strengthened by details provided by HIVe imaging: the early detection of HIV infections
associated with neuropathophysiology can be achieved with improved
magnetic resonance imaging methods (i.e., with diffusion weighted
imaging, but not yet with spectroscopy): unspecific imaging findings indicated that neurotoxicity is mediated by HIV infection of the tissues,
and was paralleling findings in histology (Bucy et al., 2011). This type
of neurotoxicity-associated tissue response apparently matches with
what has been termed here as LLNI.
The assumption that LLNI is currently under-diagnosed is further
supported in light of changing views about other types of inflammation: one type has recently been defined as parainflammation, but
many more remain unclassified as of yet (Medzhitov, 2008).
2.3. Molecular neuropathology from infections
The story does not end here: infections have been shown to induce cellular changes and dysfunction even without evidence of
inflammation. This phenomenon is described as the molecular anatomy of viral disease (Oldstone, 1987): viruses are able to cause disease
in the absence of any morphologic evidence of cell injury (Oldstone,
1990). It is unclear whether such infection-induced molecular changes
or cellular dysfunctions should be included or excluded from a definition of LLNI. Nevertheless, such molecular mechanisms should be
taken into account and could be especially relevant in psychoses.
Thus, we now have two undefined borders to LLNI: one of classical
encephalitis and one of non-inflammatory molecular pathology after
infection. If molecular pathology were to be subsumed under LLNI,
would molecular LLNI (molLLNI) then be an acceptable term for it?
2.4. Proposing ME schizophrenia (meS) as a preliminary diagnostic
category
From this dilemma, it appears that the diagnosis of LLNI in clinical
situations first requires precise observation of the basic rules established in neurology for the diagnosis of neuroinflammation (for
such see Reiber and Peter, 2001, Wildemann et al., 2010). One should,
however, be aware of the low sensitivity of methods for diagnosing
LLNI, which need to be improved (compared with Bechter et al.,
2010a). Notwithstanding these limitations in the diagnostic approach, the evidence that LLNI may prevail and be relevant in psychiatric disorders and the putative meS subgroup is considerable
(Bechter et al., 2010a). Therefore, here a preliminary categorization
of the meS subgroup is proposed and differentiated from other
schizophrenia subgroups (see Table 4, and for explanations, see the
forthcoming chapters): one might classify the various types of meS
as follows: one might diagnose primary meS, in which LLNI is related
Table 3
Brain barriers and CNS inflammation.
The immune privilege of the brain is maintained by the brain barriers and, in contrast to previous views, by extensive immune control mechanisms within the CNS and the CSF
spaces.
Blood–brain barrier (BBB) and blood–CSF barrier (BCB) represent anatomically and functionally different barriers (Engelhardt and Sorokin, 2009). The BBB was dichotomized in a
barrier for solutes versus cells (Bechmann et al, 2007). The anatomically defined BCB embraces the choroid plexus and circumventricular organs (Wolburg and Paulus, 2010).
The term BCB dysfunction (Reiber and Peter, 2001) represents an interpretation of CSF protein abnormalities which may result from interactions mainly at the meningeal–CSF
barrier and in addition at the anatomically defined BCB. The barriers between meninges and CSF spaces appears important generally but incompletely investigated and the
terminology (e.g. arachnoid barrier) appears to be inconsistently used (review in Bechter et al, in prep.).
In the clinical setting dysfunction of the BBB or the BCB have to be differentiated, but dysfunctions of both, the BBB and BCB, may prevail in parallel in one individual patient. BBB
breakdown may be demonstrated by MR imaging when fluid accumulation indicated local brain edema, which is not a highly sensitive finding in (meningo-) encephalitis
(compared with Osborn et al., 2010), or by tracer imaging, rarely applicable in clinical approaches. BBB dysfunction cannot be diagnosed by CSF investigation. In general,
the interpretation of CSF findings requires sophisticated expertise as from many possible influences CSF protein composition may change (see Wildemann et al., 2010).
Recent findings demonstrated that neuroinflammation may often begin at the meninges (Bartholomaus et al., 2009; Ransohoff, 2009), this aspect vice versa was matching the
clinical experience of an outstanding role of CSF investigation for differential diagnosis of neuroinflammatory disorders.
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K. Bechter / Progress in Neuro-Psychopharmacology & Biological Psychiatry 42 (2013) 71–91
Table 4
Preliminary criteria for etiopathogenetic subgrouping of schizophrenias.
1. Genetic schizophrenia (gS): single gene trait model with strong weight for the gene defect, accordingly assessed in the individual case, and/or shown to be of considerable
weight in population-based studies.
2. Neurodevelopmental schizophrenia (nS): early neurodevelopmental deficit or aberration, clearly assessed in the individual case and confirmed in population-based approaches to
increase the risk for schizophrenia. Such may not be exclusive for schizophrenic syndromes, may for example include affective syndromes, or autism, which may precede or parallel
schizophrenic syndrome. However, the aberrant neurodevelopment should be of considerable weight to induce in a major share of cases (specific) schizophrenic syndromes.
3. ME schizophrenias (meS): a LLNI process assessed by appropriate methods (CSF, neuroimaging, other laboratory methods) during critical disease stages. LLNI (strength and
type) may vary, e.g. in between prodromal stage and other, more or less process-active, stages.
4. Primary nS with secondary meS: a special case when an early hit onto the immune system or onto basic metabolic cellular functions induced or considerably contributed to a
late onset LLNI process.
5. Other types possibly to be differentiated with increasing knowledge.
to a known CNS infection or CNS-specific autoimmune disease.
Typical cases of primary meS would resemble prodromal meningoencephalitis or prodromal limbic encephalitis (LE). One might diagnose
secondary meS when CNS involvement is secondary to systemic autoimmune or inflammatory disease (when assessed according to established rules), and the patient presents schizophrenic syndrome. A
third category may be termed reactivated meS, in which an early infection was later reactivated during a critical disease phase such as
the onset or an acute relapse. Long dormancy phases in infections
(i.e., latency periods) are now well-documented, and therefore, such
a separate category might be justified. A fourth category, called
molS, could be considered in which the molecular pathomechanisms
secondary to the infections of the CNS are involved and the molecular
change is of sufficient strength to induce schizophrenic symptoms;
however, this classification is still a speculative one. The question
arises again of whether a border between LLNI and molS should be
defined.
In sum, there is broad evidence that beyond classical CNS inflammation (i.e., encephalitis), both with and without meningitis, a
lower degree neuroinflammation, here termed LLNI, may prevail
and be associated with (neuro-)psychiatric disease. LLNI represents
the core pathogenetic aspect in a subgroup of psychiatric disorders,
and LLNI, like classical neuroinflammation, is associated with a
range of possible syndromes. In other words, the role of LLNI is nonspecific under an etiological view and heterogeneous under a categorical diagnostic view, and LLNI includes subgroups of schizophrenia
(meS). The meS subgroup could alternatively be termed ‘organic’ or
‘symptomatic’. A definition of ME depends on the diagnostic armature
employed to assess LLNI situations in vivo, i.e., the diagnostic sensitivity provided by the available methods. With advanced CSF analysis,
we found that approximately 40% of therapy-resistant schizophrenia
cases had some CSF pathology, which probably or at least possibly
indicated LLNI (Bechter et al., 2010a). When using new methods
such as microglia imaging or new antibody tests (as with LE, see
below) to assess LLNI situations, the meS subgroup might be considerably enlarged. CSF investigation seems to be of utmost importance
in assessing LLNI, and while neuroimaging and blood investigations
play more supportive and indirect roles, they can nevertheless provide signals of CNS inflammation and, under certain circumstances,
can be more sensitive in detecting inflammation than CSF investigation (for example in LE, where CNS-specific autoantibodies seem
to be systemically produced). Differentiating a meS subgroup as its
own category may be justified, the size of the meS subgroup might
be considerable.
3. Human Borna disease virus (BDV) infection as an ME model:
a slowly emerging research area
Borna disease virus (BDV) infection was proposed as one etiology
in the ME scenario that could be relevant for a maximum of 3% of
cases in our psychiatric hospital sample (Bechter, 2001). The agerelated variance in pathogenicity (cases resulting in disease per
cases of infection), a poorly explained but well-established phenomenon in infectious diseases, was discussed with regard to an ME
subgroup of schizophrenia. The candidate was mumps virus infection
(and, with preliminary data, also BDV infection), and the ages at
which high pathogenicity (including mumps encephalitis) was observed matched with the age at which schizophrenia onset was likely;
thus, it was hypothesized that there was a causal relationship. Additionally, in large epidemiological studies, the mumps virus has been
shown to be a risk factor for psychoses, including schizophrenia
(Dalman et al., 2008).
BDV research provided a couple of models for the ME hypothesis.
BDV is a strongly neurotropic virus. Natural BD has been diagnosed
over centuries, and BD is the most frequently occurring meningoencephalitis in horses and sheep in Middle Europe (see reviews in
Carbone, 2002). Outcomes of BDV infection depend on the strain of
the virus, the patient's immune system and circumstantial factors
such as the route of infection, among others (Herzog et al., 1997).
BDV infection can trigger autoimmunity (Rott et al., 1993) or can
cause behavioral abnormalities in primates (Sprankel et al., 1978);
such findings resemble those found in human BDV research (compared with Bechter, 1998, 2001).
Accumulated findings suggest that human BDV infection may be
causally related to some neurological and psychiatric syndromes,
including schizophrenia (Bechter, 1998, Herzog et al., 1997, Richt et
al., 1997b). However, as research on human BD presented a challenge,
the field began to lose interest (Wood and Bloor, 2006) and the
widely differing findings in human BD research have raised major
concerns (Schwemmle, 2001, Schwemmle et al., 1999), and controversy has evolved within the field (Bechter, 2001, Bode and Ludwig,
2003). A meta-analysis showed that the putative human BDV sequences identified mainly in blood samples may have been artifacts
of laboratory contamination (Durrwald et al., 2007), which has been
previously suggested (Schwemmle et al., 1999) and is consistent
with previous negative findings (Richt et al., 1997a). Research on natural BD in animals detected rather clear epidemiological patterns,
with regional genetic clustering of BDV strains that pointed to the
existence of to-date unknown endemic reservoir host populations
(Durrwald et al., 2006).
It is important to note that a conclusive diagnosis of encephalitis has
to be based on a complex clinical approach, which usually requires the
inclusion of a CSF investigation, which is the gold standard. However,
the sensitivity even of CSF investigations is limited. According to the
results of the large California encephalitis project, even in the acute
phases of meningoencephalitis, a disease stage of high diagnostic sensitivity, the specific etiology of the disease was only determined in fewer
than 50% of cases (Glaser et al., 2006).
Concerning the question of human BD, it is possible that a careful
meta-analysis of blood investigations (Arias et al., 2012) can give
some guidance to BD epidemiology, but this first requires a critical
discussion of the laboratory methods used in the studies. It also
seems highly questionable whether the fact and fantasy surrounding
human BDV infections (Lipkin et al., 2011) can be resolved when the
strict diagnostic rules established through substantial experience
with human CNS infectious diseases in general were neither applied
nor carefully considered in such evaluations. The recent findings of
a multicenter study in the US of exclusive blood investigations of a
K. Bechter / Progress in Neuro-Psychopharmacology & Biological Psychiatry 42 (2013) 71–91
rather small number of subjects (Hornig et al., 2012) match with our
longstanding findings and with the findings about BDV infection in
animals but seem to provide little in the way of improved diagnostic
sensitivity, which probably cannot be achieved through blood investigations alone. The newly developed ELISA should be validated in
large epidemiological studies, including in animal populations, as
was performed and used in our studies (compared with Herzog and
Rott, 1980, Herzog et al., 2008). [It may be of notice that for validation
of the newly introduced ELISA the sera from our well validated collection were used (compared with Hornig et al., 2012).]
