- Email: [email protected]
Psychiatric syndromes other than dementia
Handbook of Clinical Neurology, Vol. 146 (3rd series) Cerebrospinal Fluid in Neurologic Disorders F. Deisenhammer, C.E. Teunissen, and H. Tumani, Editors https://doi.org/10.1016/B978-0-12-804279-3.00017-4 Copyright © 2017 Elsevier B.V. All rights reserved
Chapter 17
Psychiatric syndromes other than dementia 1
KARL BECHTER1* AND FLORIAN DEISENHAMMER2 Clinic for Psychiatry and Psychotherapy II, Ulm University, Bezirkskrankenhaus G€ unzburg, G€ unzburg, Germany 2
Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
Abstract 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.
INTRODUCTION There is wide variability 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 (Hales and Yudofsky, 2005), 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,
*Correspondence to: Professor Dr Karl Bechter, Clinic for Psychiatry and Psychotherapy II, Bezirkskrankenhaus G€ unzburg, Ludwig-Heilmeyer-Str. 4, G€unzburg, D-89312, Germany. Tel: +49-8221-96-2869, E-mail: [email protected]
286
K. BECHTER AND F. DEISENHAMMER
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 (Bechter, 2012; Bachmann et al., 2014). 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 (Lang and Pr€ uß, 2016), 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 rarely to the surprise of the psychiatric doctors (Lennox et al., 2012; Endres et al., 2015; Bechter, 2016). Overall, an increasing number of psychiatrists believe that CSF is too rarely examined in psychiatric patients (Bechter, 2013). 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.
ETIOLOGIC AND PATHOPHYSIOLOGIC CONSIDERATIONS Currently, the etiology and pathogenesis of SMI remain unclear (Tandon et al., 2013), although important general risk factors have been identified. Among these, a genetic contribution was the most relevant and has been best investigated for schizophrenia and affective spectrum disorders. Also, genetic causes (mostly single genes) were identified, but such cases remained rare and were therefore not listed in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-V: American Psychiatric Association, 2013) as a specific
diagnostic category. Nevertheless, differential diagnosis in SMI, especially in new-onset cases, includes a long list of biologic causes, all of which are rare. Apparently, the lack of specificity of psychopathologic symptoms due to diverse biologic etiologies demonstrates the major factor complicating differential diagnostic approaches in SMI. A new scenario now emerges with differential diagnosis of autoimmune encephalitis, so the conundrum of unknown etiologies of SMI (Endres et al., 2015) is currently subject to important changes. Attempts at biologic subgrouping of depression, schizophrenia, or bipolar disorder by, for example, proteomics (in blood and in CSF) have been multiple but only partly successful. The differential diagnostic sensitivity of these approaches remains limited and has not yet provided a basis for differential therapies. Previous disease models involved genetic, neurodevelopmental, and neurotransmitter alterations, a vulnerability stress model, as well as immunologic factors. As for present knowledge, the involvement of immune growth factors, hormonal pathways (Schwarz et al., 2014), or inflammatory pathways (Myint and Kim, 2014) has been indicated. Attempts to improve the outcome of depression or schizophrenia with anti-inflammatory therapy (M€uller et al., 2004) have indeed been successful and even though effect sizes were small, it points to immune involvement in this syndrome. In addition, many findings indicate an immunopathologic involvement in SMI, for example, of human endogenous retrovirus type W in schizophrenia (Leboyer et al., 2013), or inflammatory metabolites as modulators of N-methyl-D-aspartate receptor (NMDAR) in depression and suicidality (Bay-Richter et al., 2015). All these findings add to an overall scenario of a large subgroup of SMI patients presenting a variety of immunoinflammatory abnormalities which likely have some poorly understood pathogenic relevance. Markers of inflammation and stress may distinguish subsets of individuals with schizophrenia versus bipolar disorder. The brain atrophy observed in a subgroup of schizophrenia may be explained by neurodegeneration related to cytokine signaling and oxidative stress and linked to chronicity of disease (Davis et al., 2014), as well as with minor systemic inflammatory signs (Cannon et al., 2015) and microglia activation (Cannon, 2016). Lastly, systemic C-reactive protein appears to be moderately increased in bipolar disorder, though meta-analysis showed only minor associations with disease stages and severity (Fernandes et al., 2016). Infections and autoimmune disorders additively and strongly increase the risk of SMI, an important validated finding, and major schizophrenia (and broader psychosis) risk genes are located in the major histocompatibility complex and involve complement gene, which is also active in parallel in the
PSYCHIATRIC SYNDROMES OTHER THAN DEMENTIA CSF pathologies in therapy-resistant schizophrenias n = 39
CSF pathologies in therapy-resistant depression n = 24 10%
33%
31%
Neopterin Inflammation
17%
Neopterin
31%
13%
Normal
25%
Inflammation BCBD
BCBD
23%
287
17%
Systemic Infl. Normal
Fig. 17.1. Summarized data obtained from author’s own cerebrospinal fluid (CSF) studies (Bechter, 2016).
