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The Open Neurology Journal, 2012, 6, (Suppl 1-M6) 113-118
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Open Access
Diagnosis of Infectious or Inflammatory Psychosyndromes
Karl Bechter
Clinic for Psychiatry and Psychotherapy II, Ulm University, Germany
Abstract: Before an outline of the process of diagnosis and differential diagnosis in infectious and/or inflammatory psychosyndromes is given, a more general overview onto the approach to organic psychosyndromes seems useful, because in
both entities similar principles of causality conclusion are applied. Correlation does not demonstrate causality. Therefore
the principles and consensus recommendations, and limitations of causal inference to categorize psychosyndromes as being ‘organic’, is to be discussed in detail.
Keywords: Psychosyndromes, psychoses, syndromes.
1. CATEGORIES
DROMES
OF
ORGANIC
PSYCHOSYN-
The chapter F0 of ICD-10 involves all organic psychosyndromes with the exception of alcohol- and substancerelated organic disorders. This catalogue outlines various
types of dementias and deliria and many other types of organic-based psychosyndromes, ranging from hallucinosis or
catatonia, or delusion, or affective, or manic, or bipolar depressed, or mixed affective, or anxiety, or dissociative, or
emotional, to minor cognitive disturbances. An encephalitic
syndrome is not described, but a post-encephalitic syndrome.
Few criteria to diagnose an organic psycho-syndrome are
formulated including mainly two points: 1. the demonstration of a cerebral disease, or trauma, or dysfunction, or 2. the
prevalence of a systemic disease affecting the body known to
possibly associate with one of the organic psychosyndromes,
plus a relevant time-relationship (weeks or few months) in
between this organic factor and onset of psychosyndrome.
Further supporting criteria might be improvement or dissolving of psychosyndromes with improvement of the assumed
underlying organic cause, and/or a lack of another causality.
Clear operational criteria for causal inference are apparently
not available. So in reality the diagnosis of an organic psychosyndrome is basically left to the individual arbitrary opinion of the diagnosing clinician. Such is surely well working
in acute and subacute organic diseases with a rather clear
beginning and/or clear dissolving of symptoms. However, in
slow onset insults to the brain any causality conclusion remains extremely difficult. In some chronic psychosyndromes
the improvement after therapeutic intervention might mark
the point for causality inference, as we recently demonstrated
in cases with arachnoid cysts associated with organic psychosyndromes in the form of minor personality disorder,
which were reversible resp. improved after neurosurgery [1].
*Address correspondence to this author at the Ulm University, Clinic for
Psychiatry and Psychotherapy II Ludwig-Heilmeyer-Str. 2, D-89312
Günzburg, Germany; Tel: +49-8221 /96-2540 or 96-00;
Fax: 49-8221 /96-2736; E-mail: Karl.Bechter@bkh-guenzburg.de
1874-205X/12
A similar description of organic psychosyndromes like
the ICD-10 is found in DSM-VI, a major difference however
is, that the term ‘organic’ is eliminated. The term ‘delirium’
is much more broadly understood and a major criterion to
assume a causal relationship between a ‘medical disease
factor’ and the various psychosyndromes, is the presence of
a relevant or seemingly relevant time relationship between
both.
Relatively well defined criteria are available for the diagnosis of delirium in both systems, i.e. DSM-IV 293.0, ICD10 F05. However, both international classification systems
lack clear operational criteria for most of what is traditionally termed organic psychosyndromes with less severe or
moderate symptoms. In this broad spectrum of psychosyndromes mainly the experienced clinician’s opinion based on
the evaluation of findings observations and examinations, is
the clue for causality inference.