3.1. Our research on human BD
Applying strict diagnostic criteria, we investigated more than 20,000
patients over more than 25 years; this research involved more than
2000 MRIs and approximately 500 CSF investigations that were analyzed using various methods including PCR, and attempts were made
to isolate a virus from CSF and post-mortem brains (Bechter, 1998,
Herzog et al., 1997, Lieb et al., 1997, Richt et al., 1997b, Rott et al.,
1991). Based on our evaluations and on clinical findings, we assumed
that both neurological and psychiatric syndromes could be caused by
BDV infection (Bechter, 1998, 2001). The specificity of the human BDV
antibodies as assayed was confirmed through the recognition of linear
epitopes of BDV proteins (Billich et al., 2002). In some psychiatric
cases with previous BDV infection, which was evidenced by the presence of serum antibodies, CNS immunopathology was detected through
CSF investigation (Oleszak et al., 2007). Nevertheless, in only a very
few psychiatric patients BDV antibodies were produced within the intrathecal spaces, as observed through an increased antibody index
(AI) (Bechter et al., 1995, 2010a). Increased AI (CSF/serum) is now considered to be a sensitive and valid indicator of specific types of encephalitis, usually found in the chronic or post-acute phases of infections
(compared to Reiber and Peter, 2001, Wildemann et al., 2010). In
some cases, AI may persist for a long time, a phenomenon that is not
yet fully understood; however, a recent study on EBV infections with
neurological diseases raised the possibility that co-infections might be
responsible (Kleines et al., 2011).
The validity of our diagnostic approach was further confirmed by
comparison of blood, CSF and brains from naturally infected horses
suffering from acute BD (Herzog et al., 2008). Nevertheless, the overall relevance of BDV infection for human psychiatric disorders may
be overestimated; in our hospital population, it might represent a
maximum of 3% of cases, but when using strict diagnostic criteria,
we found only a few cases fulfilling the probable criteria of BDVassociated ME (see Bechter, 1998, 2010a, and unpublished), and
none were definite.
3.2. Emerging pathomechanisms relevant in BDV infections
Persistent BDV infection, virus reactivation, relapses or chronic
courses of defects have been observed in animals. Many downstream
pathomechanisms have been studied in BDV infection, including the
roles of entry factors, reactive oxygen species, neurodegeneration,
regeneration, neuroprotection, virus toxicity, inflammatory toxicity,
inflammation-induced neurotransmitter alterations, neurotransmitter
abnormalities induced by persistent noncytolytic infection, infectioninduced cellular dysfunctions including dopamine and serotonin
dysfunction, among others (for details see Clemente et al., 2010, Daito
et al., 2011a, 2011b, Dietz et al., 2004, Herden et al., 2000, 2005,
Herzog et al., 1991, Kamitani et al., 2003, Koster-Patzlaff et al., 2007,
Ovanesov et al., 2008, Planz et al., 2002, Pletnikov et al., 2002, 2008,
Schwemmle and Heimrich, 2011, Werner-Keiss et al., 2008). Another
pathomechanism was the upregulation of MHC class I-dependent
targets for CD8 T-cells on neurons upon BDV infection and the production of cytokines in neurons, which both acted directly upon CNS inflammation (Chevalier et al., 2011). BDV sequences are integrated into
75
the human genome (Belyi et al., 2010, Horie et al., 2010), these findings
raised new questions on the pathomechanisms possibly involved
(Feschotte, 2010). The involvement of endogenous viruses in multiple
sclerosis and schizophrenia has been specifically discussed for
HERV-Ws (Perron and Lang, 2010, Perron et al., 2008).
In sum, human BDV infection may be relevant for neuropsychiatric
diseases, but only for a maximum of approximately 3% of hospitalized
psychiatric patients, i.e., in less than half of the patients presenting
BDV-specific antibodies. Human BDV infection may include a subgroup of schizophrenia cases, but only rare single cases fulfill the
strict criteria for probable (low level or chronic) BDV ME and none
yet appears to be proven.
4. Where we stand in the search for the causes of schizophrenia
Presently, the neurodevelopmental hypothesis is generally preferred over the vulnerability stress hypothesis, but the former does
leave some important questions unanswered (Owen et al., 2011). Puristic genetic hypotheses have waned in recent years with the release
of results from genome-wide association studies: though an important role for genes in schizophrenia was corroborated, single genes
appear to have a low impact, and while a number of confirmed risk
genes were related to immune and basic cellular functions, only
some were related to neurotransmitter abnormalities, contrary to
previous speculations. In another important area of research, the
brain imaging field, a neurodevelopmental versus a neurodegenerative model was heavily debated. Such major lines of research will be
discussed here with respect to the ME hypothesis, with a focus on
neuroimaging findings (see also Table 5).
The 6th Symposium for the Search for the Causes of Schizophrenia in
Sao Paolo, Brazil in 2009 came to the following conclusions (Kirkbride
and Scoriels, 2009): variation in the incidence of schizophrenia exists;
the risk for individuals depends on the type of environment they are
exposed to; gene–environment-interactions may hold the key to
revealing etiological pathways; the genetic load could be confirmed,
but the outcome is characterized by largely unexplained variants;
more evidence for a neurodevelopmental compared to a neurodegenerative hypothesis may exist; there was insufficient evidence to reject
the possibility that psychotic symptoms are continuously distributed
in the general population; and finally, the need for biomarkers should
be stressed.
In addition, reviews of genetic findings have come to the following
conclusions: the underlying pathophysiology of schizophrenia remains largely unknown, there is some support for the dopamine
hypothesis, and in agreement with others, a cluster of genome-wide
significant snips lie in the MHC region, implicating the immunological
system in the pathogenesis of schizophrenia (Stefansson et al., 2009).
Another review (Bondy, 2011) has stressed the promising findings
from genome-wide association studies, which have not met initial expectations of identifying a ‘susceptibility gene’. Incorporating new approaches such as epigenetic mechanisms or gene–environmentinteractions was proposed for future studies. Another view was that
genes might be involved in entirely unexpected disease pathways,
e.g., by copy number variance or deletions; however, such pathways
were expected to lead to a spectrum of neuropsychiatric impairments
rather than to a specific schizophrenic syndrome because the genetic
overlap between diagnostic categories was strong (Rujescu, 2011).
4.1. Brain imaging
According to repeated and refined analyses of imaging results,
it seems rather clear that during a period of 10 years following the
first episode of schizophrenia, a progressive brain change occurs
that is characterized by a significant decrease in multiple gray and
white matter regions and a corresponding increase of cerebrospinal
fluid spaces, which is mainly associated with cognitive impairment
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Table 5
Major characteristics of schizophrenia: present views.
Overall view
• Variation in the incidence risk depending on the type of environment
• Genetic load important
• Gene–environment-interactions may hold the key
• Outcome characterized by largely unexplained variants
• More evidence for a neurodevelopmental as compared to a neurodegenerative hypothesis
• The underlying pathophysiology remains unknown
• Some support for the dopamine hypothesis
Genetics
• Cluster of genome wide significant snips lies in the MHC region implicating the immunological system
• Recent results not meeting initial expectations to identify a ‘susceptibility gene’
• Epigenetic mechanisms possibly involved
• Gene–environment-interaction important
• Not a specific schizophrenic syndrome related to genetic load
Neuroimaging
• Progressive brain change after first episode with significant decrease in multiple gray matter regions and multiple white matter regions and a corresponding increase of
cerebrospinal fluid spaces
• In the first ten years diagnostic classification changing
• Widely distributed gray matter abnormalities early in illness likely due to neuropil elimination, progressive over the initial years of illness
• From diffusion tensor imaging: a disorder of neural integration arising from white matter abnormalities
• Frontotemporal connectivity abnormal
• But: schizophrenia not localized in the brain!
• Early and late hit
• In part neurodevelopmental or neurodegenerative, disease process varying over time
• Special rare findings: seemingly only during acute psychotic presumably process-active stages, one may observe slight brain volume increases or microglial activation
Post-mortem
• No evidence for classical inflammation but widespread pathological alterations, findings compatible with LLNI subgroups (results not outlined in detail here; compare
Bechter and Bogerts, 2007; Steiner et al., 2011)
(Andreasen et al., 2011, Fusar-Poli et al., 2011a, 2011b, Sun et al.,
2009). The brain atrophy seems to be related to a closer packing of
neurons and also to a decreased number of neurons (Smiley et al.,
2011), which is influenced by different types of medication and the
severity of the symptoms (van Haren et al., 2011). Identifying the
types of medications that may influence the brain was complex, and
outcomes may differ between different compounds, e.g., some may
affect neuropeptide Y and corticotrophin (Nikisch et al., 2011),
while others may directly interact with inflammation (Meyer et al.,
2009). Furthermore, in the first ten years, the diagnostic classification
changes, and it seems that a final diagnosis of schizophrenia can be
linked to more severe or more active disease processes (Bromet
et al., 2011).
In the preface to a recent authoritative book on Neuroimaging in
Psychiatric Disorders, the editors M. Shenton and B. Turetsky stated
that the imaging field has provided a major in vivo contribution to
a better understanding of schizophrenia and has even supported
neuropathological approaches. This field has come to the following
conclusive statements (Shenton and Turetsky, 2011): schizophrenia
is associated with widely distributed functional brain abnormalities;
widely distributed gray matter abnormalities are observable early
on in illness and, ostensibly, premorbidly; gray matter reductions
are likely due to neuropil elimination as opposed to neuron death;
gray matter abnormalities are likely progressive, at least over the initial years of the illness; from the diffusion tensor imaging studies,
schizophrenia appears to be a disorder of neural integration arising
from white matter abnormalities, in part resulting from irregular
myelin; in terms of functional aspects of the brain, frontotemporal
connectivity specifically was found to be abnormal. However, it was
difficult to interpret all of these findings, and an ‘extremely speculative hypothesis’ was proposed regarding the underlying mechanisms
of schizophrenia; the hypothesis specified that, in any case, a late developmental trigger of schizophrenia has to be assumed (Whitford
and Shenton, 2011). This conclusion was in agreement with the commentary of Nancy Andreasen published in the same book (Andreasen,
2011): the functional and structural brain abnormalities in schizophrenia have not been localized yet, nor has the timing of the
changes been observed with sufficient clarity. The explanations for
the imaging abnormalities found in schizophrenia have had to be
shifted from the previous ‘early’ neurodevelopmental hypothesis to
a late neurodevelopmental hypothesis, i.e., a late hit hypothesis, because the time trajectories seemed in part to be neurodevelopmental
or neurodegenerative events with blurred boundaries. These recent
conclusions match with previous claims that early and late neurodevelopmental changes may be observable (Pantelis et al., 2007).
It should be noted here that, from the research on the course of
clinical symptoms, it appears that the disease process itself may vary
over time, from prodromal or basic stages to more process active
stages (compared with Klosterkotter et al., 1989, Klosterkötter, 2011).
With regard to the ME hypothesis, assuming that LLNI is relevant
in diagnostically overlapping neuropsychiatric syndromes, findings
about mood disorders may also be interesting to look at: as in the
schizophrenia research field, the neuroimaging data in this field
have not been consistent, but a set of brain regions has been described
as critical to normal and abnormal mood regulation (Holtzheimer and
Mayberg, 2011).
