[Schizophrenia--a mild encephalitis?]. / Schizophrenie--eine milde Enzephalitis?

The mild encephalitis (ME) hypothesis describes a subgroup of severe psychiatric disorders, with a focus on a subgroup of schizophrenias, in which low-level neuroinflammation (LLNI) represents the core in pathogenesis. LLNI is increasingly recognised in experimental neuroimmunology and is in principle able to explain various types of psychopathology. Epidemiology and course of schizophrenia are well compatible with the ME hypothesis, indirectly indicating that the ME subgroup may be rather large. With the ME model connected is a set of three contributing factors: genes, environment (especially infectious agents) and the immune system. The type of psychopathology observed in the individual case may heavily depend upon other conditions, e. g. pre-existing vulnerabilities. The first large-scale epidemiological study in psychiatry identified two factors during lifetime, severe infectious diseases and autoimmune diseases, as risk factors. This and clinical findings more and more support the ME hypothesis, e. g., activated monocytes or proteome changes in blood and slight CSF pathologies in more than 60 % of therapy-resistant schizophrenia, or activated microglia and dysconnectivity in neuroimaging.

Updating the mild encephalitis hypothesis of schizophrenia.

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.

Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: identification of subgroups with immune responses and blood-CSF barrier dysfunction.

Immune and inflammatory mechanisms are detected in a subgroup of treatment resistant hospitalized affective and schizophrenic spectrum disorder patients. We analysed albumin, IgG, IgA, IgM, oligoclonal IgG and specific antibodies in paired cerebrospinal fluid (CSF) and serum samples. Numerical and graphical interpretation of CSF protein data was performed by Reibergrams with a new CSF statistics tool for nonlinear group analysis with reference to a large control group (n=4100). In 41% of the psychiatric patients (n=63) we observed CSF pathologies: 14% displayed intrathecal humoral immune responses, 10% slightly increased CSF cell counts (5-8/microL) and 29% had moderate blood-CSF barrier dysfunctions, in 24% as the only pathological sign with normal IgG, IgA and IgM concentrations in CSF (p=0.9 testing the null hypothesis for intrathecal synthesis with reference to Qmean of the reference group). In the group of affective (n=24) spectrum disorders 20% displayed a systemic immune reaction as detected by oligoclonal IgG. CSF analysis and interdisciplinary clinical approach revealed 6% of psychiatric patients likely to represent a virusspecific, bacterial or autoimmune associated disorder with CNS involvement. Elevated CSF neopterin concentration in 34% of the patients was interpreted as an increased release from astrocytes or from other glia cells. The low level immune response and barrier dysfunctions are discussed on the base of a mild encephalitis pathomechanism in subgroups of psychiatric patients. CSF analysis is shown to be a useful diagnostic tool for differential diagnosis in psychiatric diseases.

Cerebrospinal fluid analysis for diagnosis of noninflammatory, dementive and psychiatric diseases.

CSF analysis contributes to differential diagnosis of noninflammatory diseases by: 1) exclusion of a chronic or acute inflammation. 2) detection of particular brain-derived proteins, surrogate markers, corresponding to the suggested diagnosis (tumor, dementia, brain hypoxia, hemorrhage, autoimmune disease, psychiatric disease, metabolic disorder, rhinorhea, Table 1) and 3. differential cell count in CSF. Interpretation of brain-derived proteins in CSF uses absolute concentrations (in contrast to CSF/serum quotients for blood-derived proteins) and must discriminate between different sources: Neuronal or glial proteins like NSE, or tau protein are evaluated using their absolute concentrations in CSF for maximal sensitivity without reference to QAlb. The leptomeningeal proteins like beta trace or cystatin C are evaluated as absolute concentrations with reference to QAlb. As application examples we review the group of dementive and psychiatric diseases. Alzheimer's disease, Parkinson's disease dementia, Lewy-body disease and frontotemporal dementia are the major causes of neurodegenerative memory impairment and dementia. Combined analysis of Tau-Protein and Beta Amyloid 1-42 in CSF represent the classic approach, meanwhile extended with further surrogate markers. In 15% of psychiatric patients with schizophrenic or affective disorders an inflammatory process could be detected which points to a brain-organic involvement. In 24% of these patients with a psychiatric disease a moderately increased albumin quotient was observed as the only unexplained pathological sign. In psychiatric diseases it has to be regarded as a serious deficit not to make at least once a CSF analysis in the patients which could modify the diagnosis (in 6%).

[Therapy-resistant depression with fatigue. A case of presumed streptococcal-associated autoimmune disorder]. / Therapieresistente Depression mit Fatigue. Fall einer vermutlichen streptokokkenassoziierten Autoimmunkrankheit.