brain itself (Benros et al., 2012; Sekar et al., 2016). A study showed clear associations in between mood disorders, infections, and autoimmune disorders (Benros et al., 2013). Microglia activation appears to be generally involved in chronic neurodegeneration and a relationship to systemic inflammation exists. Microglia activation can take place independently of the function of the blood–brain barrier; however a disturbed blood–brain barrier is associated with more severe consequences for brain functioning and brain structural changes (Perry and Teeling, 2013). Microglia activation and onset of psychosis seem to coincide (Cannon, 2016) and can be responsible for local albumin production and consequent elevated CSF albumin levels (Ahn et al., 2008). Systemic inflammation may be linked to environmental factors. For example, cytomegalovirus infection may be involved in localized brain atrophy in schizophrenia and bipolar disorder (Houenou et al., 2014). Low-grade inflammation has been linked to schizophrenia, but how the immune axis may be functionally involved remains to be explored (Doorduin et al., 2009; Anderson et al., 2013; Deakin et al., 2014; Debnath and Berk, 2016). Overall, many open questions exist with regard to the etiology and pathogenesis of SMI.
THE CSF IN DISEASES WITH ACUTE PSYCHIATRIC SYMPTOMS AT ONSET The potential misdiagnosis of SMI as a so-called primary psychiatric disorder versus neurologic disorders presenting with psychiatric symptoms constitutes a diagnostic challenge (Bechter, 2016), particularly since the many potential differential diagnoses of infectious and autoimmune causes are rare or unknown (Meyding-Lamade and Bechter, 2005). With the recent advent of emerging new methods to detect CNS autoantibodies in blood and CSF, the prevalence of SMI cases rediagnosed as a type of limbic encephalitis or autoimmune encephalitis has increased. In addition, an emerging number of cases have presented with limbic encephalitis without CNS
autoantibodies; diagnosis requires combined clinical methods and possibly brain biopsy. It has been suggested that up to 10% of cases of new-onset psychosis may causally be related to neuro-(auto-) inflammation (Bechter et al., 2010; Najjar et al., 2013). As shown in Figure 17.1, about 30–40% of new-onset cases of schizophrenia and affective disorders present with minor CSF pathologies (Bechter et al., 2010). When new CSF markers such as neopterin are included, in a population of therapy-resistant SMIs some minor CSF pathology was found in 70% of patients (Bechter, 2016). Analyzing results from research projects investigating CSF and serum cytokines, it appears that all therapy-resistant psychiatric cases on the affective and schizophrenic spectrum presented with some cytokine CSF abnormalities (Maxeiner et al., 2009, 2014). In another study determining surface markers of CSF cells by flow cytometry, affective and schizophrenic spectrum cases presented with normal CSF cell numbers but about one-third of cases demonstrated inflammatory activation similar to the activated status found in CSF cells from patients with defined neuroinflammatory disorders (Maxeiner et al., 2009). Although results of a standard CSF examination (including protein and glucose and/or lactate concentrations, cell counts, and determination of intrathecal immunoglobulin synthesis) may be slightly abnormal in many