Another interesting case was two definite developmental disorders
and their manifestations in neuroimaging: complex changes in the
brain's structure and functioning over time, including surprising
local volume increases, have been found, and some abnormal developmental trajectories have rather clearly been assessed (Herrington
and Schultz, 2011, Minshew, 2011, Santos and Meyer-Lindenberg,
2011). In comparison, the abnormalities of developmental trajectories in schizophrenia seem only to be partly categorized as aberrant
neurodevelopmental trajectories or seem to be either rather late or
at least not necessarily early (see also White et al., 2003, 2009,
2010, 2011a, 2011b).
A rare study using short-term repeated imaging during acute
psychotic phases showed brain volume increases that were normalized a few weeks later, cautiously interpreted as being due to slight
brain swelling from inflammation during short-lived acute phases
(Garver et al., 2008). Other rare studies have found microglial activation in the brain tissue of patients who died from suicide in acute psychotic phases (Steiner et al., 2008), and microglial activation has also
been found during acute psychosis using PET in vivo (Doorduin et al.,
2009). Microglia are sensors of pathological events in the CNS; they
K. Bechter / Progress in Neuro-Psychopharmacology & Biological Psychiatry 42 (2013) 71–91
are a parameter in CNS inflammatory responses (Kreutzberg, 1996,
Raivich et al., 1999) and work protectively or destructively (Glezer
et al., 2007, Saijo and Glass, 2011). Memory T cells persisting in the
brain following an MCMV infection can induce long-term microglial
activation via interferon-gamma (Mutnal et al., 2011). Microglia interact with other cellular systems and with volume transmission
mode (see below).
In explaining abnormalities of brain structure and function over
time, one must consider a complex array of pathogenetic factors, including independent pre-existing and interacting factors. The need
for this consideration can be illustrated through the example of cortical thickness, which is often investigated in schizophrenia. It appears
that cortical thickness is in part genetically determined (Kochunov et
al., 2011) and is influenced by medication (van Haren et al., 2011)
and social stress, such as adverse childhood experiences (Benedetti
et al., 2011). However, cortical thinning could clearly be a consequence of LLNI, trauma or various types of toxicity. Interestingly, in
the schizophrenia subgroup with adverse childhood experiences, cortical thickness seems to be normal, whereas in a non-schizophrenic
group, cortical thickness appeared to increase as a result of adverse
childhood experiences; the interpretation was that the combined
effect of cortical thinning from schizophrenia and cortical thickening
from adverse childhood experiences resulted in a cortex that appeared
to be normal with respect to the aforementioned schizophrenia subgroup (Benedetti et al., 2011).
In sum, abnormalities and changes in brain structure and volume
are frequently observed in the course of schizophrenia over time,
from prodrome to the acute, chronic, and relapsing phases. These
changes used to be referred to as neurodevelopmental, but during
the last years, neurodegenerative aspects have increasingly been
assessed. A consistently abnormal developmental trajectory related
to one early hit has not been safely demonstrated. Consensus reports
now suggest that the story is more complicated and that a so-called
‘late hit’ seems to be a minimal requirement in explaining the structural brain changes occurring during the early years of disease. The
changes and dysfunctions over time possibly involve the whole
brain, with no clear local preferences. Similar conclusions have been
reached in the histopathology field (Steiner et al., 2011), not
reviewed here. Disconnectivity, atrophy and complex structural alterations accompanied by dysfunction, or specific rare findings such as
microglia activation and CSF pathology (see above) have yet to be
explained. Apparently, there are many interacting factors and pathological aspects, including genetic and non-genetic factors, that influence the neurodevelopmental phenotype. When considering LLNI
as a possible factor, it should be recognized that neurodegeneration
is a typical consequence of neuroinflammation, but overall outcome
depends on many interacting downstream factors, including neuroprotection, repair capacity, pre-existing factors such as stressful experiences, and medication, as well as factors that remain unknown.
Present neuroimaging methods are rather sensitive to detect the indirect consequences of CNS inflammation, such as atrophy or structural
abnormalities, and new imaging methods with high magnetic field
strengths may further improve detection sensitivity and differential
diagnosis (Bustillo et al., 2010). However, neuroimaging methods
are often not sensitive enough to directly detect CNS inflammation,
and they seem to be insensitive to LLNI situations. Therefore, a more
detailed analysis of the diagnostic possibilities and limitations in supposed LLNI situations is of interest.
5. Diagnosis of CNS inflammatory disorders and LLNI
The limitations on the detection of LLNI with currently available
diagnostic methods may be examined in light of a look into classical
inflammatory CNS disorders. The established diagnostic methods
are neuroimaging and CSF investigation.
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5.1. Neuroimaging
Direct signs of CNS inflammation include water accumulation
(swelling), blood exudation and local tissue destruction, especially
visible in an MRI; frequent indirect signs represent meningeal enhancement (in the case of accompanying meningitis), and atrophy
may become visible in the post-acute phase (Osborn et al., 2010).
Both focal and distributed atrophy may develop over time in chronic
neuroinflammation, the best-studied example of which was multiple
sclerosis (MS) (Calabrese et al., 2009, Grassiot et al., 2009). Interestingly, the contributions of cortical gray matter atrophy and ventricle
enlargement underlying neuropsychological impairment appear at
least in part to be independent in MS (Tekok-Kilic et al., 2007). However, there are differences among different types of CNS inflammatory
disorders. CNS involvement in generalized autoimmune disorders
such as neurodermitis or systemic lupus erythematodes is generally
difficult to assess (Bertsias and Boumpas, 2010). The type of atrophy
in MS differs from that in generalized autoimmune disorders, though
there is some overlap with regard to hemispheric white matter lesions (Coban et al., 1999). In an experimental autoimmune encephalitis (EAE) model, cortical atrophy correlated with disease duration
when cerebellar white matter lesions were detected at an early time
point, demonstrating that myelin-specific autoimmune responses
can lead to brain atrophy in an otherwise normal CNS (MacKenzieGraham et al., 2006). However, local atrophies (for example, of the
thalamus) may be observed in MS for unknown reasons (Houtchens
et al., 2007), and atrophic process in MS can improve with stem cell
transplantation (Rocca et al., 2007).
5.2. Developing limbic encephalitis
Another example of previously often undetected neuroinflammation
is limbic encephalitis (LE): prodromal stages, typically of several
weeks, are associated with a variety of psychiatric syndromes. The diagnosis of LE is established with the onset of neurological hard signs
or through findings from CSF or brain imaging and to a large extent
by detection of CNS-specific autoantibodies. Slight brain swelling or
minor hyperintensities may be observed early in neuroimaging and
probably represent minor signs of encephalitis, but often, the neuroimaging results are normal. In some cases, hyperintensities observed in
MRIs, which are a direct sign of neuroinflammation, have persisted
for months or years, although progressive temporomesial atrophy usually develops without direct signs of inflammation (Urbach et al.,
2006). Early LE ideally follows the scenario assumed in the ME hypothesis because various psychiatric syndromes are associated with an apparently emerging LLNI process (compared with Dalmau et al., 2011,
Irani et al., 2010, Irani and Vincent, 2011, Pruss et al., 2010, Vincent et
al., 2004, 2011). The short time of transition from the prodrome to
the classical encephalitis stage strongly suggests that the psychiatric
symptom spectra observed during preceding stages were associated
with non-classical CNS inflammation, or with LLNI as proposed here
as a term. Based on this evidence, the protagonists of LE research
have speculated that the cases identified may represent only the tip
of the iceberg (Vincent et al., 2011). Indeed, an increasing number
of cases with prominent psychiatric symptoms were identified (De
Nayer et al., 2009, Graus et al., 2010, Zandi et al., 2011); some showed
symptoms such as epilepsy combined with psychiatric symptoms
(Bien et al., 2007). The LE story again confirms the unspecificity rule
of ‘hits’ to the brain; in the cases of low-level and classical encephalitis,
the hit is associated with a broad spectrum of psychiatric symptoms
that may change over time, and one individual case might pass through
several nosological categories of psychiatric disorder during short time
periods. It should be noted that the new laboratory methods to detect
CNS autoantibodies have mainly improved the diagnosis of LE, whereas
neuroimaging has often been inconclusive.
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5.3. LLNI in schizophrenia
Through use of advanced CSF investigation methods, we found
approximately 40% of cases of therapy-resistant schizophrenia to be
classified as possible or probable LLNI (or meS) (Bechter et al.,
2010a), further supported and enlarged by cases demonstrating activated CSF cells by normal cell counts (Maxeiner et al., 2009). CSF abnormalities in schizophrenia have also been reported also by others
(Holmes et al., 2006, Huang et al., 2006, 2007, Stanta et al., 2010),
and all of these findings are consistent with ME hypothesis in general.
Incomplete LE cases have also been suspected (see above), and indeed,
in a preliminary study, CNS-specific autoantibodies were found in approximately 10% of cases with acute schizophrenia (Steiner et al., 2011).
Findings about the schizophrenia subgroup having a previous
HSV-1 infection coincide with the assumption of an LLNI process:
the local gray matter differences were attributable to neither medication, chronicity, nor comorbid substance use (Prasad et al., 2007), and
this finding was supported through the long-term observation of
cases (Prasad et al., 2011). Similar approaches have subgrouped
schizophrenia cases according to immune activation phenotype
(Garver et al., 2003), which would be similarly consistent with the
LLNI concept. Nevertheless, more specific and additional methods of
investigation are needed for many reasons, not the least of which is
the likely broad panel of infectious agents involved in schizophrenia,
as has been suggested by epidemiological studies.
In sum, the present methods of diagnosing CNS inflammation or
classical encephalitis are of rather limited sensitivity, whereas the indirect signs of neuroinflammation, such as meningeal enhancement and
atrophy, the latter of which develops with some time delay, are sensitively detected. It is nearly impossible to detect diffuse low-level CNS
inflammation with present imaging methods, although such LLNI situations have been documented to prevail over considerable time periods
in experiments and in human disease, e.g., during the prodromal stages
of LE. Indirect signs of LLNI in schizophrenia may be mild atrophy, minor
local hyperintensities, or local swelling over short time periods. In the
meS subgroup (Table 6), several or many infectious agents seem to be
involved, and differing types of LLNI may evolve as a result. Specific
types of encephalitis may differ from others in important ways; e.g.,
HIV encephalitis (HIVe) is characterized by a continually high virus
load within the brain. This feature strongly differs from those found in
most other CNS infections, but even in HIVe, the search is on for more
sensitive methods (Bucy et al., 2011). The clinical symptomatology involved in both classical meningoencephalitis and LLNI situations may
generally include a spectrum of psychiatric symptoms or syndromes,
and with increasing severity of the inflammatory process, more and
more neurological hard signs or ‘organic’ psychiatric symptoms may
evolve. The symptom spectra in CNS inflammation are thought to be
influenced by pre-existing independent factors and liabilities, not the
least of which are genetic. The rare studies performed on schizophrenias using sensitive methods such as microglia imaging or CSF investigations produced results supporting the view that LLNI may be
underdiagnosed in psychiatric disorders in general and in schizophrenia specifically; this was also strikingly evidenced by recently detected
LE-associated psychiatric disorders. CSF investigation appears to represent the gold standard for research into the meS subgroup. This is not
contradicted in principle by recent experiences with LE because a strict
diagnosis of CNS inflammation is also difficult in LE; however, methods
for detection of the CNS-specific autoantibodies in the blood are sensitive in LE, which is highly suggestive of an inflammatory involvement
of the brain. Nevertheless, any safe diagnosis of CNS inflammation and
especially of LLNI requires a broad clinical approach.
