Clinical Signs for Identifying Autoimmune Encephalitis in Psychiatric Patients

Autoimmune mechanisms causing diverse psychiatric symptoms are increasingly recognized and brought about a paradigm shift in neuropsychiatry. Identification of underlying antibodies against neuronal ion channels or receptors led to the speculation that a number of patients go misdiagnosed with a primary psychiatric disease. However, there is no clear consensus which clinical signs in psychiatric patients should prompt further investigations including measurement of anti-neuronal autoantibodies. We therefore aimed to analyze the presenting symptoms in patients with autoimmune encephalitis and the time between symptom onset and initiation of antibody diagnostics. For this, we recruited 100 patients from the Charité Center for Autoimmune Encephalitis between May and October 2016, including all types of autoimmune encephalitides. Psychiatric abnormalities were the most common clinical symptoms and were the presenting sign in 60%. One-third of patients were initially hospitalized in a psychiatric ward. All patients positive for antibodies against the N-methyl-d-aspartate receptor showed behavioral changes, hallucinations, memory deficits, catatonia, or delusions. Patients positive for antibodies against other cell surface or intracellular antigens were often hospitalized with a psychosomatic diagnosis. The time between occurrence of first symptoms and antibody testing was often alarmingly prolonged. In patients with symptom onset between 2013 and 2016, the mean delay was 74 days, in cases diagnosed between 2007 and 2012 even 483 days, suggesting though that increased awareness of this novel disease group helped to expedite proper diagnosis and treatment. By analyzing the medical records in detail, we identified clinical signs that may help to assist in earlier diagnosis, including seizures, catatonia, autonomic instability, or hyperkinesia. Indeed, reanalyzing the whole cohort using these “red flags” led to a 58% reduction of time between symptom onset and diagnosis. We conclude that the timely diagnosis of an autoimmune psychiatric disease can be facilitated by use of the described clinical warning signs, likely enabling earlier immunotherapy and better prognosis. Also, the threshold for cerebrospinal fluid analysis and autoantibody testing should be low

Human gestational N‐methyl‐d‐aspartate receptor autoantibodies impair neonatal murine brain function

Objective: Maternal autoantibodies are a risk factor for impaired brain development in offspring. Antibodies (ABs) against the NR1 (GluN1) subunit of the N-methyl-d-aspartate receptor (NMDAR) are among the most frequently diagnosed anti-neuronal surface ABs, yet little is known about effects on fetal development during pregnancy. Methods: We established a murine model of in utero exposure to human recombinant NR1 and isotype-matched nonreactive control ABs. Pregnant C57BL/6J mice were intraperitoneally injected on embryonic days 13 and 17 each with 240μg of human monoclonal ABs. Offspring were investigated for acute and chronic effects on NMDAR function, brain development, and behavior. Results: Transferred NR1 ABs enriched in the fetus and bound to synaptic structures in the fetal brain. Density of NMDAR was considerably reduced (up to -49.2%) and electrophysiological properties were altered, reflected by decreased amplitudes of spontaneous excitatory postsynaptic currents in young neonates (-34.4%). NR1 AB-treated animals displayed increased early postnatal mortality (+27.2%), impaired neurodevelopmental reflexes, altered blood pH, and reduced bodyweight. During adolescence and adulthood, animals showed hyperactivity (+27.8% median activity over 14 days), lower anxiety, and impaired sensorimotor gating. NR1 ABs caused long-lasting neuropathological effects also in aged mice (10 months), such as reduced volumes of cerebellum, midbrain, and brainstem. Interpretation: The data collectively support a model in which asymptomatic mothers can harbor low-level pathogenic human NR1 ABs that are diaplacentally transferred, causing neurotoxic effects on neonatal development. Thus, AB-mediated network changes may represent a potentially treatable neurodevelopmental congenital brain disorder contributing to lifelong neuropsychiatric morbidity in affected children

Earth Virtualization Engines (EVE)

To manage Earth in the Anthropocene, new tools, new institutions, and new forms of international cooperation will be required. Earth Virtualization Engines is proposed as an international federation of centers of excellence to empower all people to respond to the immense and urgent challenges posed by climate change

Earth Virtualization Engines (EVE)

To manage Earth in the Anthropocene, new tools, new institutions, and new forms of international cooperation will be required. Earth Virtualization Engines is proposed as an international federation of centers of excellence to empower all people to respond to the immense and urgent challenges posed by climate change

Das HKÜ-Verfahren. Die Rolle des Jugendamts in Verfahren internationaler Kindesentführungen in Deutschland

Diese Arbeit kann in der Bereichsbibliothek Hüfferstiftung (Sozialwesen) eingesehen werden

The microbiome and the role of antineuronal autoantibodies as risk factors for neuropsychiatric symptoms

