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Gerd Huber (1921-2012) was an influential West German psychiatrist and neurologist of the postwar period. Especially his studies with imaging techniques on the question of brain atrophy, the long-term course and the basic symptoms of schizophrenic disorders made a significant contribution to the research of schizophrenia and were discussed internationally. The Huber Archive, which was handed over to Bezirkskrankenhaus Günzburg, is currently being catalogued for research purposes. The archive contains Huber's private and professional papers, his writings, and a small partial archive of Kurt Schneider. These archival records not only reflect the development of Gerd Huber's academic career, but also are significant for research on the history of psychiatry in postwar West Germany, the development of concepts in the fields of schizophrenia research and biological psychiatry, the history of universities and everyday life, and other topics.Gerd Huber (1921–2012) war ein bedeutender westdeutscher Psychiater und Neurologe der Nachkriegszeit. Vor allem seine Studien mit bildgebenden Verfahren zur Frage der Hirnatrophie, zum Langzeitverlauf und zu den Basissymptomen der schizophrenen Erkrankungen leisteten einen wesentlichen Beitrag zur Erforschung der Schizophrenie und wurden international diskutiert. Der an das Bezirkskrankenhaus Günzburg übergebene Huber-Nachlass wird aktuell für die Forschung erschlossen. Der Nachlass enthält private und berufliche Unterlagen Hubers, seine Werke sowie einen kleinen Teilnachlass von Kurt Schneider. Diese Archivalien spiegeln nicht nur die Entwicklung der akademischen Laufbahn von Gerd Huber wider, sondern sind bedeutend für die Erforschung der Geschichte der Psychiatrie in der Nachkriegszeit in Westdeutschland, der Entwicklung der Konzepte auf den Gebieten der Schizophrenieforschung und der biologischen Psychiatrie, der Universitäts- und Alltagsgeschichte und anderer Themen.

ZusammenfassungGerd Huber (1921–2012) war ein bedeutender westdeutscher Psychiater und Neurologe der Nachkriegszeit. Vor allem seine Studien mit bildgebenden Verfahren zur Frage der Hirnatrophie, zum Langzeitverlauf und zu den Basissymptomen der schizophrenen Erkrankungen leisteten einen wesentlichen Beitrag zur Erforschung der Schizophrenie und wurden international diskutiert. Der an das Bezirkskrankenhaus Günzburg übergebene Huber-Nachlass wird aktuell für die Forschung erschlossen. Der Nachlass enthält private und berufliche Unterlagen Hubers, seine Werke sowie einen kleinen Teilnachlass von Kurt Schneider. Diese Archivalien spiegeln nicht nur die Entwicklung der akademischen Laufbahn von Gerd Huber wider, sondern sind bedeutend für die Erforschung der Geschichte der Psychiatrie in der Nachkriegszeit in Westdeutschland, der Entwicklung der Konzepte auf den Gebieten der Schizophrenieforschung und der biologischen Psychiatrie, der Universitäts- und Alltagsgeschichte und anderer Themen.

Primary schizophreniform psychoses are thought to be caused by complex gene–environment interactions. Secondary forms are based on a clearly identifiable organic cause, in terms of either an etiological or a relevant pathogenetic factor. The secondary or “symptomatic” forms of psychosis have reentered the focus stimulated by the discovery of autoantibody (Ab)-associated autoimmune encephalitides (AEs), such as anti-NMDA-R encephalitis, which can at least initially mimic variants of primary psychosis. These newly described secondary, immune-mediated schizophreniform psychoses typically present with the acute onset of polymorphic psychotic symptoms. Over the course of the disease, other neurological phenomena, such as epileptic seizures, movement disorders, or reduced levels of consciousness, usually arise. Typical clinical signs for AEs are the acute onset of paranoid hallucinatory symptoms, atypical polymorphic presentation, psychotic episodes in the context of previous AE, and additional neurological and medical symptoms such as catatonia, seizure, dyskinesia, and autonomic instability. Predominant psychotic courses of AEs have also been described casuistically. The term autoimmune psychosis (AP) was recently suggested for these patients. Paraclinical alterations that can be observed in patients with AE/AP are inflammatory cerebrospinal fluid (CSF) pathologies, focal or generalized electroencephalographic slowing or epileptic activity, and/or suspicious “encephalitic” imaging findings. The antibody analyses in these patients include the testing of the most frequently found Abs against cell surface antigens (NMDA-R, CASPR2, LGI1, AMPA-R, GABAB-R), intracellular antigens (Hu, Ri, Yo, CV2/CRMP5, Ma2 [Ta], amphiphysin, GAD65), thyroid antigens (TG, TPO), and antinuclear Abs (ANA). Less frequent antineuronal Abs (e.g., against DPPX, GABAA-R, glycine-R, IgLON5) can be investigated in the second step when first step screening is negative and/or some specific clinical factors prevail. Beyond, tissue-based assays on brain slices of rodents may detect previously unknown antineuronal Abs in some cases. The detection of clinical and/or paraclinical pathologies (e.g., pleocytosis in CSF) in combination with antineuronal Abs and the exclusion of alternative causes may lead to the diagnosis of AE/AP and enable more causal therapeutic immunomodulatory opportunities.