primary psychotic disorders, such as schizophrenia or depression (Table 17.1), there is a substantial lack of specificity. However, CSF investigation plays a pivotal role in differential diagnosis, as shown in Table 17.2. CSF changes in infectious and malignant diseases are dealt with in other chapters. Psychiatric symptoms due to endocrine, metabolic, genetic, or systemic disorders usually do not require CSF examination unless the symptoms are poorly explained by the underlying disease, e.g., sudden onset of psychiatric symptoms in long-lasting metabolic disorders. We will next expand on autoimmune encephalitis because an increasing number of specific CSF markers, i.e., autoantibodies, are often present in patients
288
K. BECHTER AND F. DEISENHAMMER
Table 17.1 Reported minor cerebrospinal fluid (CSF) abnormalities in severe mental illness Albumin increase/total protein increase Intrathecal immune response (OCBs, Igs) CSF cell increases Elevated cytokine concentrations
+++ ++ + +
Patient cohorts varied with regard to psychiatric diagnosis, disease duration, and medication, in part also with regard to methods in these CSF studies, which hampered comparability. Nevertheless an idea about replicated findings can be given; replication of abnormal findings respectively indicated by +, ++, +++. Igs, immunoglobulins; OCBs, oligoclonal bands.
with predominantly psychiatric symptoms and permit a definite diagnosis. In a systematic study on the prevalence of CNS autoantibodies, where a schizophrenia cohort was retrospectively reanalyzed, the authors found anti-NMDAR autoantibodies in about 10% of cases Table 17.2 Differential diagnosis of acute psychosis regularly or potentially requiring cerebrospinal fluid (CSF) examination (Meningo-) Encephalitis of infectious etiologiesa Viruses: adeno-, arenaviruses, herpesviruses, myxoviruses, enteroviruses Bacteria: Mycoplasma tuberculosus, Borrelia burgdorferi, pneumococci, streptococci Parasites/protozoa/fungi: Plasmodium falciparum, Toxoplasma gondii, Babesia spp., Trypanosoma, and others CNS autoantibody-associated encephalitis: see Table 17.3b Neoplastic disorders, e.g., carcinomatous leptomeningitis, metastases Metabolic disorders, e.g., porphyria, electrolyte disturbances Endocrine disorders, e.g., hyperthyroidism Systemic disorders, e.g., adrenoleukodystrophy, collagenosis, sarcoidosis, lupus erythematosus Toxic and allergic encephalopathies Genetic disorders, e.g., Huntington disease, Wilson disease Genetic a
Some patients may present with various psychiatric syndromes, including delirium, in the early stages of these specific types of meningoencephalitis. Such patients frequently are admitted to psychiatric hospitals. The diagnostic procedures that should be performed, including CSF examination, are identical to those recommended in meningoencephalitis with neurologic symptoms (see respective chapters in this book). b Most cases of central nervous system (CNS) autoantibody encephalitis present with various and varying psychiatric syndromes in prodromal (or initial) stages; neurologic symptoms typically emerge later in more advanced disease stages. In addition, there is emerging evidence of CNS autoantibody-negative types of limbic encephalitis presenting with similar symptoms to CNS autoantibody-positive cases. For details see Meyding-Lamade and Bechter (2005), and other chapters in this book.