6. Neurodevelopmental, genetic, ME and other schizophrenias?
Neurodevelopmental schizophrenia was conceptualized as an
early, usually prenatal, hit during neurodevelopment. In experiments,
the timing rather than the type (infectious agent, immune response
factors) of hit was important for disturbed neurodevelopment
(Meyer et al., 2006). This finding resonates with the epidemiological
evidence on pre- and perinatal hits in schizophrenia for factors such
as hunger (St Clair et al., 2005, Susser and Lin, 1992), infections or
birth complications (Brown, 2011a). Premorbid or inborn aberrations
such as minor physical anomalies are more frequent in the schizophrenic population (Dean et al., 2006), and individuals with these
abnormalities may constitute a subgroup with an increased risk of
schizophrenia. Animal experiments have not covered the whole neurodevelopmental period, nor have studies of humans, but covering
the whole developmental period is apparently necessary, as timing
seems to be the major determinant of neurodevelopmental aberrations.
Recent transcriptome analysis has enlarged the number of periods that
should be considered: 7 periods of embryonic or fetal development, 5
periods from birth to adolescence, and 3 periods in adulthood (Kang
et al., 2011). To define neurodevelopmental schizophrenia, study of
these 15 different neurodevelopmental periods and their associated
specific aberrations is required. The typical age of schizophrenia onset
should match with the transcriptome-based categorization of young
adulthood period, defined as 20 years ≤ age b 40 years. However, transition to psychosis might be a process-active stage (Klosterkotter et al.,
1989) and thus not necessarily a neurodevelopmental process, and
the strong claims about a ‘late hit’ (see above) present a challenge to
Table 6
Major pathomechanisms and sites involved in LLNI.
• Brain barriers: BBB, BCB, meningeal–CSF barrier (see also Table 3)
• Endogenous CNS immunity: established by and involving probably all types of CNS cells, especially microglia and astrocytes, and even neurons, and humoral signaling
(McGeer and McGeer, 1995).
• Wiring transmission (WT): mainly represented by synaptic transmission, WT is balanced by VT (see Fuxe et al., 2010).
• Volume transmission (VT): mainly mediated by extracellular CNS fluid (ECF), moved by the pulsatile brain throughout the extracellular CNS spaces, ECF being in exchange
with CSF. VT model includes many different signaling molecules, e.g. cytokines, reactive oxidative species, gasses, and many others. Effects depend from the location where
interaction takes place and what receptors are expressed at resident cells.
• CSF cells: play a previously underestimated role for CNS functioning and CNS immunity in health and disease (Schwartz and Kipnis, 2011; Schwartz and Shechter, 2010).
• CSF signaling: incompletely investigated, apparently involving signals from various sources, including the choroid plexus, hypothalamus, CSF cells, and others, and with links
to ECF
• Peripheral cerebrospinal fluid outflow pathway (PCOP): CSF is flowing out through cribriform plate and along all brain nerves and peripheral nerves into peripheral tissues
(Cserr and Knopf, 1992). A possible interaction between CSF contents and nerves at peripheral sites and in addition with peripheral tissues was hypothesized to possibly
explain unexplained findings in subgroups of major psychoses including schizophrenia, and in neuroinflammatory disorders in general (Bechter, 2011). Also CSF cell trafficking was demonstrated through the cribriform plate (Goldmann et al., 2006; Kaminski et al., 2012) and in preliminary study along peripheral nerves (Schmitt et al., 2011b).
• Molecular mechanisms: molecular transport mechanisms play a major role for the exchange at the brain barriers (Redzic, 2011).
• Anatomical distribution of pathologies in schizophrenia: a common pathogenetic link of the distributed dysfunction and abnormalities of CNS found in schizophrenia is open.
VT (and CSF signaling) extending according to the PCOP hypothesis into periphery (see above) could explain distributed intraparenchymal and distributed cortical involvement and in addition involvement of peripheral parts of nerves (as for example shown for the olfactory system) and even the involvement of peripheral tissues like muscle
lesions. Thus the LLNI scenario may prevail widely distributed anatomical sites in parallel and thus could in principle represent a common pathogenetic link for anatomically
distributed but pathophysiological similar dysfunctions (Bechter, 2011).
K. Bechter / Progress in Neuro-Psychopharmacology & Biological Psychiatry 42 (2013) 71–91
the validity of the neurodevelopmental model for a majority of schizophrenia cases.
6.1. Early and late hits to the brain?
What is meant by a ‘hit’? Does this term refer to the onset of a true
neurodevelopmental aberration, or does ‘hit’ simply mean that some
pathogenetic process seems to go on? In the literature, it seems that
some event early in neurodevelopment was understood as an early
hit, whereas in the case of the recently introduced term ‘late hit’, it
is rather unclear what is meant; it seems to refer to something that
has happened to the brain. Various types of insults to the brain
could be considered, including an LLNI process, which could combine
(or not) with early neurodevelopmental aberrations. Until now, the
question has remained open as to whether an early hit in schizophrenia is definitely necessary to produce schizophrenia, whether such a
hit represents just one possible risk factor, or whether an exclusive
neurodevelopmental trajectory is in play. When applying strict diagnostic rules, neurodevelopmental schizophrenia should only be diagnosed when an early hit induced neurodevelopmental abnormalities
and the early hit was clearly assessed in the individual case and
placed into a defined developmental period with appropriate criteria
regarding the timing of the associated developmental abnormalities.
Such strict rules seem justified in comparison to several other defined
neurodevelopmental diseases, including monoamine neurotransmitter diseases, autism spectrum disorders or intellectual disabilities
(see below).
Another possibility is that a late hit was directly related to an early hit,
but the early hit was to the immune system (Gorczynski et al., 2011).
This possibility would correspond to both the neurodevelopmental
hypothesis and the ME hypothesis; however, the early hit would not induce the developmental aberrations of the CNS, and the late hit could
well be related to an LLNI process. Such a scenario, however, does not
match with the usual neurodevelopmental concept of schizophrenia,
for which a specific developmental trajectory has been proposed, whereas inflammatory mechanisms mentioned as a possibility were not
matching with the neurodevelopmental model as proposed (compared
with Brown, 2011b).
Late consequences from early hits could also result from epigenetic
processes or from genes involved in the metabolic pathways of DNA
biosynthesis that may take place at many time points during life and
seem to represent common risk factors in schizophrenia, bipolar disorder and unipolar depressive disorder (Peerbooms et al., 2011). In such
types of early hits to basic metabolic functions, the later consequence
might be similar to that resulting from a hit to the immune system: an
increased liability to a late-onset LLNI process.
6.2. Unspecificity and heterogeneity in neurodevelopmental disorders
and in CNS inflammation
Overall, present knowledge suggests that schizophrenia is a heterogeneous disorder (Brown and McGrath, 2011), and this matches
with the unspecificity rule for any hit to the CNS, including infections
or LLNI. This also holds true for genetic disorders, though some relative specificity is possible (compared with monoamine neurotransmitter disorders). Thus, in general, emerging ‘specific’ schizophrenic
symptoms may be related to whether the brain systems involved
are able to produce such symptoms, as occurs in neurological disorders, and may become prominent with the increasing severity of
pathology and dysfunction of the brain systems involved. Some
symptoms may appear as non-specific, while others may appear as
rather specific or easily identified at the psychopathological level.
The latter may primarily depend upon pre-existing genetic liabilities
and only in part on the pathogenetic process itself, which may, however, be central to the disease (compare also 7).
79
In defined neurodevelopmental disorders, more than 100 different
gene defects are identified as causing intellectual disability and an increased risk for several psychiatric and neurological disorders. The
causal genes are often involved in fundamental cellular processes
that are pivotal for normal brain development and function, whereas
only a few genes are involved in synapse function, contrary to previously speculation (Najmabadi et al., 2011). In prospective studies on
several developmental disorders, including autism, some differences
between single gene defects have become apparent, but mainly
broad overlap and similarities have been observed: findings of
minor specificity were that in autism associated with generalized
overgrowth more severe symptoms were associated with more overgrowth (Chawarska et al., 2011). The complexity of early growth patterns in disabled populations was considerable, showing different
types of disturbed development that deviated from controls with typical development, and interestingly, overlap was particularly observed in bodily and social impairments but not as much in brain
developmental trajectories. These recent insights are of special interest here because both autism and intellectual disabilities are associated with an increased risk for schizophrenia-type psychoses and other
psychiatric disorders.
6.3. Early infections
Others have recently presented splendid reviews on the role of early
infections in schizophrenia (Brown, 2011c, Brown and McGrath, 2011,
Fatemi et al., 2012). The risk attributed to three early infections (by
Toxoplasma gondii, herpes simplex virus, and rubella virus) was calculated to explain 33% of schizophrenia cases in the population. However,
when looking into the details of what is possibly the best-studied case
of human intrauterine infection, the rubella endemic in New York, the
story appears to be complex (compared with Brown et al., 2001):
approximately one half of offspring exposed to rubella during pregnancy became psychiatrically diseased in later life, suffering from a broad
spectrum of psychiatric disorders including schizophrenia. Thus, again
in light of this case of intrauterine infection, the unspecificity rule
with regard to psychiatric syndromes has clearly been confirmed. For
postnatal infections, the unspecificity rule is also evident. The world
influenza epidemic, which was often cited as an example of an intrauterine hit, was also complex; Menninger reported mainly adult
cases of exposure and, to my knowledge, not one single intrauterine infection. The population surviving the influenza infection experienced a
considerably increased prevalence of a spectrum of neuropsychiatric
disorders, including depression and schizophrenia, shortly after the influenza infection (Menninger, 1994).
6.4. Complex disease scenario
Apparently, cohorts with definite abnormal neurodevelopment
(and abnormal systemic development) show an increased schizophrenia risk, but the aberrant neurodevelopmental trajectories in themselves do not lead, at least not in the majority of cases, specifically to
schizophrenia. Nevertheless, a neurodevelopmental schizophrenia (nS)
subgroup likely prevails. The single causal factor of aberrant neurodevelopment has an apparently strong influence on the development
of schizophrenia, although the symptoms themselves may be shaped
by interacting pathogenetic aspects. In this scenario, a late hit seems unnecessary or would have little weight in the development of the disease.
However, when an independent factor with a strong weight such as a
late hit in addition to an early hit is needed to induce the disease, this
is representative of a two-factor model, and the disease should not simply be termed a neurodevelopmental disorder. Conversely, when an
early infection does little or no harm if it is not reactivated later, the
major pathogenetic event determining the disease may even be considered to be the late one, and the early hit would also constitute a necessary risk. At present, the research base needed to assume that there
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K. Bechter / Progress in Neuro-Psychopharmacology & Biological Psychiatry 42 (2013) 71–91
are definite aberrant neurodevelopmental trajectories in schizophrenia
in general is not sufficient, although a subgroup with aberrant neurodevelopment and an increased risk for schizophrenia can be assumed
beyond doubt to prevail.
In sum, LLNI situations may possibly be involved in a late hit model of
schizophrenia. It is informative to consider the role of risk genes in autism and intellectual disabilities with rather clear neurodevelopmental
trajectories, at least in the majority of cases (see below), in addition to
other slowly emerging diseases such as autoimmune disorders: risk
genes represent liability factors but seem to weigh heavily in only a minority of cases (see Fathman et al., 2005, Rioux and Abbas, 2005 and
below). Longstanding experience with the prodromal phases of classical
meningoencephalitis (compared with Bechter, 2001) and recent examples such as LE clearly suggest that undetected LLNI has the potential
to explain the late hit in a schizophrenia subgroup. Such an assumption
is corroborated as complex genetic traits that seem to be relevant in
the majority of cases of schizophrenia, and this coincides with a gene–
environment interaction scenario, which is often stressed as necessary.