The most advanced categorization of organic psychosyndromes may be found in G. Huber’s textbook [2], which is
therefore preferred here. Huber differentiates acute or reversible types versus chronic or irreversible types of organic
psychosyndromes. A diagnosis of acute organic psychosyndromes is rather clear when accompanying neurological
symptoms were assessed. According to various diagnostic
descriptions, be it textbooks, ICD-10, or DSM-IV, the main
symptom interpreted as ‘organic’ represents the disturbances
of consciousness. Difficult is the diagnosis of organic psychosyndromes if consciousness is not disturbed, which on
the other hand definitely is not an obligate symptom even of
the acute exogenic reaction type, first described by Bonhoeffer (see below), and usually not found in chronic organic
psychosyndromes. Organic psychosyndromes lacking neurological symptoms and lacking disturbances of consciousness
were described as functional psychoses or ‘Durchgangssyndrome’ (transit syndromes). Durchgangssyndromes include
various types of psychopathology, e.g. affective and schizophrenic type psychoses, and a variety of ‘minor’ psychosyndromes presenting with a broad range of psychiatric symptomatology (see above and [3]). Causality inference in such
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cases is a priori difficult because of the general unspecificity
of psychosyndromes to be discussed below.
The proposal of G. Huber to rank organic psychosyndromes according to their validity of causal inference is
exemplary, though not yet accepted in the international diagnostic systems: First-rank organic psychosyndromes include
deliria, dementia and amnestic syndromes, all of them including disturbed consciousness or severe disturbances of
cognitive functioning, such symptoms allowing a rather safe
causality inference of organic brain dysfunction yet on a
psychopathological level. Second-rank organic psychosyndromes involve various types of organic personality disorders, catatonic or delusional syndrome, hallucinosis, affective syndromes, anxiety, obsessive-compulsive syndromes,
but also ‘neurasthenia’ (this term may in the English literature embrace such terms like fatigue and incapacity syndrome), or solely minor cognitive disturbances. Chronic
organic psychosyndromes were by G. Huber according to
Kurt Schneider staged into three severity levels, i.e. pseudoneurasthenia (mild), organic personality disorder (medium),
and dementia (severe). This staging is also not internationally accepted but in my view a very useful clinical categorization, because giving an evaluated information about the
strength of causality or relevance of the respective organic
factor for the observed respective psychopathology. This
classification holds as a special subgroup also for infectious
and inflammatory (autoimmune, toxic, post-traumatic, accompanying) psychosyndromes. Note: The terminologies are
often confusing when comparing various sources including
certain terms of psychopathology which cannot be outlined
here in detail. For example functional psychoses according to
G. Huber is a clearly organic syndrome whereas functional
syndromes according to Fish’s clinical psychopathology [4],
means psychogenic syndromes in the old triadic system.
2. THE UNSPECIFICITY OF ORGANIC PSYCHOSYNDROMES
But why is the clinical assessment and causal inference
of organic psychosyndromes that difficult? The major reason
seems the general unspecificity of psychopathological syndromes associated with organic brain dysfunction, the type
of psychopathology being widely irrespective of the underlying specific causality factor. All known etiologies of psychiatric disorders including genetic ones are generally nonspecific [5], i.e. any known specific single etiology can induce a rather similar range of psychiatric syndromes or
symptoms, so that on a cross sectional time point of disease
the respective syndrome or symptom cannot be specified
from the symptom level, though in the severe stages an organic syndrome can be clearly assessed. In lower degree
organic psychosyndromes even this primary categorization
of ‘organic’ is tentative. Nevertheless, with increasing severity of an organic process over time more and more characteristic symptoms may evolve in the diseased, eventually leading to some ‘relative’ specificity as termed in G. Huber’s
textbook and finally to ‘organic’ level of symptoms, the
latter even on an exclusive psychopathological level then
clearly to be categorized as ‘organic’.
The traded dichotomy between organic and functional
disorders and a third category of psychogenic disorders
Karl Bechter
(=triadic system) appeared outdated [6]. A problem however
remained in the present international diagnostic classification, that is the lack to try to differentiate between etiology
and pathogenesis, and to neglecting psychogenesis as a third
possibility or as interacting factors [7], and widely neglecting
the general interdependence between psychological and
organic factors in psychopathology [8]. So in conclusion, the
problem of a clear categorization of organic psychosyndromes seems not solved yet. For years it was proposed to
improve etiological research by including specific biological
markers into the diagnostic categorization itself [5, 7, 9].