BackgroundAutoimmune encephalitis (AE) is an important consideration during the diagnostic work-up of secondary mental disorders. Indeed, isolated psychiatric syndromes have been described in case reports of patients with underlying AE. Therefore, the authors performed a systematic literature review of published cases with AE that have predominant psychiatric/neurocognitive manifestations. The aim of this paper is to present the clinical characteristics of these patients.MethodsThe authors conducted a systematic Medline search via Ovid, looking for case reports/series of AEs with antineuronal autoantibodies (Abs) against cell surface/intracellular antigens combined with predominant psychiatric/neurocognitive syndromes. The same was done for patients with Hashimoto encephalopathy/SREAT. Only patients with signs of immunological brain involvement or tumors in their diagnostic investigations or improvement under immunomodulatory drugs were included.ResultsWe identified 145 patients with AE mimicking predominant psychiatric/neurocognitive syndromes. Of these cases, 64% were female, and the mean age among all patients was 43.9 (±22.1) years. Most of the patients had Abs against neuronal cell surface antigens (55%), most frequently against the NMDA-receptor (N = 46). Amnestic/dementia-like (39%) and schizophreniform (34%) syndromes were the most frequently reported. Cerebrospinal fluid changes were found in 78%, electroencephalography abnormalities in 61%, and magnetic resonance imaging pathologies in 51% of the patients. Immunomodulatory treatment was performed in 87% of the cases, and 94% of the patients responded to treatment.ConclusionsOur findings indicate that AEs can mimic predominant psychiatric and neurocognitive disorders, such as schizophreniform psychoses or neurodegenerative dementia, and that affected patients can be treated successfully with immunomodulatory drugs.

We congratulate Guasp et al.1 for this study, which includes the complex task of neurologic investigation for patients with psychosis. It is encouraging to see neurologists engaging with this important issue.

Encephalitis has an estimated prevalence of ≤0.01%. Even with extensive diagnostic work-up, an infectious etiology is identified or suspected in Cnp−/− mice lacking the structural myelin protein 2′-3′-cyclic nucleotide 3′-phosphodiesterase (Cnp) with a “cocktail” of NMDAR1 peptides. Cnp−/− mice exhibit early low-grade inflammation of white matter tracts and blood–brain barrier disruption. Our novel mental-time-travel test disclosed that Cnp−/− mice are compromised in what–where–when orientation, but this episodic memory readout was not further deteriorated by NMDAR1-AB. In contrast, comparing wild-type and Cnp−/− mice without/with NMDAR1-AB regarding hippocampal learning/memory and motor balance/coordination revealed distinct stair patterns of behavioral pathology. To elucidate a potential contribution of oligodendroglial NMDAR downregulation to NMDAR1-AB effects, we generated conditional NR1 knockout mice. These mice displayed normal Morris water maze and mental-time-travel, but beam balance performance was similar to immunized Cnp−/−. Immunohistochemistry confirmed neuroinflammation/neurodegeneration in Cnp−/− mice, yet without add-on effect of NMDAR1-AB. To conclude, genetic brain inflammation may explain an encephalitic component underlying autoimmune conditions.