Nevertheless, a gene–environment interaction could also be involved
in a neurodevelopmental subgroup. For the differential diagnosis of
various schizophrenia subgroups, it was necessary to define the major
pathogenetic constraints, particularly during the disease-active stages,
that prevail during critical disease periods from prodrome to transition
or during relapse in chronic stages, during which some LLNI process
may go on nevertheless (see also the CSF findings cited above and the
comparison to autoimmune disorders).
6.5. New old problems in schizophrenia research
The present difficulties in schizophrenia research seem to not differ
much from previous discussions about the neuropathology of schizophrenia (Harrison and GRoberts, 2000). In a critical foreword from
Janice Stevens, three major concerns about the neurodevelopmental
model were noted: 1. the question of pathological heterogeneity and
its relationship to the clinical syndrome; 2. the controversy concerning
the location of the pathological changes; and 3. the timing of pathology.
6.6. Neurotransmitter disorders
Bearing in mind these concerns, the research into neighboring
disorders of abnormal neurotransmission may first be considered:
Parkinson's disease was the first disorder for which an underlying
neurotransmitter abnormality was identified. Parkinson's disease, meanwhile, is not explained by dopamine abnormalities alone, which are part
of a complex disease process with a yet unknown etiological background
(Braak and Del Tredici, 2008). The dopamine hypothesis of schizophrenia is widely accepted, and dopamine appears to be undoubtedly important in schizophrenia (Carlsson et al., 2004, Rolls et al., 2008) and has
been shown to be directly involved in prodrome (Fusar-Poli et al.,
2011c). The interpretation of the antipsychotic occupancy of dopamine
receptors in schizophrenia is moving towards a better understanding
of antipsychotic drug development and therapeutic approaches (Nord
and Farde, 2011) rather than towards an understanding of the whole disease process. Such a change in interpretation seems very similar to that
experienced in Parkinson's disease.
Looking into the details regarding the heterogeneous group of
monoamine neurotransmitter disorders (Kurian et al., 2011) is further
informative: a developmental delay was accompanied by a spectrum
of neurological and neuropsychiatric symptoms often beginning in
infancy or early childhood, although onset may occur at any age.
Pterin, dopamine and serotonin metabolism disturbances can be primary,
or secondary, or of unknown origin. The diagnosis is based on a detailed
clinical history and physical examination, appropriate assessments of
neurotransmitters in the CSF, genetic screening, and the exclusion of
mimicking disorders. The etiology is often genetic, and a schizophrenia
subgroup has not been described. This nevertheless indicates that single
genetic causes of aberrant neurodevelopment can produce a complex
syndromal pattern, that differing ages of onset can occur, although
onset usually occurs early in infancy (as for autism spectrum disorders
and mental disability), and that the clinical approach requires multilevel
diagnostics. Interestingly, CSF investigation, but not blood investigation
alone, may be able to demonstrate neurotransmitter imbalance (Kurian
et al., 2011).
6.7. Timing of hits and diagnostic and therapeutic approaches
In schizophrenia, early neurodevelopmental hits that have been
identified include hunger and infections (compared with Brown,
2011c, Susser and Lin, 1992); late hits that have been identified include cannabis use (De Hert et al., 2011). Many infections, according
to recent large epidemiological studies, are associated with an increased risk of various psychoses, including schizophrenia (Brown,
2011a, Brown et al., 2004, Buka et al., 2001, Dalman et al., 2008,
Gattaz et al., 2004, Koponen et al., 2004, Niebuhr et al., 2008,
Westergaard et al., 1999, Yolken and Torrey, 2008). In large studies
from Denmark, both autoimmune diseases and late infections additively and considerably increased the risk of schizophrenia (Benros
et al., 2011), whereas early infections did not or did so only a little
(Nielsen et al., 2011). However, epidemiological studies are not the
only type of study that can be informative; it could be that a number
of agents are not yet known, as was clearly suggested, for example, by
the results of the large California Encephalitis Project, in which slightly less than 50% of cases were clearly identified, even in acute meningoencephalitis (compared with Glaser et al., 2006). Therefore, it is
also of interest to perform small studies searching for specific viruses,
e.g., parvovirus B19, which was associated with both autoimmune
disorders (Pugliese et al., 2007) and psychoses (Adamson et al.,
2011, Hobbs, 2006), or for BDV (see above).
Regarding the question of heterogeneous schizophrenias under a
categorical view, critical phases during the course of the disease, or
so-called process active stages (Klosterkotter et al., 1989), may be
the key to a better understanding of the disease itself; it appears to
be of particular interest that only a portion of the at-risk cases will
ever transit from the prodromal disease stages to full-blown psychoses (Klosterkötter, 2011, Riecher-Rossler et al., 2009, Simon et al.,
2011). Diagnostic approaches especially have to consider the timing
of the diagnostic intervention with regard to the interpretation of
the results, as can be seen with an extraordinarily well investigated
neuroinflammatory disorder, multiple sclerosis (see below).
In sum, there is increasing evidence that schizophrenia is a heterogeneous disorder. Therefore, appropriate research and terminology
should be available for delineating in a balanced manner the respective
weight of the contributing factors involved in what is likely to be a complex etiopathogenetic scenario of risk factors, hits and modulatory factors. Early hits in general increase the risk of disease, but this may not
be easily detected through cross-sectional investigation in the clinic.
Nevertheless, factors or syndromal constellations assessed carefully
during critical disease stages such as the acute psychotic phase at the
disease onset or during a relapse would carry heavy weight with regard
to the underlying pathogenesis, at least for that specific stage. Whether
early risk factors may be necessary or only possible risk factors remains
very difficult to determine. Major pathogenetic factors may also combine and thus be of note for subgrouping. As long as there is no definite
knowledge that a neurodevelopmental aberration is needed, patients
with such a history should be not considered to constitute the only
pathogenetic subgroup. Here, preliminary categories for subgrouping
heterogeneous schizophrenias are formulated (see Table 4); however,
no operational criteria are included, as they would need to be determined through a consensus procedure. The results of recent elegant
studies (Clarke et al., 2011, Dickerson et al., 2012, Wang et al., 2011)
point to such subgrouping. Thus it was tempting to probe the proposed
K. Bechter / Progress in Neuro-Psychopharmacology & Biological Psychiatry 42 (2013) 71–91
etiopathogenetic classification including a categorization of diagnostic
strength by such datasets at the individual case level.
7. Gene–environment interaction and ME hypothesis
A major point consistently stressed is that environmental factors
should play a more important role in schizophrenia than previously assumed and that neither genes (Bondy, 2011), though significant, nor
the dopamine hypothesis (Nieratschker et al., 2010) may fully explain
the etiology of psychoses. It is clear that more research is needed
(Insel, 2010). In an insightful and critical discussion about the neurodevelopmental hypothesis (Fatemi and Folsom, 2009), the role of a
gene–environment interaction in the pathogenesis of schizophrenia
was not doubted, and viral and bacterial infections were addressed as
candidates.
7.1. Environmental factors in schizophrenia and in autoimmune disorders
Among the candidates for environmental factors, one might differentiate between risk factors and contributing factors, both of which
play a possibly variable role in an interactive pathogenetic scenario
over time. To differentiate required factors (conditio sine qua non)
from secondary contributing factors, it may be especially important
to focus on the eventual transition from risk states to diseased states.
A telling example of such a transition is the onset and course of
autoimmune disorders (Fathman et al., 2005, Rioux and Abbas, 2005),
most of which relate to complex genetic traits, as does schizophrenia.
General autoimmune disorders require three factors — genes, the environment and the immune system — which may become relevant during
the disease process at different time points and even repeatedly at different pathogenetic levels. Autoimmune disorders may be initiated by
infections via a couple of pathways (Mills, 2011), and disease outcomes
seem to be considerably shaped by (local) tissue responses (Matzinger
and Kamala, 2011). Similarly, when trying to better understand the
complex pathophysiology of schizophrenia with respect to the gene–
environment interactions involved, the inclusion of such new immunological concepts seems necessary.
Among the environmental factors identified in schizophrenia are
urban living and migration, the responsible pathogenetic mechanisms are thought to represent social stress (van Os et al., 2010).
Specific mechanisms have been identified (Lederbogen et al., 2011).
However, stress factors may be easily overestimated, as shown in
previous examples, such as gastroduodenal ulcers, and possibly in
schizophrenia as well (Kirkbride and Scoriels, 2009). Conversely, infections causing chronic diseases have often been difficult to identify;
prominent recent examples include helicobacter pylori infection
causing gastroduodenal ulcers (compared with Marshall, 1990),
papilloma virus infections causing cervical cancer (compared with zur
Hausen, 2001), and, years ago, two important neuropsychiatric disorders: the viral etiology of poliomyelitis and the spirochetal etiology of
general paresis and tabes dorsalis. The etiologies in both of these latter
cases were difficult to prove and hardly accepted (Bechter and
Hodgkiss, 1995). In retrospect, the major hurdle for causality inferences
in such infections has always been the overall low pathogenicity (i.e.,
the number of diseased per the number of infected) within the population. With regard to schizophrenia, environmental factors resulting in
exposure to pathogens in people who may not have developed antibodies or pathogen resistance factors (e.g., newly acquired pathogens
are more harmful for immigrants not used to these pathogens) are another option (Fatemi and Folsom, 2009), although there may be some
contribution of social stress as well.
7.2. Gene–environment interaction in psychiatric disorders in general
A most intriguing model of a gene–environment interaction for
psychiatric disorders, including schizophrenia, has been presented
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by Uher (2009): the evolution-informed framework (EIF) hypothesis
elegantly explains the interaction between environmental and genetic factors over time within populations. The critical point, that risk
genes prevail despite a strong negative impact of the disease on the
number of offspring produced, suggests that environmental factors
must be evolutionary recent. Uher mentioned infectious agents only
in a co-authored paper (Caspi et al., 2010). Here, it is proposed that
infectious agents appear to be ideal candidates for evolutionarily recent environmental factors, but they remain difficult to identify (see
above). It is intriguing to combine the EIF hypothesis with another informative epidemiological scenario described in a milestone observational study of wild sheep: a complex interrelationship between
survival, number of offspring and adaptive immunity to changing environments was found. In short, fitness correlates of heritable variation in
antibody responses were related to variance in reproduction over the
long term, and self-reactive antibodies were associated with adult survival during harsh winters, depending on the variance of the pathogen
load (Graham et al., 2010). Such a scenario of natural selection and
autoimmune responsiveness related to genetic variation and changing
environment would be coherent with the pathomechanisms suggested
in an meS subgroup, and it could explain a considerable subgroup of
schizophrenias overall because the two major findings, the continuous
genetic risk level within the population and the late hit, could be
explained with ME.
In a categorical view, a major or ‘causal’ role for the suspected LLNI
process may be attributed to the immune system because the immune system is mainly responsible for adaptation to the environment. With regard to an epidemiological scenario, exposure of the
individual to the specific infectious agent may be considered to be
most important and relevant if prevention of the infections were
possible; however, it is problematic that ubiquitous infections with
overall low pathogenicity are hardly preventable. Therefore, from a
practical perspective, the immune system in such a scenario is of
the greatest relevance. However, the positive and negative effects of
such genes may come to be recognized only in relation to certain infectious agents prevailing within the population. This is illustrated,
for example, by the major changes of immune reactiveness that
have evolved with civilization; e.g., the eradication of helminths
seems to have shifted TH-1–TH2-immune-responsiveness to fall
under other mechanisms, thus explaining the increasing prevalence
of autoimmune and allergic diseases, a scenario referred to as the
hygiene hypothesis (Allen and Maizels, 2011).