These approaches remained preliminary. For example in the
psychoimmunology field despite a wealth of interesting
findings clearly supporting a role of low level neuroinflammation in the causation of some severe psychiatric disorders
[10], there is a lack of accepted parameters and criteria to
define the role of neuroinflammation in psychiatric disorders. But this is the case in general for organic psychosyndromes at least for the majority of the less severe, i.e. second-rank organic psychosyndromes including pseudoneurasthenia and organic personality disorder. So, in these
cases representing a broad range and a relevant quantity of
organic psychosyndromes, causality inference is to a large
part left to the experienced clinician by traded rules [11].
Apparently the diagnostic crisis in psychiatry and the limited
construct validity of DSM-IV and ICD-10 [12] may only
step by step be overcome in forthcoming versions of the
international diagnostic classification systems.
The acute exogenous reaction type (AERT) described by
Bonhoeffer [13] represents a similar pattern of symptoms
related to various organic insults to the brain typically associated with disturbances of consciousness. The recently described mixed type encephalopathies (MTE) are very similar
to the AERT [14]. The MTE represents a definite organic
brain syndrome (delirium), primary diagnosis based on clinical observations, the psychopathology including disturbed
consciousness (in most of the time present), and on medical
findings. Nevertheless, even with modern technologies it
remains very difficult to objectify the diagnosis, which may
remain not rarely based exclusively on the observed psychopathological symptoms and causality inferred by time course
to some medical problem or factor found in parallel [14].
The underlying causes of MTE are various. This raises the
question why psychopathological syndromes are that similar
and why organic psychosyndromes are a generally unspecific
consequence of organic brain dysfunction. The complexity
of the brain itself with extended redundancies of so many
functional systems and distributed networks, known from a
wealth of neuroscience findings, can apparently explain. This
complexity is immanent to brain construction, i.e. distributed
networks and redundancy. Redundancy is surely useful from
an evolutionary point of view, e.g. to avoid complete failure
of systems, in the case of dysfunction. But similar dysfunctions may result from insults at various locations [15], and
from differing pathologies often leading to similar symptoms. Nevertheless, to some hotspots more specific symptoms, e.g. well known for motor symptoms, may arise. However, redundancy and wide distribution of functions is especially true for psychic functional networks spanning often
throughout the whole brain. Function in such networks is
distributed therefore widely unspecific psychopathological
Diagnosis of Infectious or Inflammatory Psychosyndromes
The Open Neurology Journal, 2012, Volume 6 115
syndromes arise. With complex investigations into the single
case, some differentiation of dysfunction of networks on a
biological basis can be achieved [16]. Beyond, brain structure and function varies with neurodevelopment, apparently
also changing and determining the type of symptoms observed. Especially early insults into the brain may have enduring consequences depending more from the ages where
an insult occurs than from the specificity of the insult [17],
such may presumably leading to a ‘relative’ specific type of
symptoms. In insightful studies the differentiation of various
organic causal factors for minor organic psychosyndromes in
personality disorders has very preliminary been assessed
[18].
When considering only one certain neurotransmitter
system, for example the serotonergic system in the adult
brain, relative unspecificity is also seen on such a system
level: it was shown that depressive-like behaviour in animals
is counter regulated by the serotonergic cell circuitry in itself, serotonergic cells being located in various brain areas
and interconnected, so that the action of a given serotonergic
compound is very difficult to predict and understand. The
final outcome of pharmacological modulation within the
serotonergic system depends from some internal changes on
the interaction between serotonergic neurons [19]. Systematic approaches to define small localised modular networks
as part of larger networks to more specifically explain psychopathology [20], seem interesting but are just beginning.
In conclusion, the unspecificity of organic psychosyndromes represents a yet unsolved challenge at the symptom
level, which appears to a considerable extent peculiar to the
brain organisation itself. A diagnosis of organic psychosyndromes can be made by combining clinical and technical
approaches to one patient and evaluating all phenomena and
findings in one. This means for the clinical approach to the
patient that diagnosing an organic psychosyndrome will
continue to need both, extraordinary clinical experience and
technical expertise, usually by bringing experts together to
evaluating one patient’s disease to come to valid conclusions. The categorization proposed by G. Huber is especially
important for second-rank organic psychosyndromes. An
underrecognition of second-rank organic psychosyndromes
in the clinical approach may have negative consequences for
the patient.