Autoimmune Enzephalitiden gewinnen in der Neuropsychiatrie zunehmend an Bedeutung. Dennoch sind antineuronale Antikörper nicht ausreichend im differenzialdiagnostischen Denken innerhalb des klinischen Alltags berücksichtigt. In wie weit sie einen Risikofaktor für die Entstehung neuropsychiatrischer Symptome darstellen und solche eventuell sogar bei Kindern durch den Einfluss auf die fetale Hirnentwicklung in der Schwangerschaft auslösen, soll in dieser Dissertation beleuchtet werden. Außerdem soll untersucht werden, ob eine spezifische Mikrobiom-Zusammensetzung einen Risikofaktor für die Entstehung eben dieser antineuronaler Antikörper darstellt. Im Zentrum dieser Arbeit stehen daher drei Studienansätze. In einer retrospektiven Kohortenstudie mit N=100 PatientInnen mit verschiedenen Formen einer autoimmunen Enzephalitis stellten antineuronale Antikörper einen Risikofaktor für die Entwicklung neuropsychiatrischer Symptome dar. Zwei Drittel aller Patienten (N=60, 60%) wiesen psychiatrische Auffälligkeiten auf und ein erheblicher Anteil (N=31, 31%) wurde initial psychiatrisch hospitalisiert. Es wurden Symptome und klinische Hinweise identifiziert, die bei psychotischer Symptomatik als Warnhinweise für das zu Grunde liegende autoimmune Geschehen dienen können. Mit der Etablierung dieser „red“ und „yellow flags“ konnte bei einer Patientengruppe hypothetisch eine Reduktion der Zeit bis zur Diagnosestellung von 74 auf 31 Tage (um 58%) erzielt werden. Um herauszufinden, ob antineuronale Antikörper ebenfalls einen Risikofaktor für die Entwicklung neuropsychiatrischer Symptome bei Kindern via diaplazentarer Übertragung in der Schwangerschaft darstellen, wurden in einer prospektiven randomisierten kontrollierten Studie Seren N= 120 gesunder Mütter von Kindern mit psychiatrischen Erkrankungen auf das Vorhandensein von antineuronalen Antikörpern getestet. Dieser Studienansatz war Teil einer grundlagenwissenschaftlichen Arbeit, gemäß der antineuronale Antikörper die fetale Hirnentwicklung in der Schwangerschaft beeinflussen können. Durch die Übertragung von monoklonalen humanen NMDAR-Antikörpern auf schwangere Mäuse konnten beim Nachwuchs verschiedene neuropsychiatrische Symptome ausgelöst werden. Passend dazu ließen sich in den Seren von Müttern mit psychisch erkrankten Kindern leicht erhöhte NR1-IgG-Titer finden. Im dritten Studienansatz wurden in einer retrospektiven Fall-Kontroll Studie Stuhlproben von N=28 PatientInnen mit NMDA-Rezeptor Enzephalitis mittels 16S rDNA Sequenzierung analysiert. Dass eine veränderte Mikrobiom-Zusammensetzung in einem Zusammenhang zum Auftreten der NR1-Antikörper stehen könnte, konnte nicht belegt werden. Die Zusammensetzung des Mikrobioms von Patienten war vergleichbar mit gesunden Kontrollen. Schlussfolgernd könnten antineuronale Antikörper sowohl einen Risikofaktor für die Entwicklung neuropsychiatrischer Symptome bei Erwachsenen als auch für die kindliche Hirnentwicklung in der Schwangerschaft darstellen. Ob neuropsychiatrische Erkrankungen wie ADHS oder Schizophrenie dadurch beeinflusst werden, sollte mittels weiterer Studien umfassender erforscht werden. Um eine Verbesserung der Früherkennung autoimmuner Enzephalitiden zu erreichen, könnten die erarbeiteten klinischen Warnzeichen einer AIE („red und yellow flags“) hilfreich sein.Autoimmune encephalitis is becoming increasingly important in neuropsychiatry. Nevertheless, antineuronal antibodies are not sufficiently taken into account in the differential diagnostic thinking within everyday clinical practice. This dissertation will examine the extent to which they represent a risk factor for the development of neuropsychiatric symptoms and possibly even trigger them in children through their influence on fetal brain development during pregnancy. In addition, it will investigate whether a specific microbiome composition represents a risk factor for the development of antineuronal antibodies. The focus of this work is therefore on three study approaches. In a retrospective cohort study with N = 100 patients with various forms of autoimmune encephalitis, antineuronal antibodies were a risk factor for the development of neuropsychiatric symptoms. Two thirds of all patients (N = 60, 60%) exhibited psychiatric abnormalities and a significant proportion (N = 31, 31%) were initially hospitalized for psychiatry. Symptoms and clinical indications were identified which, in the case of psychotic symptoms, can raise suspicion for the underlying autoimmune events. With the establishment of these “red” and “yellow flags”, it was possible to hypothetically reduce the time to diagnosis from 74 to 31 days (by 58%) in one patient group. To find out whether antineuronal antibodies also represent a risk factor for the development of neuropsychiatric symptoms in children via diaplacental transmission during pregnancy, sera from 120 healthy mothers of children with psychiatric disorders were tested for the presence of antineuronal antibodies in a prospective randomized controlled trial. This study approach was part of a basic scientific work according to which antineuronal antibodies can influence fetal brain development during pregnancy. By transferring monoclonal human NMDAR antibodies to pregnant mice, various neuropsychiatric symptoms could be triggered in the offspring. In line with this, slightly increased NR1 IgG titers were found in the sera of mothers with mentally ill children. In the third study approach, stool samples from N = 28 patients with NMDA receptor encephalitis were analyzed using 16S rDNA sequencing in a retrospective case-control study. It could not be proven that an altered microbiome composition could be asscoiated with the development of the NR1 antibodies. The composition of the patient’s microbiome was comparable to that of healthy controls. In conclusion, antineuronal antibodies could represent a risk factor for the development of neuropsychiatric symptoms in adults as well as for brain development in children during pregnancy. Whether neuropsychiatric diseases such as ADHD or schizophrenia are influenced by this should be researched more comprehensively through further studies. In order to improve the early detection of autoimmune encephalitis, the developed clinical warning signs of an AIE (“red and yellow flags”) could be helpful