Primar psychotische Storungen aus dem schizophrenen Formenkreis sind nach heutigem Verstandnis Erkrankungen, die durch eine komplexe Interaktion zwischen Genen und Umwelt bedingt sind. Sekundaren psychotischen Storungen liegt eine zumindest mit Wahrscheinlichkeit benennbare organische Ursache im Sinne einer Erstverursachung (Atiologie) oder einer benennbaren Sekundarursache (Pathogenese) zugrunde. In diesem Kontext spielen Autoantikorper(AK)-assoziierte Autoimmunenzephalitiden (AEs) bzw. Autoimmunpsychosen eine zunehmend wichtige Rolle. Innerhalb der Gruppe AK-assoziierter AEs mit neuropsychiatrischer Symptomatik kommt die Anti-N-Methyl-D-Aspartat-Rezeptor-Enzephalitis am haufigsten vor. Psychopathologisch werden bei AEs zu Beginn oft polymorphe psychotische Symptome beobachtet, im Verlauf oder bereits initial treten jedoch meist weitere neurologisch-internistische Phanomene hinzu. Im Rahmen des heterogenen Syndroms einer steroidresponsiven Enzephalopathie mit Schilddrusen-AK (Hashimoto-Enzephalopathie) sind auch klassische psychotische Storungsbilder beschrieben.

A dysfunction of the glutamatergic transmission, especially of the NMDA receptor (NMDAR), constitutes one of the main biological substrate of psychotic disorders, such as schizophrenia. The NMDAR signaling hypofunction, through genetic and/or environmental insults, would cause a neurodevelopmental myriad of molecular, cellular, and network alterations that persist throughout life. Yet, the mechanisms underpinning NMDAR dysfunctions remain elusive. Here, we compared the membrane trafficking of NMDAR in three gold-standard models of schizophrenia, i.e., patient’s cerebrospinal fluids, genetic manipulations of susceptibility genes, and prenatal developmental alterations. Using a combination of single nanoparticle tracking, electrophysiological, biochemical, and behavioral approaches in rodents, we identified that the NMDAR trafficking in hippocampal neurons was consistently altered in all these different models. Artificial manipulations of the NMDAR surface dynamics with competing ligands or antibody-induced receptor cross-link in the developing rat brain were sufficient to regulate the adult acoustic startle reflex and compensate for an early pathological challenge. Collectively, we show that the NMDAR trafficking is markedly altered in all clinically relevant models of psychosis, opening new avenues of therapeutical strategies.

Immunological explanatory approaches are becoming increasingly important in schizophrenia research. In this context, the function of the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCSFB) plays an essential role. Different adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), are key elements in sustaining the integrity of the BBB and BCSFB. The objectives of this study were to (1) compare the levels of different cell adhesion molecules in the CSF of patients with schizophrenia spectrum disorders to those of patients with unipolar depression and (2) analyze their association with the established markers of the BBB/BCSFB function (CSF total protein and albumin quotient (AQ)). Therefore, a total of 40 patients with schizophrenia spectrum disorder and 39 age- and sex-matched control patients with unipolar depression were analyzed. The levels of soluble ICAM-1 (s-ICAM-1), soluble VCAM-1 (s-VCAM-1), and plasminogen activator inhibitor 1 (PAI-1) in the CSF were measured using a magnetic bead multiplexing immunoassay. The levels of sICAM-1 (p &lt, 0.001), sVCAM-1 (p &lt, 0.001), and PAI-1 (p &lt, 0.001) in the CSF were significantly higher in patients with schizophrenia spectrum disorder than in patients with unipolar depression. In addition, a significant correlation of sVCAM-1 levels with total protein concentrations (r = 0.454, p = 0.003) and AQ levels (r = 0.512, p = 0.001) in patients with schizophrenia spectrum disorders was observed. The results revealed that sICAM-1 and sVCAM-1 levels in the CSF were higher in patients with schizophrenia spectrum disorder than in those with depression. These circulating signaling molecules may indicate endothelial dysfunction causing impaired BBB/BCSFB function in patients with schizophrenia spectrum disorders. Consistent with this view, a highly significant correlation of sVCAM-1 with CSF protein and AQs was detected. Upregulation of these cell adhesion molecules might be indicative of a proinflammatory immune response underlying the BBB/BCSFB disturbance in a subgroup of patients with schizophrenia spectrum disorders. The significance of the study is limited by its retrospective research design and by the absence of a healthy control group. The assay used was not previously established for the measurement of CSF. Further translational and controlled studies of the role of different cell adhesion molecules in schizophrenia are needed.