3. PSYCHOLOGICAL
ACTION
AND
ORGANIC
INTER-
Another important, rather unsolved aspect of causality
inference and categorization of ‘organic’ aspects of psychosyndromes is, that the psychological level of functioning is
apparently in itself able to establish ‘organic’ consequences
or phenomena: this was recently shown in many studies with
functional magnetic resonance imaging (fMRI), but nevertheless long known: the will or the psychological activity can
lead to ‘organic’ consequences, first shown with the
Bereitschaftspotential [21, 22]. Nevertheless it is interesting
to see that some ‘low level organic changes’ within the brain
as demonstrated in a body of evidence for posttraumatic
stress disorder, was shown to be possibly reversed by psychotherapy in somatoform disorder [23]. A recent surprising
demonstration of long-term consequences of psychological
insults was that stressful family environment may lead to
enduring changes in neurodevelopment, cortical thickness
was increased yet in adulthood [24]. Possible psychological
consequences of variant neurodevelopment have also been
shown [18]. Should we then call such changes ‘organic’?
Probably or somehow yes. Nevertheless, there are likely
limitations for such psychological to organic interaction. Of
note is also that organic pathologies of the brain may not
necessarily have any psychopathological consequences.
4. CLINICAL DIAGNOSIS OF NEUROINFLAMMATION
Organic causes of psychosyndromes include the category
of neuroinflammatory disorders. Acute neuroinflammation is
described as encephalitis or meningoencephalitis which may
after four weeks be diagnosed as chronic. A generally accepted time-frame is however not established and may not be
justified regarding the biological mechanisms, which generally differ between acute and chronic neuroinflammation
[25] but not necessarily by defined timeframe.
Classical acute encephalitis or meningoencephalitis is
characterized by typical symptoms including neurological
symptoms, which in initial stages may be minor or just beginning. The clinical examination is completed by technical
findings: imaging is most convenient and nearly always
applied, allowing in part of the cases yet a final diagnosis
though nor specific etiologies can be assessed nor imaging
represent the most sensitive approach [26]. The gold standard, i.e. the most sensitive approach to diagnose meningoencephalitis, remains CSF investigation. Differential diagnosis of encephalitis is rather difficult, many agents and
causes including toxic causes are to be considered. Chronic
neuroinflammation and low level neuroinflammation is more
difficult to assess. To interpret CSF findings, though characteristic in acute meningoencephalitis, less easy in acute encephalitis without meningitis and very difficult in low level
neuroinflammation, needs specific education. With expertise
but which cannot be outlined here relatively safe conclusions
can be made, (compare [27]). Some important principle
might be described, especially that from recent developments
of CSF analysis in clinical neurology, which were adopted to
clinical psychiatry [28]: investigate always paired CSFserum samples taken at one time point from the patient,
allowing to evaluate the dynamics of exchange between the
blood and CSF compartment at specific time point. In both
compartments all immune globulin subclasses should be
investigated and the respective quotients compared to Qalbumin. These CSF/serum quotients with new hyperbolic
functions overcome the previous linear functions or formula
or indexes, the latter not in all conditions exact. A final classification of each case then will be made by involving all
parameters evaluated in one set of CSF/serum findings including cells, an approach helpful to generally reduce false
positive findings. Outliers and errors within one dataset or
implausible laboratory findings are more likely to be identified when seeing all data in one case at once. By such approach, inflammatory versus non-inflammatory CSFs can be
differentiated rather well. A non-inflammatory CSF nevertheless cannot absolutely exclude cases of even an acute
encephalitis. Such has been learned from illustrating clinical
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cases in longstanding experience in clinical neurology. For
the cerebral cortex or the CSF from subarachnoid spaces
above the tentorium, the lumbar CSF investigation may not
be sensitive (compare [27, 29]). This likely relates to the
general CSF flow patterns and CSF recirculation pathways
[30].