7.3. Contributive environmental and developmental factors
Beyond the primary pathogenetic factors discussed above, there
may be secondary contributive environmental factors as well as
completely independent developmental factors; the latter may be
neither early neurodevelopmental in nature nor involved in neurodevelopment, but may rather be involved in general development,
including immune system development.
Epigenetic dysregulation by environmental factors has been discussed in detail for HERV-W expression in different tissues relevant
in multiple sclerosis and schizophrenia and for related immune responses with regard to the molecular pathways involved in inflammation (compared with Perron and Lang, 2010). For HERV-W, a
life-long scenario of a determinant interaction between infectious
agents and HERV-W genes has been proposed to explain the actual
development and cause of schizophrenia (Leboyer et al., 2011); this
scenario would also perfectly match with the ME hypothesis.
Overall, it appears plausible that a complex scenario involving an interaction between the immune system, genes and changing environments may be implicated in schizophrenia and in LLNI. Two especially
critical aspects of the epidemiology of schizophrenia could nicely coincide with the gene–environment interaction and the meS subgroup as
defined here: 1. The preferred age of schizophrenia onset, because it
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matches with the age-related variance of pathogenicity (high pathogenicity during the preferred age of onset) of a number of infectious
agents. Long-known modulating factors of schizophrenia onset, such
as stress, sex and hormones, would also match because they also modulate immune-inflammatory responses. 2. The continuously high prevalence of schizophrenia risk genes in the population despite a strong
disadvantage regarding progeny may interrelate with advantages
for survival lent by the heritable variation of immune responses with
varying pathogen loads (compared with the wild sheep study above).
The burden of schizophrenia for humans and the disadvantage for the
CNS may represent the negative side of the immune system's associated
advantages for survival under changing environmental conditions. Infectious agents involved in such a scenario are expected to have low
pathogenicity overall, as they are well-adapted to by the host and
lead to harm in only a few of the infected, but to have the potential to
becoming pathogenic under certain environmental circumstances
(e.g., co-infections and others) and in response to age-related variations
of the immune inflammatory response (see also Bechter, 2001).
Immune inflammatory responsiveness is the major adaptive system
that living organisms use to cope with the environment. Recent insights
into CNS immunology suggest that the CNS is not spared from immunity (see fallen immune privilege); instead, the CNS seems better protected, and CNS-specific inflammatory mechanisms are more complex
than immune responses in other tissues, thus increasing the general
plausibility of the ME concept. Previously unprecedented interactions
are just beginning to be understood to have surprisingly strong impacts
on various disease outcomes, e.g., the influence of gut microbiota on
inflammation, autoimmune disease and cancer (Tlaskalova-Hogenova
et al., 2011).
In sum, gene–environment interactions represent an important
aspect in the etiopathogenesis of schizophrenia and could be involved
in various subtypes of schizophrenia; it is highly plausible that they
are involved in the proposed meS subtype. Pathogenetic processes involved in schizophrenia vary over time, and one early and one late hit
were proposed; however, the specific characteristic pathomechanisms
of these hits remain to be better defined. The longstanding disease process that occurs over years must be explained, not only in terms of the
associated consequences for the function and structure of the CNS, as
well as the associated epidemiological aspects of disease course, but
also in terms of the consequences for the development of the gene
pool within the population over time. The required factors in autoimmune diseases are genes, the environment and the immune system,
and the environmental factors often seem to be infectious agents, although they have only been partially identified thus far. A rather similar
scenario could pertain to the meS subgroup because ME could well explain even a long-term disease process, whether it is initiated from
latency after early infection and reactivation or from a late infection
that interacts with previous infections and other interacting factors that
have become relevant over time. Additionally, ME and the immunegenetic background could coincide with population-related aspects of
risk increases under changing environmental factors, with downstream
consequences for the whole population, which may change direction
over time. As the meS subgroup could elegantly explain several major aspects of schizophrenia and its epidemiology, such as the continuously
high level of risk genes within the population despite the disadvantage
with regard to the number of progeny, as well as the preferred age of
onset, this subgroup could be of considerable size. The most specific
findings from CSF studies would support such view, although CSF analysis is not yet considered to be sensitive enough with respect to other
available methods (compared with Bechter et al., 2010a). A prevailing
LLNI pathomechanism, the core aspect of the ME hypothesis, remains difficult to assess in vivo.
A full understanding of disease pathomechanisms would also require a characterization of the respective immune response states of
the organism over time. From this characterization, the complex interactions that occur over time could be better understood and
categorized as either classical inflammation at some time points or
as intermediate states of immune regulation or struggles with the environment based on the individuals immune system at other time
points, a model which has been outlined in principle in computational immunology (compared with Cohen, 2007).
8. An emerging ME scenario
Here, further pathomechanisms involved possibly in the meS scenario are more closely examined. It remained difficult to delineate the
precise role of infectious agents identified as schizophrenia risk factors with regard to the pathogenetic mechanisms involved (Yolken
et al., 2011). Some agents seem involved at the onset of disease
(Bechter, 2001, Dickerson et al., 2007, Leweke et al., 2004), suggesting
an initiating role; however, this remains to be proven. Furthermore,
this verification must be conducted separately for each agent because
each agent associates with specific aspects of this virus or retrovirus,
e.g., endogenous retrovirus HERV-W (Perron et al., 2008) or herpes
virus 6a which is directly involved in the immune-inflammatory response (Arbuckle et al., 2010). Such differences were demonstrated
when comparing for example just three well investigated CNS infections (Bentivoglio et al., 2011).
8.1. Persistent infections
Emerging knowledge about persistent, latent or dormant infections
demonstrated that transitions between dormant and reactivated or partially active infected states may be more important for disease than previously assumed (Dworkin and Shah, 2010, Kerschensteiner et al.,
2009). The complex scenario of persistent infections, involving both
good and bad for the infected individual, was demonstrated in detail
for the Helicobacter pylori infection (Arnold et al., 2011, Willyard,
2011). Interactions between different infections in one infected host
were increasingly recognized, though they are not reviewed extensively
here. Furthermore, unconventional, inherent determinants may precipitate a diseased state only when an infection was present (Cadwell et al.,
2010). It is worth noting that mechanisms were subject to considerable
change over time (Bentivoglio et al., 2011).
While persistent viruses and bacteria can exist over the long term in
metabolic inactive states and thus survive without growth, dormant
cells may sense when conditions improve and reinitiate growth
(Dworkin and Shah, 2010). In a surprising clinical example, a dormant
virus was unprecedentedly involved in peripheral immune response,
first presumed to be an adverse drug event, but when studied in more
detail, it appeared to be related to a reactivated EBV infection triggered
by the drug. Thus, transformed B-lymphocytes induced the cutaneous
and vascular symptoms of DRESS (drug reaction with eosinophilia and
systemic symptoms) (Picard et al., 2010).
8.2. CNS endogenous immunity
Many new aspects of CNS-specific endogenous immunity have
been explored (Bentivoglio et al., 2011, McGeer and McGeer, 1995)
and may plausibly be involved in LLNI. For instance, synaptic dysfunction was likely involved in meS, LLNI may be either primary or secondary effect from infection, autoimmunity or other insults, as
disturbed neuronal transmission plausibly represents the functional
extreme of any CNS pathology. However, synaptic dysfunction may
often not demonstrate the primary disease process, as found even
for the majority of neurotransmitter disorders identified to date
(see above). A seemingly simple fact should also be considered; that
is, neurons represent only a minority of CNS cells and need continuous support from glia, an aspect which was underestimated in CNS
research including schizophrenia research (Nave, 2010). Additionally,
the role of microglia, which is easily activated, is only beginning to be
understood in more detail. This will not be further discussed herein.
K. Bechter / Progress in Neuro-Psychopharmacology & Biological Psychiatry 42 (2013) 71–91
8.3. Volume transmission
Another basic mechanism rarely discussed in context with schizophrenia but of apparent importance for normal CNS functioning and,
thus, likely for disease, is the volume transmission (VT) mode concept.
The VT mode balances the so-called wiring transmission (WT), the latter represented mainly by synaptic transmission (Agnati et al., 1995).
Pathological alterations of the VT mode can be assumed to be involved
in the LLNI processes because CNS extracellular fluids provide general
signaling functions throughout the CNS (Fuxe et al., 2010). Furthermore, VT links to CSF signaling (in two directions), thus the functional
relevance within the CNS parenchyma is clearly demonstrated (Fuxe
et al., 2010, Lehtinen et al., 2011). The role of the extracellular fluid
space in CNS infections was illustrated in Toxoplasma infection where
a rapidly developing kinesis-associated system of reticular fibers plays
an important role for the movement of infiltrating immune cells to defeat toxoplasma (Wilson et al., 2009). Toxoplasma was one specific risk
factor in schizophrenia (Yolken and Torrey, 2008).
However, it has also been determined that sterile inflammation
can be activated within the brain by non-specific sensing mechanisms
(Chen and Nunez, 2010, Mills, 2011).
8.4. Downstream mechanisms
Pathomechanisms may primarily or secondarily be involved in
immune-inflammatory responses within the CNS in the form of alterations of neurogenesis (Belarbi et al., 2011, Ekdahl et al., 2009),
oxidative stress (Trushina and McMurray, 2007), antioxidant capacity (Gawryluk et al., 2011), chronic neuroinflammation and neurodegeneration (Lynch and Mills, 2012), neuroprotection (Ehrenreich
et al., 2008, Hellweg et al., 1998), autoimmunity (Jefferies et al., 2011),
immune neural glial interactions (Lynch and Mills, 2012), CSF cells
(Schwartz and Kipnis, 2011), infection- or inflammation-associated
neurotransmitter metabolism (Prandovszky et al., 2011), metabolic
imbalances (Myint et al., 2011), anti-inflammatory activation (Meyer,
2011). Even seemingly unrelated factors such as modulation from exercise (Gleeson et al., 2011), neurocognitive training (Eack et al., 2010), or
various types of stress (see for general interactions Dantzer et al., 2008)
may relate to LLNI.
8.5. Links between CNS and systemic factors
Surprisingly, direct interactions exist between systemic immunity and
the CNS (Saxton et al., 2011). For example, commensal microbiota may
trigger autoimmune demyelination (Willyard, 2011) or in other ways interact with CNS autoimmunity (Dunne and Cooke, 2005, Grace et al.,
2011). Treatments may also interact through various mechanisms with
the immune response itself (Martins-de-Souza et al., 2011, Nikisch et
al., 2011, Piontkewitz et al., 2009). That such interactions have in vivo relevance was demonstrated by the use of psychopharmaca in experimental
autoimmune encephalitis (Musgrave et al., 2011). Pathomechanisms involved in infections include size, geometry, kinetics of molecular patterns
(Bachmann and Jennings, 2010), and others (see, also, BDV infection discussed herein).
8.6. Multiple sclerosis
The ME scenario may, in various aspects, be similar to the rather
well-investigated case of MS where a role of risk genes is proven
(Sawcer et al., 2011) as several infectious agents seem to represent
triggers (compared with Bostrom et al., 2009, McLeod et al., 2011,
Wallin et al., 2009). Thus, the disease is considered an autoimmune
disease. Pathogenetic details were extensively studied in experimental
models, mainly experimental autoimmune encephalitis (EAE), and the
best model represents Theiler's virus infection (Oleszak et al., 2004).