The encephalitis lethargica (EL) epidemic swept the world from 1916 to 1926 and is estimated to have afflicted between 80,000 to one million people. EL is an unusual neurological illness that causes profound sleep disorders, devastating neurological sequalae and, in many cases, death. Though uncommon, EL is still occasionally diagnosed today when a patient presents with an acute or subacute encephalitic illness, where all other known causes of encephalitis have been excluded and criteria for EL are met. However, it is impossible to know whether recent cases of EL-like syndromes result from the same disease that caused the epidemic. After more than 100 years of research into potential pathogen triggers and the role of autoimmune processes, the aetiology of EL remains unknown. The epidemic approximately coincided with the 1918 H1N1 influenza pandemic but the evidence of a causal link is inconclusive. This article reviews the literature on the causes of EL with a focus on autoimmune mechanisms. In light of the current pandemic, we also consider the parallels between the EL epidemic and neurological manifestations of COVID-19. Understanding how pathogens and autoimmune processes can affect the brain may well help us understand the conundrum of EL and, more importantly, will guide the treatment of patients with suspected COVID-19-related neurological disease, as well as prepare us for any future epidemic of a neurological illness.

A historical and personal perspective is presented from research on the involvement of Bornavirus infection into the etiology of neurological and psychiatric disorders and the road to propose the Mild Encephalitis (ME) hypothesis of severe mental disorders, including a supportive role of Pula congresses herein. ME hypothesis was initially criticized by many though yet early on supported by striking results from experimental treatments of severe therapy-resistant schizophrenic and affective syndromes, both types of severe mental disorders responding well to CSF filtration, and later increasingly from CSF studies in psychiatric cohorts. Recent, accumulated findings from internationally performed studies demonstrate an important role of immune-inflammatory abnormalities in large subgroups of severe psychiatric disorders. Beyond, in small subgroup of cases just now first international consensus criteria were established, how to define and treat Autoimmune Psychosis (AP). These AP criteria match with an autoimmune subtype of ME. Such new diagnosis for psychiatry is most relevant in clinical practice as majority of AP/ME cases can be successfully treated with various, rather aggressive, immune-modulatory treatments. Further, ME and AP subtypes are expected to prevail and become described in the future.

Im Kontext der sekundaren, organisch bedingten schizophreniformen Psychosen spielen Autoantikorper (AK)-assoziierte Autoimmunenzephalitiden (AEs) eine zunehmend wichtige Rolle. Bei entsprechendem Verdacht wird eine organische Diagnostik inklusive Labor, MRT, EEG und Liquordiagnostik empfohlen. Die AK-Testung sollte zunachst ein Screening fur die haufigsten assoziierten AK gegen neuronale Oberflachenantigene (NMDA-Rezeptor[R], CASPR2, LGI1, AMPA-R, GABAB-R), intrazellulare Antigene (Hu, Ri, Yo, CV2/CRMP5, Ma2 [Ta], Amphiphysin, GAD65), Schilddrusengewebe (TG, TPO, TRAK) und antinukleare Antigene (ANAs) beinhalten. Die AK gegen Oberflachenantigene und GAD65 sollten direkt im Serum und Liquor untersucht werden. Seltenere AK konnen ggf. im zweiten Schritt erganzt werden. Mittels Immunfluoreszenz-Suchtests auf Hirnschnitten von Nagetieren lassen sich auch bisher unbekannte AK entdecken. Der Nachweis eines AK in Kombination mit pathologischen Zusatzbefunden kann zur Diagnosestellung einer AE fuhren und therapeutische Alternativen mit Immunmodulatoren ermoglichen.