After a tick bite and erythema chronicum migrans, a 31-year-old patient developed headaches, fatigue, multilocular pain and therapy-resistant depression with cognitive disturbances. Antibodies against Borrelia and Borna disease virus, high antibody titers against streptococci at the point of most severe depression and blood-CSF barrier dysfunction were found. Streptococcal antibody titers were normal 2 years before and 4 years after. With penicillin treatment and tonsillectomy, therapy-resistant depression improved. We suggest that the whole syndrome was streptococcal-associated autoimmune disease.

Low avidity of human serum antibodies for Borna disease virus antigens questions their diagnostic value.

Borna disease virus (BDV) can induce neurological disease in animals. Since viral nucleic acid, infectious particles and antibodies recognizing BDV antigens were found at higher frequencies in psychiatric patients than in healthy controls, BDV is suspected to cause psychiatric disorders in humans. However, the human origin of these viruses has recently been questioned. To diagnose BDV infections, sera are usually analyzed for antiviral antibodies by indirect immunofluorescence (IFA) on virus-infected cells. This study reveals that the reactive antibodies in human sera mainly recognized the BDV phosphoprotein, whereas animal sera preferentially detected the viral nucleoprotein. Immunoglobulin (Ig) G in sera of experimentally or naturally infected animals bound to the viral antigen with high avidity, ie resisting 3 M urea, whereas reactive IgG in human sera did not. Longitudinal studies showed that reactive human antibodies persisted for many years without gaining high avidity for BDV antigens, indicating that they were probably not induced by BDV but rather by infection with an antigenically related microorganism of unknown identity or by exposure to other related immunogens.

Borna disease virus infection in animals and humans.

The geographic distribution and host range of Borna disease (BD), a fatal neurologic disease of horses and sheep, are larger than previously thought. The etiologic agent, Borna disease virus (BDV), has been identified as an enveloped nonsegmented negative-strand RNA virus with unique properties of replication. Data indicate a high degree of genetic stability of BDV in its natural host, the horse. Studies in the Lewis rat have shown that BDV replication does not directly influence vital functions; rather, the disease is caused by a virus-induced T-cell mediated immune reaction. Because antibodies reactive with BDV have been found in the sera of patients with neuropsychiatric disorders, this review examines the possible link between BDV and such disorders. Seroepidemiologic and cerebrospinal fluid investigations of psychiatric patients suggest a causal role of BDV infection in human psychiatric disorders. In diagnostically unselected psychiatric patients, the distribution of psychiatric disorders was found to be similar in BDV seropositive and seronegative patients. In addition, BDV-seropositive neurologic patients became ill with lymphocytic meningoencephalitis. In contrast to others, we found no evidence is reported for BDV RNA, BDV antigens, or infectious B DV in peripheral blood cells of psychiatric patients.

[Pathogenicity of Borna disease virus in psychiatric and neurologic disorders of humans. Current status of research and critical comments]. / Zur Pathogenität von Borna-disease-Virus für psychiatrische und neurologische Störungen beim Menschen. Derzeitiger Forschungsstand und kritischer Kommentar.

Demonstration of BDV-specific serum antibodies, the isolation of BDV from cerebrospinal fluid of neuropsychiatric patients, and the recent demonstration of BDV antigen and BDV-RNA in human brain tissues strongly suggest that BDV can infect humans. Isolation of BD virus from brain tissue is needed for final proof. There is still great controversy about the question of whether BDV antigen, BDV-RNA or BDV can be detected in peripheral blood monocytes or not. Overall, the question of pathogenicity of BDV infection for humans is wide open. Investigations of human cerebrospinal fluid indicate that BDV might cause human lymphocytic meningoencephalitis and so-called symptomatic psychoses in rare cases. Seroepidemiological studies suggest a widely non-specific but possibly pathogenic role of BDV in a spectrum of psychiatric disorders.

Failure to detect Borna disease virus infection in peripheral blood leukocytes from humans with psychiatric disorders.

The presence of antibodies reactive with Borna disease virus (BDV) in the sera of some patients with certain psychiatric illnesses has been taken as evidence that this veterinary neurotrophic virus may occasionally infect and cause psychiatric disorders in humans. In this paper, we report the results of our studies concerning the detection of BDV-specific RNA in blood cells from patients with psychiatric diseases. Contrary to the results obtained by others, we have found no evidence for the presence of BDV-RNA in such cells. Prior work with BDV sequences in the assay environment, together with the exquisite sensitivity of RT-PCR, may account for the sporadic appearance of false positive evidence that BDV-specific RNA is present in human blood cells.

Molecular characterization of Borna disease virus from naturally infected animals and possible links to human disorders.