Over time, complex pathogenetic events emerge, as represented in
83
EAE and in MS brains. Immune responses involving complex inflammatory mechanisms and various arms of the immune system emerge even
locally within the CNS (Krishnamoorthy et al., 2009, Meinl et al., 2006,
Skulina et al., 2004). It is noted that psychiatric symptoms are frequent
in MS, including rare schizophrenia type psychoses (Gross and Huber,
2007), and brain imaging findings demonstrated considerable similarities in between MS and schizophrenia subgroup (Davis et al., 2003).
8.7. How do specific schizophrenic symptoms emerge?
Neuroinflammation may lead to a range of psychiatric syndromes
along pathways from exposure to chronic illness or disability, which
are difficult to disentangle because they are always subject to change
depending on various human behavioral traits (O'Connor et al.,
2006). The involvement of genes in a broad picture of abnormalities
in schizophrenia has been recognized (Verrall et al., 2010). Why, in
the case of LLNI situations or in classical CNS inflammation in one individual, schizophrenia-like psychosis develop, whereas other psychiatric syndromes develop in other cases, remains nevertheless
unanswered. Beyond pre-existing liability factors, especially genetic
ones, in the neurodevelopmental presentation as an endophenotype
and for various downstream factors emerging over time, neurotransmitter functioning may likely be involved and plausibly rather specific symptoms may easily emerge at these levels of the CNS functional
system, and in addition depend from the topology of pathology (this
aspect has been in part discussed in the neuroimaging section, more
to be found in a neurophysiological and functional imaging field not
reviewed here). Risk genes involved in the schizophrenia subgroup
were expressed in human induced pluripotent stem cells from schizophrenic patients (Brennand et al., 2011). As these single risk genes
were mainly involved in neuronal functioning, they may preferably
contribute to the type of symptoms evolving but not necessarily to
the disease process itself. From this perspective, these genes should
similarly be involved in MS associated or other ‘organic’ schizophrenic type psychoses, which remains to be shown.
In sum, the ME scenario provides a multitude of immune pathological mechanisms and states involved in LLNI and influenced by the interaction between genes and environment, thereby shaping an emerging
immune inflammatory response over time. Neurotropic infections
have the potential to induce numerous pathologies and downstream
events ranging from neurodevelopmental aberrations to LLNI and classical neuroinflammation and even including infection-induced cellular
dysfunction on the molecular level. Infections may trigger LLNI, which
may occur at many time points during the lifetime of an individual. At
certain ages, an individual is either more or less sensitive to harmful
specific infections, several of which present with high pathogenicity at
ages of preferred disease onset; this is a finding that seems of special interest for research on the meS subgroup. Reactivation, autoimmunity or
infection-induced molecular pathomechanisms may be involved. CNS
dysfunctions relating to these various mechanisms may emerge and
change over time, influenced by the type of the endogenous CNS immune response in interaction with systemic immunity. Major sites of
CNS endogenous immune responses represent the ECF and the CSF
spaces and, thus, involve the whole brain at many sites. However, the
primary triggers of LLNI, such as infections, autoimmunity, toxicity or
trauma, are difficult to demonstrate because they may not be present
after the onset of the disease, and in the case of persistent infections,
they are generally difficult to detect.
A teaching example for the research situation in schizophrenia
may represent general autoimmune disorders in which three major
factors are required: genes, environment and immune system. The
course characteristics of autoimmune disorders resemble, in various
ways, the course characteristics of schizophrenia, such as prodrome,
variability, transition, non-transition, relapse, chronicity, and defect.
When accepting the terminology of a meS subgroup, one might further differentiate primary from secondary meS. Nevertheless, LLNI
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may also be involved in neurodevelopmental schizophrenia, e.g., as a
late hit. Both unspecificity and convergence of pathomechanisms are
not unusual as different etiologies produce surprisingly similar diseases,
e.g., similar syndromal outcome from heterogeneous genetic causes
(Auerbach et al., 2011) or molecular pathology from genetic and
non-genetic aspects converging to finally relevant pathomechanisms
(Voineagu et al., 2011).
Persisting infections may play a more important role than presently
assumed. Diagnostic difficulties with persistent infections are not singular to the neuropsychiatric field, as evidenced from a resume about the
present standing of research into tuberculosis. Although this research
was well funded over many years because of its enormous impact on
human health, the methods remained insensitive and clinical diagnoses
remained difficult regarding the individual case requiring a broad array
of diagnostic approaches, including a century old sputum microscopy
(Lawn and Zumla, 2011). These issues were compounded by the diagnostic challenge of tuberculous meningitis. Similar difficulties of diagnosis can be found in late lyme neuroborreliosis (compared with
Fallon et al., 2009, Stanek et al., 2012) and in prodromal stages to
HIVe or LE. In such contexts, the findings suggesting the prevalence of
a meS subgroup appear promising.
9. The peripheral CSF outflow pathway and the anatomy
of schizophrenia
The explanations of the pathophysiology of schizophrenia, not the
rarely preferred simplified views of a chronic stable disease, focused
on synaptic pathologies to explain the entire disease. In fact, symptoms and underlying dysfunctions in schizophrenia are apparently
widely distributed and involve both the gray and white matter, in
other words, the whole brain. In addition, it appeared that both
peripheral and central neuronal dysfunction underlie the symptoms
observed when investigating for olfactory dysfunction (review see
Bechter, 2011). Dysautonomia is also frequent in psychoses, including
schizophrenia, which seems related to central dysfunction but may
include a peripheral site of neuronal dysfunction (Bar et al., 2004,
2010). The same seems true for abnormal pursuit eye tracking
(compared with Lencer et al., 2011). Such parallelism of peripheral
and central neuronal dysfunction must be explained and could, for
example, relate to cellular receptors or cellular metabolic dysfunction
expressed at the central and peripheral sites. Furthermore, systemic
pathologies, such as proteome abnormalities (Bahn and Schwarz,
2011) or activated blood monocytes (Drexhage et al., 2010b), could
mediate such peripheral and central dysfunction. But there were
also some unexplained findings such as subtle muscle lesions that resembled lesions found in meningoencephalitis apparent in approximately 50% of the cases (Meltzer and Crayton, 1974). The muscle
lesions could have been replicated and, thus, were speculatively
attributed to a genetic abnormality (Flyckt et al., 2000).
In addition to systemic abnormalities and central and peripheral
neuronal dysfunction, the underlying pathogenetic principle must
be explained by the change in brain structure and function over
time in all aspects. A genetic aberration could, in general, underlie
such a situation as observed in the monoamine neurotransmitter disorders, preferably when genes were related to basic cellular functions. However, in nS, one should identify the time trajectories of
abnormal neurodevelopment, which was incomplete (see above).
When nS represented a major subgroup, such as the prevailing hypothesis of schizophrenia, one would expect that as in monoamine
neurotransmitter disorders, several types of nS would be found and
symptom patterns would vary such that disease onset would relate
to a certain developmental period in which the respective etiology
was active. In detailed studies of symptom patterns in different
schizophrenia risk groups, each of the subgroups presented a similar
distribution of symptom patterns (Ribbe et al., 2011); this finding is
not consistent with the idea of neurodevelopmental schizophrenia.
According to the watershed model, the risk genes involved in schizophrenia are proposed to be few (Brennand et al., 2011); this, however, has yet to be proven and may not explain causality of disease
(see above).
Distributed CNS pathology and dysfunction involving gray and
white matter is, together, often termed disconnectivity and confirmed
from various approaches including neuroimaging (see above), histopathology (Schmitt et al., 2011a), and neurophysiology (Foxe et al., 2011,
Mulert et al., 2011a, 2011b, Strik et al., 2002) or from combined
approaches (Heuser et al., 2011). Explanations of this complexity of aberrations arising in parallel at various sites and systems of the CNS remain preliminary (see, for example, Andreone et al., 2007 and the
discussions herein). Influences from psychopharmacological treatment,
although demonstrated, represent a negligible aspect with regard to
understanding the disease (de Castro-Manglano et al., 2011). The experimental findings for the VT mode were corroborated in the meanwhile (Agnati et al., 2010, Fuxe et al., 2010), representing an
important physiological pathway with a consistent importance of the
flow of the ECF throughout the brain moved by the pulsating brain
with each cardiac cycle, and involving, in parallel, the CSF flow (compared with Bechter, 2011, Fuxe et al., 2010, Gupta et al., 2009, 2010).
The PCOP pathway (Bechter, 2011) was first determined to be important in immunology in that CNS antigens are released along this pathway into the periphery to induce CNS-specific immune responses
(Cserr and Knopf, 1992). In research approach cases, therapy-resistant
depression or schizophrenia was improved with cerebrospinal fluid filtration (Bechter et al., 1999, 2000) before being found to be an effective
treatment of neurological autoimmune disorder Guillain–Barré syndrome (Wollinsky et al., 2001). Clinical observations during CSF filtration suggested a direct role of CSF signaling within the subarachnoid
spaces and at peripheral sites and initiated the PCOP hypothesis,
which could be relevant for psychoses, including schizophrenia, and
for neurodegenerative and neuroinflammatory disorders in general
(Bechter, 2011), although this remains highly speculative.
When assuming that sites of the pathway itself may be involved in
pathology from CSF signaling along brain nerves and peripheral nerves
and even into the tissues connected by the nerves (Bechter, 2011),
many aspects of the PCOP hypothesis must be further studied. Yet
known is for example, that CSF cells are trafficking into the periphery
along the PCOP, as demonstrated in experiments at the cribriform
plate (Goldmann et al., 2006, Locatelli et al., 2012) and in humans
along the peripheral nerves in a first case (Schmitt et al., 2011b). Interestingly, the role of CSF cells was previously underestimated with respect to their apparent importance for CNS immunity in general
(Schwartz and Kipnis, 2011, Schwartz and Shechter, 2010) and their
rather direct influence on cognitive functions (Derecki et al., 2010).
10. Conclusion
This update was given with a personal background of clinical experience of more than 30 years in psychiatry that included continuous responsibility of a specialized ward for young schizophrenic patients with
complicated and therapy-resistant courses. Individual cases of schizophrenia have been personally followed for more than 30 years and
have been found to demonstrate surprising unpredictability and variance of courses. At the extremes, one case of initially therapy-resistant
psychosis was successfully treated and after one year never relapsed
during about 30 years. At the other extreme, cases of devastating
courses within a few years, or the rare case that began with schizophrenia and after 10 years presented as multiple sclerosis with unusual
course aspects. Gerd Huber and co-workers showed these extremes in
a milestone study over the long term (Huber et al., 1979) demonstrating
an extraordinary variation of courses then differentiated in twelve subtypes. Such course variability was broadly confirmed in a number of
studies in the meanwhile though subtyping was not introduced in the
established diagnostic systems. The recent views from the scientific
K. Bechter / Progress in Neuro-Psychopharmacology & Biological Psychiatry 42 (2013) 71–91
field on schizophrenia indicate there is only a partial understanding of
the disorder (see Table 5). Accordingly, there is a strong argument
against a revival of a simplistic all inclusive hypothesis. An approach
of etiopathogenetic subgrouping of schizophrenia according to the
major constraints of results (as given in Table 4) appears preferable as
the overwhelming consensus in research is that schizophrenia represents a heterogeneous disorder. The developments in medicine in general and in psychiatry specifically, e.g., the autism spectrum disorders,
which have often been mentioned with an overlap and similarity to
schizophrenic disorders, clearly argue against the view that one size
fits all or that there may be a single appropriate approach. Furthermore,
the unspecificity of psychiatric symptoms is a well-established phenomenon, implicitly suggesting that the heterogeneity of etiologies is
just the other side of one coin. Nevertheless, to develop criteria for an
appropriate subgrouping of schizophrenia of different etiopathogenetic
types of schizophrenia will remain a challenge for psychiatric research,
especially when developing consensus criteria.