In acute encephalitis, the various specific etiologies can
be detected rather sensitively by PCR methods in the first
week of disease, or less sensitive in later stages, by assessing
specific antibody CSF/serum indices (compare [31]). However, a negative PCR finding or a normal specific antibody
index does not exclude a specific etiology [27]. Just to mark
where we stand. Even in large recent studies attempting to
improve the differential diagnosis of acute encephalitis, a bit
less than 50% of cases were clearly classified by etiology
[32]. In meningoencephalitis apparently, yet unknown infectious agents seem to prevail.
In chronic (meningo-)encephalitis the sensitivity of methods including CSF investigation is considerably less clear
and less conclusive. So such a diagnosis may be more arbitrary also for psychosyndromes. For the most relevant bacteria leading to chronic meningoencephalitis, borrelia species,
treponema pallidum, mycobacteria, tuberculosis and listeria
monocytogenes, there are relatively well established signs
and findings. Nevertheless, a major debate is going on about
the sensitivity of the methods in these cases, even when clear
neurological symptoms were present or accompanying
symptoms like severe chronic pain and other symptoms of
chronic meningoencephalitis prevailed. The technical programs, i.e. the approach to the single patient for a safe diagnosis are fluent, but the more a sophisticated knowledge
basis of CSF evaluation is important. For example, a pure
blood-CSF-barrier dysfunction may suggest low level neuroinflammation when other explanations in a clinical framework view appear unlikely (compare [33]). Or the type of the
intrathecal immune class response may be characteristic for
certain diseases like tuberculosis or neuroborreliosis. So by
combining various parameters and including case history and
findings, a more and more specific conclusion in the single
case can be drawn. For neuroborreliosis a characteristic data
pattern is a dominant IgM class intrathecal immune response
combined with blood-CSF-barrier dysfunction increased cell
count and normal lactate (compare [34]). Other unspecific
chemokine or cytokine findings were just reported as characteristics [35]. Other unspecific parameters are useful in other
diseases (compare [27]).
Such laboratory aspects can however the least well be
approved in research on organic psychosyndromes associated with neuroinflammation, because many cases may show
only low level neuroinflammation and because of the general
unspecificity of symptoms described above. Nevertheless, in
severe neuroinflammation often first-rank organic symptoms
may present as part of the syndrome some time. However,
pure psychopathological syndromes without neurological
symptoms or other types of second-rank organic psychosyndromes (see above), is much more difficult to diagnose as
organic or inflammatory. Thus, it is important to adopt the
most advanced methods known in neurological syndromes,
and to include interdisciplinary knowledge about the approach to neuroinflammation into conclusions regarding
Karl Bechter
inflammatory or infectious organic psychosyndromes. When
combining clinical findings and technical findings and
evaluating even borderline aberrations of these measures
with respect to time course of psychopathology, one may
come to plausibility conclusions, then important for therapeutic approaches.
5. SPECIAL CASE: THE MILD ENCEPHALITIS (ME)
HYPOTHESIS
A major part of severe psychiatric disorders, the previously so-called endogenous or idiopathic psychosis may and
seems to be related to some underlying organic basis according to the opinion of many psychiatric researchers. Nevertheless, it remained very difficult to pinpoint such underlying
causes. Immune abnormalities and insults from various infectious agents have been proposed to be involved, eventually low level neuroinflammation seems to explain a considerable subgroup of cases with severe psychiatric disorders
from the affective and the schizophrenic type [10]. Therapeutic approaches in therapy-resistant cases with depression
or schizophrenia are beginning, although no diagnostic parameters were approved up to now. In own studies we recently found in more than 40% of cases with affective or
schizophrenic disorders certain CSF abnormalities best interpreted as indicating low level neuroinflammation, thus
supporting the ME hypothesis in a considerable subgroup of
cases [33]. This was complemented by finding abnormal
activation patterns of CSF cells, despite normal CSF cell
numbers, in part of these cases [36]. Abnormal CSF rather
strongly indicates some abnormality within the brain. One
can rather firmly assume that in patients with low level inflammatory CSF and prevailing psychosis, the patient may
suffer from a low level neuroinflammatory disease i.e.,
neuroinflammation to represent the cause or pathogenetic
basis of the respective psychiatric disorder. The unspecificity
rule outlined above, should especially in low level neuroinflammation be taken in mind. The ME hypothesis was further supported by recent results from experimental therapeutic studies, with COX2 blockers [37], CSF filtration [38, 39],
and neuroprotective [40-42], as well as immune-suppressive
approaches [43].