According to present concepts, primary psychotic disorders in the schizophrenia spectrum are probably caused by a complex interaction between multigenetic vulnerability and causally relevant environmental factors. In contrast, secondary psychotic disorders are the result of likely identifiable organic factors either in terms of a first causation (etiology) or a secondary cause (pathogenesis). In this context, autoantibody(ab)-associated autoimmune encephalitis (AE) plays an increasingly important role. Within the group of ab-associated AE with neuropsychiatric symptoms, anti-N-methyl-D-aspartate receptor encephalitis is the most prevalent one. Psychopathologically, polymorphic psychotic symptoms are often observed at onset of AE; however, over the course of this condition or even initially other neuropsychiatric phenomena are also common. The ill-defined entity of a steroid-responsive encephalopathy with thyroid antibodies (Hashimoto's encephalitis) is a heterogeneous syndrome that may also comprise isolated psychotic disorders presenting as classical schizophrenia.

In the context of secondary, possibly organic schizophreniform psychoses, autoantibody(AB)-associated autoimmune encephalitis (AE) plays an increasingly important role. If this is suspected, clinical investigations, including laboratory, magnetic resonance imaging, electroencephalography and cerebrospinal fluid (CSF) analyses are recommended. The AB screening should include the most frequent ABs against neuronal cell surface antigens (NMDA receptor [R], CASPR2, LGI1, AMPA-R, GABAB-R), intracellular antigens (Hu, Ri, Yo, CV2/CRMP5, Ma2[Ta], amphiphysin, GAD65), thyroid tissue (TG, TPO, TRAK), and antinuclear antigens (ANAs). The ABs against cell surface antigens and GAD65 should be examined directly in serum and CSF. Less frequent ABs can be looked for in a second step. Furthermore, immunofluorescence tests on brain slices of rodents may identify previously unknown ABs. The detection of ABs in combination with further findings can lead to the diagnosis of AE which implies new therapeutic opportunities with immunomodulators.

Introduction In today’s psychiatry only a minority of psychiatry inpatients with severe mental illness (SMI) undergo CSF diagnostics. Autoimmune encephalitis and mild encephalitis There is increasing evidence that refined differential diagnosis is advantageous for a subgroup of patients before beginning psychopharmacological treatment. In any clinical case of suspected autoimmune encephalitis or classical encephalitis of any etiology CSF investigation is required. Evidence for the mild encephalitis hypothesis comes from recent CSF studies. Basics of CSF analysis in psychiatric disorders Cytology, protein analysis (albumin, IgG, IgA, IgM) and oligoclonal IgG and lactate. Parallel analysis of the CSF with serum samples and calculation of CSF/serum quotients is base for interpretation of immunoglobulin patterns in Reibergrams, data compilation in cumulative CSF data report for the individual patient. Immune and cytokine findings in SMI Many markers of immune activation/inflammation have been found. The scenario matches with the known triangle in autoimmune disorders: genes, agents, environment. Actual CSF studies in severe mental illness About 79% of therapy resistant cases with affective or schizophrenic spectrum disorders showed low level CSF abnormalities Conclusion There is strong support for the view that CSF analysis should be performed in routine differential diagnosis at the onset of SMI more often than presently done in clinical routine in psychiatric hospitals. Outlook CSF research will gain increasing relevance for psychiatric research. Preliminary definitions/descriptions of ME or mild neuroinflammation can be found, but no consensus definition is available yet.

The Bezirkskrankenhaus (BKH) Gunzburg was founded in 1915 as a state hospital for psychiatry in Bavaria/Germany. The psychiatric state hospitals were typically situated in rural areas outside big cities. In the 1970s a movement of country wide psychiatry reform was going on involving the state hospitals with their large numbers of severely ill psychiatric patients in reform and research projects. By 1977 the Bezirkskrankenhaus Gunzburg represented a center for nervous system disorders involving psychiatry, neurosurgery and neurology departments. The first 25 years of the new Gunzburg psychiatry university department were embedded in a general development in Germany.