Infectious agents are risk factors for schizophrenia, usually explained
in a developmental scenario (Brown, 2011a). However, a late hit can
hardly been explained by aberrant neurodevelopment, if not directly involving immune mechanisms, and a recent milestone study from
Denmark was surprisingly well compatible with the ME scenario:
both, severe infections and autoimmune disorders during lifetime, increase additively and non-specifically the risk of psychoses including
schizophrenia (Benros et al., 2011).
For the meS subgroup proposed here, this update of the ME hypothesis demonstrates an emerging knowledge about LLNI situations that
prevail within the CNS, widening the basis for the assumption that
LLNI may underlie a variety of psychiatric disorders, especially subgroups of affective and schizophrenic type psychoses. The evidence of
overlap between affective and schizophrenic disorders with regard to
risk genes and, therefore, disease pathogenesis is strongly corroborated
from large genetic studies and was well compatible with the longknown unspecificity of organic etiologies, including encephalitis for
psychoses. LLNI situations differ from classical neuroinflammation in
that LLNI represents a low degree inflammation but may nevertheless
be able to induce psychiatric disorders including schizophrenia emerging within a complex pathogenetic scenario. Such a perspective was
corroborated from findings in experimental neuroimmunology and
from research in newly detected CNS inflammatory disorders, especially limbic encephalitis where during the prodromal phase, various psychiatric syndromes prevail though classical CNS inflammation has yet
to be found. Many researchers consider schizophrenia to represent a
heterogeneous disorder, and broad consensus was found, especially
within the neuroimaging literature, that a so-called late hit is required
to explain the observed pathologies. Thus, something must happen to
or occur in the CNS around the critical disease phases from prodrome
to disease onset and especially during the first years after onset. This
hit apparently leads to considerable disturbances of brain function
and even brain structure. However, the quality of the hit remained
undefined. Many aspects of the findings in neuroimaging and in neuropathology match the view that this hit could be represented by an LLNI
process. LLNI pathomechanisms could explain core aspects of the observed pathology through the type of the pathomechanism involved
and the specific topological issues, i.e., the widely distributed brain dysfunction. The brain barriers (blood–brain barrier, blood–CSF barrier,
meningeal–CSF barrier) and respective interactions among the bodily
compartments involved and the CSF cells play a more important role
in CNS functioning than previously assumed. Such new insights align
well with the ME hypothesis.
Disturbances mediated by extra-cellular CNS fluid and CSF, together
in exchange with the systemic blood compartment, have the potential
to explain, by a common pathogenetic link like LLNI, major findings in
schizophrenia by anatomy, especially the ‘non-localization’ (see
above), meaning anatomically widely distributed pathologies, and possible various pathophysiologies, which include distributed brain
85
dysfunction; emerging disturbed brain structure including slight atrophy involving both gray and white matter, course variability resembling
the course variability of autoimmune disorders (including the prodromal phase, transition, non-transition, chronicity, relapse, processactive stages and defect).
The parallelism between central and peripheral neural dysfunction in schizophrenia, e.g., the olfactory system, or the findings of aberrant proteomics and of monocytes activation in peripheral blood,
clearly suggests that schizophrenia should, in part, be understood as
a systemic disease with a preferential involvement of the brain rather
than being considered an exclusive brain disease. The pathways and
mechanisms of the bidirectional pathways between the brain and
the peripheral immune system are important and previously unknown mechanisms become evident (Anthony et al., 2012).
The majority of schizophrenia cases seem related to complex genetic traits, which is a scenario resembling that found in autoimmune
disorders, because a number of infectious agents seem to be involved.
Important epidemiological aspects of schizophrenia, such as the preferred age of onset, the continuous high risk gene pool within
populations despite low numbers of progeny and the role of infections (age-related variance of pathogenicity), would well align with
the ME hypothesis. General autoimmune disorders require three factors (gene, environment, immune system), thus constituting a paradigm for the meS subgroup. Many infections present with overall
low pathogenicity within the populations, which is consistent with
the ME hypothesis, though it is difficult to research because the contribution of a single agent is hidden and dependent of interacting factors. The infectious agent may, nevertheless, represent the conditio
sine qua non (needed factor), e.g., see the recent story with gastric
ulcer and helicobacter pylori infection. An overlap between schizophrenia and other psychiatric syndromes produced from similar
LLNI causes is expected as the meS subgroup presumably links to certain genetic and other pre-existing liability factors. A recent CSF study
performed according to the advanced CSF analytic methods, validated
in thousands of patients mainly from neurology, demonstrated LLNI
being most likely present in a subgroup of approximately 40% of the
therapy-resistant cases of schizophrenia. With more sensitive
methods to assess LLNI, the size of this subgroup will likely be larger
based on a preliminary study with the newly detected autoantibodies
discussed in LE research (Steiner et al., 2011).
The schizophrenia research field is a leading field in psychiatric research since the decennia with regard to developing refined methods
and with regard to epidemiological approaches. However, the research field has not, to date, been successful in subgrouping the
etiopathogenesis. Although less research effort has been put into the
research of organic psychiatric disorder when presenting as nondementive syndromes, these rarer organic psychotic and nonpsychotic, i.e., personality, disorders could promote the development
of valid diagnostic criteria for schizophrenia and other psychiatric disorders with an organic etiopathogenesis or partial organic contribution. However, the accepted diagnostic systems, DSM IV and ICD-10,
do not provide operational criteria to classify organic psychiatric disorders, but rather rely on a formula that is applied to a clinician's evaluation criteria. This is a preliminary level of categorization, although
in organic psychiatric disorders, this is the best available possibility
for evaluating and strictly defining criteria. For some single cases of
personality disorder or therapy-resistant depression, the appropriate
‘organic’ classification has been exemplified: a case of possible streptococcal infection associated autoimmune-related therapy-resistant
depression was classified as probable ‘organic’ when including the
therapeutic effect from penicillin treatment plus a follow-up of five
years that included the results from neuroimaging and laboratory
testing and CSF investigations (Bechter et al., 2007). Cases of possible
arachnoid cysts associated personality disorders were classified as
probable when rapid improvement after neurosurgical treatment of
arachnoid cysts was noted. It was, as a consequence, suggested to
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K. Bechter / Progress in Neuro-Psychopharmacology & Biological Psychiatry 42 (2013) 71–91
revise the current weak operational criteria (Bechter et al., 2010b).
Apparently, there is a need to improve consensus criteria for nondementive organic psychiatric disorders as a general challenge for
psychiatry including schizophrenic and other psychiatric disorders
with partial ‘organic’ aspects in pathogenesis (Bechter, in press).
The major challenge, therefore, is the improved categorization of
the findings in an improved diagnostic approach, which should include the major compartments involved in disease pathogenesis,
i.e., the brain itself, blood as a systemic indicator, and, presently
underscored, the CSF. The importance of combining these three
major bodily compartments in the diagnostic approach is illustrated
in the autism spectrum disorders where it is expressively claimed
that even in genetically caused autism spectrum disorders, CSF investigation is needed in addition to other approaches for a correct differential diagnosis (see above). More detailed proposals for the
diagnostic categorization in this respect cannot be made in this review because it would require a careful discussion of the validity of
methods, limits of sensitivity, and the immanently more general limitation of the approaches to understand brain diseases, apparently
often only valid when combining many approaches and findings.
With improved diagnostic methods, improved therapeutic success
is expected. In fact, several indications are available that suggest the
therapeutic effects related to neuroprotective and anti-inflammatory
aspects along with anti-inflammatory medications are helpful (not
reviewed here). As etiologies, pathophysiological details and, over
time, the type of LLNI pathomechanisms may vary, the preferred research and diagnostic approach is at the individual case level. New
specific methods that are more sensitive to detecting LLNI are required but should be based and validated by the longstanding clinical
experience available in the neurological and, especially, CSF research
field. The number of mechanisms most likely involved in an LLNI situation is constantly increasing, which makes the situation for research attractive and challenging.
With regard to the neurodevelopmental hypothesis of schizophrenia, it was recommended to carefully observe the expertise in neighboring fields, e.g., in developmental cognitive neuroscience (Bunge, 2012)
or neurodevelopmental epilepsy (Bozzi et al., 2012), to differentiate
the possible neurodevelopmental insults onto the brain with regard to
their variant syndromal outcome. With regard to the meS subgroup,
new insights into the role of endogenous viruses in evolution and host
biology seems interesting which demonstrate a close interaction (and
continuous battle) between viruses and hosts, including many conventional viruses (Feschotte and Gilbert, 2012). New views about the role
that immunity plays in multiple sclerosis (Locatelli et al., 2012) are
surely insightful as MS represents the best studied inflammatory CNS
disorder in humans. The recent insight that inflammation in experimental autoimmune encephalitis is beginning at the meninges (see
above) was confirmed in human multiple sclerosis when investigating
biopsy material: the results contradicted the previous assumption that
cortical atrophy was non-inflammatory, instead appeared associated
with short-lived inflammation (Lucchinetti et al., 2011). A similar scenario of short-lived classical inflammation hardly to be detected, was
assumed in the ME hypothesis and exemplified for BDV infection
models, nevertheless recognizing that other types of LLNI may prevail
in meS subgroup (compared with Bechter, 2001).
In conclusion, psychiatry's need to adopt a highly active and growing psychoimmunology approach to psychiatric disorders which has
led to some fascinating results (Licinio, 2010) (compare the abstracts
of the 11th Psychoimmunology Expert Meeting March 2012), is promoted here. For example, one small, pioneering but growing field
with interdisciplinary views is the specific approach of HERV-W elements, which examines its relevance in MS and in schizophrenia
(Leboyer et al., 2011, Li et al., 2011). In a second example, a recent
milestone study from Denmark shows the additive effect of infections
and autoimmune disorders during life time on psychosis risk (Benros
et al., 2011). In a third example, this is the emerging findings from CSF
studies indicating LLNI to prevail in a schizophrenia subgroup
(Bechter, 2011, Maxeiner et al., 2009, Oleszak et al., 2007), and in a
fourth example the imaging of the underlying neuroinflammatory
process by microglia activation or indirect signs (in the interpretation
from an ME perspective!) of structural abnormalities (see above), or
progressive membrane phospholipid change in first episode schizophrenia with gradual inclusion of brain regions with an initial increase followed by a decrease of metabolites (Miller et al., 2012). As
the details of these studies demonstrate that change is often observed
the method one size fits all may not be successful in such a complex
disease as schizophrenia represents instead the diagnostic approach
should be based on strict rules in a broad clinical validate experience
of possibilities and limitations of these methods and combining various approaches in one case in both, research and, when validated, in
individual cases as is the typical approach to the clinical medicine and
why not in subgrouping schizophrenia. The recent controversy in limbic encephalitis research seems to demonstrate that the discussion
outlined here with the updated ME hypothesis is at the heart of the
problem: in clinically strictly defined limbic encephalitis the neuroimaging and CSF findings are very sensitive and the clinical patterns
found match with the type of autoantibodies (Dalmau, 2012), whereas in schizophrenia subgroup of antibody-mediated encephalitis both,
neuroimaging and CSF investigation, may not be sensitive and serum
investigation was considered to be possibly sufficient (Lennox et al.,
2012); however, there is an ongoing debate, e.g. whether aggressive
treatments as used in strictly defined limbic encephalitis may be justified or not in schizophrenia subgroup presenting with CNS autoantibodies just in serum.
Acknowledgment
For continuous support of the CSF studies and studies on the elucidation of possible role of BDV for psychiatric disorders we thank
the Margarete-Ammon-Stiftung (Munich).
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