In this review data are presented which indicate a high degree of genetic stability of BDV in his natural host, the horse. Despite this high degree of sequence conservation, variation in antigenicity was found, which did not influence the pathogenic properties of the virus. In addition, the correlation between BDV-seropositivity and a variety of psychiatric and neurological disorders in humans is discussed. In diagnostically unselected psychiatric patients we found a similar distribution of psychiatric disorders in BDV seropositives compared to seronegatives. Investigations of cerebrospinal fluid revealed cases of BDV encephalitis in BDV seropositive psychiatric and neurological patients. In contrast to others, we have found no evidence for the presence of BDV-RNA or BDV in human peripheral blood leucocytes.

Research strategies in 'slow' infections in psychiatry.

The research processes in the elucidation of the causes of general paresis, the first slow infection in psychiatry, and of Kuru, the first slow virus infection in man, were considered. The errors and difficulties encountered may contribute to the formulation of research strategies for contemporary work on possible persistent infections with unknown viruses as a cause of psychiatric disorders. Clinical obsservation, bold hypotheses and methodological advances appear more valuable than diagnostic categorization in etiological research into psychiatric disorders. The low heuristic value of diagnosis is due to the lack of specificity of psychiatric symptoms and syndromes, especially in low grade organic disturbances.

Investigations of cerebrospinal fluid in Borna disease virus seropositive psychiatric patients.

Borna disease virus (BDV) appears to cause meningoencephalitis and schizophreniform psychosis in sporadic cases according to earlier cerebrospinal fluid (CSF) inoculation experiments (Rott et al, 1991). However, CSF parameters in BDV seropositive psychiatric patients proved nearly all normal; only the most sensitive CSF/serum index I-BDV for intrathecally produced BDV specific IgG was pathologic in 10.5-29.0% (according to different methodological limits) of patients. An increase in sensitivity was attempted to detect specific IgG in CSF in a part of the cases by concentration. Concentration procedure does not significantly increase methodological bias according to a statistical analysis of the results. Our findings support the hypothesis that BDV may cause or contribute to the pathogenesis of a diagnostically broad pattern of psychiatric syndromes. The occurence of a spectrum of diagnoses is expected from non-specificity of psychiatric symptoms in other infectious diseases of the brain as well as from results in experimental Borna disease (BD) in animals, when a majority of the animals showed rather unspecific symptomatology due to slight, preferentially limbic encephalitis. Slight deficiencies from an earlier BDV infection could explain continuing symptoms in a part of the cases. Recurrences years after infection are well known in experimental and natural BD in animals. It remains open, whether this mechanism could play a more prominent role in a form of "symptomatic" cyclothymia and "symptomatic" schizophrenia, although the results of CSF investigations are more clear in BDV seropositive patients with major psychoses.

[Is there a special indication for fluphenazine in therapy refractory hallucinations?]. / Gibt es eine spezielle Indikation für Fluphenazin bei therapieresistenten Halluzinationen?

On one of our rehabilitation wards, we observed several schizophrenic patients with therapy resistant hallucinations to exhibit complete recovery after being given fluphenazine (2-7.5 mg a day, orally); previously, they were found to be therapy resistant on other potent neuroleptics, including clozapine. It appears that in selected patients fluphenazine has a special antihallucinatory effect.

[Expanded nuclear magnetic resonance studies in Borna disease virus seropositive psychiatric patients and control probands]. / Erweiterte kernspintomographische Untersuchungen bei Borna-disease-Virus -seropositiven psychiatrischen Patienten und Kontrollen.

There is growing evidence, that Borna Disease virus (BDV) or a variant may cause neuropsychiatric disorders in humans. The presence of specific BDV serum antibodies indicates an earlier contact with BDV. Earlier MRI results showing a raised prevalence of white matter lesions in BDV-seropositive psychiatric patients, possibly indicating encephalitic lesions, are not confirmed in this extended study, however in BDV-seropositive psychiatric patients the occurrence of cerebral atrophy seems to be more frequent, a finding compatible with hydrocephalus e vacuo found in animals after BDV-encephalitis. Because encephalitic lesions in BD are predominantly found in the gray matter of the brain, which is hardly visualized by MRI, the failure to detect lesions in BDV-seropositive patients could be due to methodological problems.

[Disordered coping with illness by personal prejudices of patients with schizophrenic psychoses]. / Gestörte Krankheitsverarbeitung durch eigene Vorurteile bei Patienten mit schizophrenen Psychosen.

Negative prejudices against psychiatry and psychiatric patients are a reality today. But prejudices are also existent in the patients self, especially in schizophrenic patients, leading to adverse therapeutic reactions. Prejudices of the patients himself may be a hidden, unconscious problem in some cases of treatment resistance in rehabilitation of schizophrenic patients. Therapeutic strategies are discussed on the basis of case reports.