Since somatic or somatosensory tinnitus (ST) was first described as a subtype of subjective tinnitus, where altered somatosensory afference from the cervical spine or temporomandibular area causes or changes a patients tinnitus perception, several studies in humans and animals have provided a neurophysiological explanation for this type of tinnitus. Due to a lack of unambiguous clinical tests, many authors and clinicians use their own criteria for diagnosing ST. This resulted in large differences in prevalence figures in different studies and limits the comparison of clinical trials on ST treatment. This study aimed to reach an international consensus on diagnostic criteria for ST among experts, scientists and clinicians using a Delphi survey and face-to-face consensus meeting strategy. Following recommended procedures to gain expert consensus, a two-round Delphi survey was delivered online, followed by an in-person consensus meeting. Experts agreed upon a set of criteria that strongly suggest ST. These criteria comprise items on somatosensory modulation, specific tinnitus characteristics, and symptoms that can accompany the tinnitus. None of these criteria have to be present in every single patient with ST, but in case they are present, they strongly suggest the presence of ST. Because of the international nature of the survey, we expect these criteria to gain wide acceptance in the research field and to serve as a guideline for clinicians across all disciplines. Criteria developed in this consensus paper should now allow further investigation of the extent of somatosensory influence in individual tinnitus patients and tinnitus populations.

This chapter aims to provide an overview of the burgeoning field of psychoneuroimmunology as it relates to psychiatric and neuropsychiatric disorders. It is a relatively young field, having come of age only recently, but the progress that has been made just in the past three decades has exceeded all expectations. It is fair to say that the field has opened up new horizons in our understanding of the complex interrelationships between the immune and nervous systems or as is otherwise referred to as the brain-immune interaction. Hitherto unknown biochemical pathways have been identified, and their complex interactions with neurotransmitters and immune mediators present opportunities for innovative research and identification of new targets for drug development. Biomarkers are being established that hold great promise for more precise diagnostic classification of psychiatric disorders but also understanding of the high comorbidity between specific psychiatric disease entities and a host of medical and neurological diseases. At the same time, immune biomarkers, neurotrophins, and antibodies enable prediction of response and understanding of treatment resistance. Imaging techniques of increasing sophistication hold great promise for visualization of aberrant connectivity and dysfunctional brain circuitry. The goal of practicing personalized psychiatry is now closer to becoming reality than ever before in the history of our specialty. The coauthors of this chapter have each contributed subsections commensurate with their individual expertise.

There is wide variability in how psychiatry guidelines and textbooks address the question of cerebrospinal fluid (CSF) diagnostics in the screening of psychiatric disorders. A United States-based textbook confirms that there is no consensus about which laboratory investigation should be routinely performed in psychiatric patients, but with respect to CSF diagnostics, the differences are even more striking. A survey among European experts showed a wide variety of opinions regarding clinical use and criteria in various countries of Europe and worldwide: some psychiatrists, mostly university hospital-based, recommended performing CSF diagnostics in every patient first experiencing severe mental illness (SMI), but especially in patients from the schizophrenia spectrum, whereas others almost never perform CSF examinations themselves and usually refer patients to neurology departments if necessary. Minor neurologic signs are generally frequent in SMI, mainly in affective and schizophrenic disorders. Even with neurologic signs present, there are no clear guidelines regarding CSF evaluation, leaving doctors with experience-based decision making. However, the field is evolving. A recent review provides helpful yellow and red flags for differential diagnosis of SMI from autoimmune encephalitis; interestingly, minor CSF abnormalities are considered a red flag, suggesting that CSF should be routinely performed in acute psychiatric patients. There are reports of single cases identified as an established neurologic disorder: patients within affective and schizophrenic spectrum disorders systematically underwent CSF examination, and were rediagnosed based on CSF results. This was often to the surprise of the psychiatric doctors. Overall, an increasing number of psychiatrists believe that CSF is too rarely examined in psychiatric patients. This chapter provides an overview of differential diagnostic issues in SMI, particularly for new-onset cases. The general recommendations regarding CSF examination procedures can be found in other chapters of this book. Here we focus on specific aspects of differential diagnosis in SMI. Also, there will be an overview of admittedly limited CSF research efforts in psychiatric disorders, focusing on more recent CSF studies. CSF studies in SMI performed with state-of-the-art methods, for example proteomics or assessments of cytokines, were intriguing but difficult to interpret and required critical considerations regarding respective methodology, an undertaking which is outside the scope of this chapter.