6. CSF AND NEUROINFLAMMATION
But what is the role of CSF in neuroinflammation? According to recent neuroimmunological insights, the CSF
spaces probably represent a previously underestimated interface between periphery and CNS, playing an important role
in immune surveillance in health and disease [44]. This recent interpretation is backed by the longstanding clinical
experience in neurology where apparently the CSF spaces
are of extraordinary importance for diagnosis of neuroinflammation. According to recent studies in the initial phase
of neuroinflammation, for example in experimental allergic
encephalomyelitis, inflammation begins at the meninges, i.e.
close to or within the subarachnoid spaces and CSF [45].
What happens during neuroinflammation within the brain
during various infections is also increasingly studied in detail. The mechanisms are surprisingly complex, differing in
Diagnosis of Infectious or Inflammatory Psychosyndromes
The Open Neurology Journal, 2012, Volume 6 117
between various infections in remarkable aspects, and surely
these mechanisms not always do fulfil the classical definition
of inflammation [46]. Modern definitions of inflammation in
general are beyond previous classical inflammation involving a complex set of soluble and cellular factors [47]. Different types of low level neuroinflammation have been mentioned, however, criteria to differentiate low level from classic neuroinflammation are not available, though proposals
were made. For example, in experiments the consequences
of toxic insults within the CNS are called inflammatory but
clearly not covered by classical definitions of neuroinflammation [48]. The basis for the clinical term ‘mild encephalitis’ and the ME hypothesis (compare [49]) was a multitude
of evidences from clinical and experimental findings that
low level neuroinflammation may prevail though not easily
be diagnosed by available methods in the clinic, but nevertheless may from a body of experimental evidence be able to
induce a variety of psychiatric and neuropsychiatric symptoms, especially a subgroup of affective and schizophrenic
disorders [49]. Such view appears increasingly supported
now [10].
questions. CSF investigation seems a key to better understand neuroinflammation, especially in the clinical approach.
7. OUTLOOK
[6]
The concepts in immunology, also with respect to neuroimmunology are in rapid progress. For example, the role of
the blood-brain-barrier [50], and the function of the bloodCSF-barrier [51, 52], are newly understood. This bears important consequences for the understanding of neuroinflammation in general. The role of meningeal vessels in early
neuroinflammation was only recently understood and with
this the role of the CSF spaces. A poorly investigated aspect
is however that of CSF signalling and recirculation. CSF
signalling and flow characteristics could play an important
role in the pathophysiology of neuropsychiatric diseases
including neurodegeneration [53]. CSF signalling however
may not only be involved in the pathogenesis of symptoms
by involving all CNS structures lying within the subarachnoid spaces, or close to the subarachnoid spaces, but may
even induce peripheral symptoms via the peripheral cerebrospinal fluid outflow pathways (PCOP), for example possibly
involved in polyneuropathy or dysautonomia or muscle lesions found in psychiatric disorders [30]. A number of
poorly explained clinical symptoms such as diffuse pain in
depression or in fibromyalgia, or similar but more severe
symptoms in classical acute meningoencephalitis may be
explained by such an interaction between pathological CSF
contents and nerve roots, and in addition with brain nerves
and peripheral nerves along the PCOP. The physiological
cell trafficking into the CSF spaces [54-56] is apparently
important in health and disease [44].In contrast, CSF trafficking out of the CSF spaces is not well studied yet. This
may be a considerable gap of knowledge also for pathophysiology. Recently we were able to demonstrate for the
first time in a rare single case that leukaemia cells apparently
followed the PCOP and induced local infiltrations of nerves
and skin [57]. In conclusion, neuroinflammation and especially low level neuroinflammation bears many unsolved
CONFLICT OF INTEREST
The authors confirm that this article content has no conflicts of interest.
ACKNOWLEDGEMENTS
Declared none.
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© Karl Bechter; Licensee Bentham Open.
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