Despite a not insignificant number of anatomical and experimental studies describing the distribution and movement of the cerebrospinal fluid several questions were answered controversially, leaving room for objections and doubts. Some of these controversies I have tried to address by new experiments. Before going on to describe these studies, some short anatomical notes on the membranes that cover the central nervous system may be appropriate. Bichat described the anatomical membranes as follows: in between the fibrous lining of the brain-vertebral cavity, the dura mater and the vascularized coat of the spinal cord (the pia mater) a space covered by a serous skin is interposed, the parietal part of which is integrated with the inner side of the dura mater; and the visceral part in contrast is detachable from the underlying pia mater. The watery fluid of the brain-spinal-cord cavity discovered by Cotugno received more attention by Magendie, who initially placed it [ the fluid ] within the serous space described by Bichat, convincing himself [Magendie] however later, that it [ the fluid ] is present in between the visceral sheet of the arachnoid and the pia mater.

The discovery of the ‘glymphatic’ pathway has shed new light on the cerebrospinal (CSF)–brain interstitial fluid (ISF) exchange process (Iliff et al., 2012). In new anatomically defined terms, the glymphatic pathway now represents a brain-wide pathway where CSF flows through the brain and spinal cord parenchyma and exchanges with ISF from periarterial to perivenous spaces in a route interconnected by aquaporin 4 water channels present on glial cells (Iliff et al., 2012). The new concept of the glymphatic pathway has evolved from the older concept of bulk flow of ISF from brain parenchyma to the ventricular CSF referred to as the “ependymal pathway” (Brightman, 1965a,b). The glymphatic pathway is important for detoxification of the brain (and spinal cord), a cleaning process that appears to be driven by adrenergic tone (Xie et al., 2013), arterial pulsatility (Iliff et al., 2013b), level of arousal (Xie et al., 2013), and aging (Kress et al., 2014). For decades, brain pulsations have been observed directly during neurosurgical procedures. Pulsation of the CSF was first qualitatively described in vivo using fluoroscopy (Du Boulay, 1966) and then validated using non-invasively using magnetic resonance imaging (MRI) (Sherman and Citrin, 1986; Sherman et al., 1986). A comprehensive review of this topic by Wagshul and coworkers was recently published (Wagshul et al., 2011). Phase-contrast MRI was later used to quantify CSF pulsation in selected parts of the ventricular CSF spaces, followed by quantitative flow visualization in the entire subarachnoid and ventricular spaces through computational flow reconstruction from phase-contrast MRI data (Gupta et al., 2010; Cheng et al., 2012; Siyahhan et al., 2014). Major aspects of CSF flow dynamics and outflow pathways are now more fully characterized (Wagshul et al., 2006; Oreskovic and Klarica, 2010; Bulat and Klarica, 2011). All of these experimental and mathematical modeling studies have led the conclusion that for example ‘pressure pulsatility’ in the brain functions as an internal biosensor of intracranial compliance (Wagshul et al., 2011) which is heightened in chronic hydrocephalus (Greitz, 2004). CSF reabsorption via the arachnoid villi into the dural sinuses to the blood or through the nasal lymphatics have been previously documented in seminal papers (Boulton et al., 1996; Abbott, 2004; Johnston et al., 2004). Nevertheless, important questions pertaining to CSF drainage remain unanswered. For example, the exact anatomy of the subarachnoid spaces along cranial and spinal nerves, the functional (quantitative and directional) relationship between influx of CSF into the brain and lymphatic drainage of CSF-ISF, and the potentially fluctuating outflow volumes at the various exit points along the complex outflow pathways, which under normal conditions may be dependent on posture, activity and state of consciousness. The influence of body posture and respiration on CSF outflow and transport has been characterized; and continues to be investigated using MRI techniques with improved temporal resolution (Bradbury et al., 1981; Bradbury and Westrop, 1983; Alperin et al., 2005; Yamada et al., 2013). However, another exceedingly important area that is only partially understood is how physiological movement and various motor activities affects CSF movements and outflow patterns. This lack of information is paradoxical because the influence of motor activity is clearly playing a prominent role on CSF-ISF exchange and clearance (Bechter, 2011). For example, local muscle tone change associated with yawning changes CSF dynamics (Walusinski, 2014). To our knowledge, one of the best studies on CSF flow and outflow pathways have been performed by Heinrich Quincke and described in a paper he published in “Archiv fur Anatomie, Physiologie und wissenschaftliche Medicin” in 1872 (Quincke, 1872). In his studies, Quincke experimented with freely moving animals, injecting the particulate dye cinnabar (Mercury(II) sulfide, HgS) into the intrathecal spaces of dogs, cats, and rabbits, all animals with high motor activity, and analyzed the dye’s distribution throughout the body after days, weeks or months postmortem.

There is wide variability in how psychiatry guidelines and textbooks address the question of cerebrospinal fluid (CSF) diagnostics in the screening of psychiatric disorders. A United States-based textbook confirms that there is no consensus about which laboratory investigation should be routinely performed in psychiatric patients, but with respect to CSF diagnostics, the differences are even more striking. A survey among European experts showed a wide variety of opinions regarding clinical use and criteria in various countries of Europe and worldwide: some psychiatrists, mostly university hospital-based, recommended performing CSF diagnostics in every patient first experiencing severe mental illness (SMI), but especially in patients from the schizophrenia spectrum, whereas others almost never perform CSF examinations themselves and usually refer patients to neurology departments if necessary. Minor neurologic signs are generally frequent in SMI, mainly in affective and schizophrenic disorders. Even with neurologic signs present, there are no clear guidelines regarding CSF evaluation, leaving doctors with experience-based decision making. However, the field is evolving. A recent review provides helpful yellow and red flags for differential diagnosis of SMI from autoimmune encephalitis; interestingly, minor CSF abnormalities are considered a red flag, suggesting that CSF should be routinely performed in acute psychiatric patients. There are reports of single cases identified as an established neurologic disorder: patients within affective and schizophrenic spectrum disorders systematically underwent CSF examination, and were rediagnosed based on CSF results. This was often to the surprise of the psychiatric doctors. Overall, an increasing number of psychiatrists believe that CSF is too rarely examined in psychiatric patients. This chapter provides an overview of differential diagnostic issues in SMI, particularly for new-onset cases. The general recommendations regarding CSF examination procedures can be found in other chapters of this book. Here we focus on specific aspects of differential diagnosis in SMI. Also, there will be an overview of admittedly limited CSF research efforts in psychiatric disorders, focusing on more recent CSF studies. CSF studies in SMI performed with state-of-the-art methods, for example proteomics or assessments of cytokines, were intriguing but difficult to interpret and required critical considerations regarding respective methodology, an undertaking which is outside the scope of this chapter.

Growing data point to the overlap between psychosis and pathological processes associated with immunological dysregulation as well as inflammation. Notably, the recent discovery of antibodies against synaptic and neuronal cell membrane proteins such as anti-N-methyl-d-aspartate receptor provides more direct evidence of the etiological connection between autoimmunity and subsequent hazard of psychosis. Here, we advocate the use of term “autoimmune psychosis,” as this term suggests that autoimmune disorders can masquerade as drug-resistant primary psychosis, and this subtype of psychosis has anatomical and immunological footprints in the brain, despite the frequent absence of structural abnormalities on conventional brain MRI. Furthermore, this term might serve as a reminder not to overlook appropriate neurological workup such as neuroimaging and EEG testing, as well as CSF analysis, for cases with acute or subacute atypical onset of neuropsychiatric presentations including those dominated by acute psychotic symptoms. We propose etiologically and serologically oriented subclassification as well as multi-modal diagnostic approach to address some of the challenges inherent to early diagnosis of patients presenting with atypical and refractory new-onset psychotic symptoms of autoimmune origin. This is particularly relevant to the diagnosis of seronegative but probable autoimmune psychosis (SPAP) that might masquerade as antipsychotic drug-resistant primary psychotic disorder. This distinction is therapeutically important as autoimmune-related psychotic symptomatology can frequently respond well to timely treatment with proper immune modulatory therapies.

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