diagnosed with schizophrenia. In addition, in 2 cases the minor neurologic signs noticed in the charts were in retrospect considered to fulfill diagnostic criteria of NMDAR encephalitis, meaning 2 cases had to be reclassified (Steiner et al., 2013). The possible meaning of NMDAR autoantibodies in nearly 10% of remaining cases, though intriguing, was difficult to interpret in relation to the pathophysiology of schizophrenia. In another study, a similarly high prevalence of anti-NMDAR antibodies in schizophrenia patients was found; these authors suggested that CNS autoantibodies were pathogenic only when blood–brain barrier function was disturbed (Hammer et al., 2013, 2014; Ehrenreich et al., 2016). In most patients with autoimmune encephalopathies the respective autoantibodies can be detected in serum, but CSF is more sensitive (Herken and Pr€uss, 2017). In the spectrum of autoimmune encephalitis, NMDAR-associated disease is relatively distinct. It affects mostly patients younger than 45 years (95%), and 37% are even younger than 18 years. The ratio of female-to-male patients is roughly 4:1. In children younger than 12 years and adults older than 45 years the sex distribution is more balanced. Typical symptoms are abnormal behavior (psychosis, delusions, hallucinations, agitation, aggression, or catatonia) with or without insomnia, followed by dysfunction of speech, dyskinesia, memory deficits, autonomic instability, and disturbance of consciousness (Dalmau et al., 2011). Epileptic seizures may occur at any time. In a large study it was found that, 1 month after onset, 87% of patients had four or more of the following symptoms: abnormal behavior and cognition; memory deficit; speech disorder; seizures; abnormal movements (orofacial, limb, or trunk dyskinesias); loss of consciousness or autonomic dysfunction; central hypoventilation; and cerebellar ataxia or hemiparesis (Titulaer et al., 2013). Other forms of autoimmune encephalitis are associated with a variety of autoantibodies (Table 17.4), but a specific antibody may not be present, although the clinical syndrome is suggestive. For this reason, a consensus group recently suggested diagnostic criteria that do not include detection of autoantibodies (Table 17.3). These syndromes are frequently dominated by limbic encephalitis, but other features may hint at a particular antibody type. However, caution is advisable because there is overlap of clinical presentations between different entities and sometimes unusual or unexpected symptoms may occur as antibody testing becomes more widely available. Also, one should always be aware of the fact that a tumor might be the underlying cause. Antibodies against the antigens Ma2, LGI1, GABAB receptor, AMPA receptor, and glutamate decarboxylase are also predominantly associated with limbic encephalitis
PSYCHIATRIC SYNDROMES OTHER THAN DEMENTIA Table 17.3 Proposed diagnostic criteria for autoimmune encephalitis Diagnosis can be made when all four of the following criteria have been met: 1. Subacute onset (rapid progression of less than 3 months) of working-memory deficits, seizures, or psychiatric symptoms suggesting involvement of the limbic system 2. Bilateral brain abnormalities on T2-weighted fluidattenuated inversion recovery magnetic resonance imaging highly restricted to the medial temporal lobes 3. At least one of the following: ● Cerebrospinal fluid pleocytosis (white blood cell count of more than 5 cells per mm3) ● Electroencephalogram with epileptic or slow-wave activity involving the temporal lobes 4. Reasonable exclusion of alternative causes (Lancet Neurol. 2016; 15(4): 391–404).
(Leypoldt et al., 2015), whereas other antigens are more often associated with different syndromes (Table 17.4). Anti-IgLon5-associated disease frequently presents with sleep disorders, mostly sleep apnea and rapid eye movement sleep behavior disorders, and gait instability, mostly ataxia, dysphagia, and diplopia (Gaig et al., 2017). The clinical hallmark of patients with DPPX antibodies is unexplained diarrhea and weight loss followed by encephalopathic symptoms. In patients with antiGABAaR antibodies, the predominant syndrome is encephalitis with a high risk of seizures or status epilepticus, sometimes leading to a comatose state. In general, specific antibodies in autoimmune encephalitis can be detected in CSF and blood. However, there is evidence that investigation of CSF is slightly more sensitive (Gresa-Arribas et al., 2014), which is why CSF should always be analyzed in suspected cases, particularly when serum antibodies cannot be detected. In the following the individual entities will be discussed with respect to particular CSF findings.
Methods of detection of specific antibodies to neural cell surface antigens Classic onconeuronal antibodies targeting intracellular proteins with linear epitopes can be detected with various techniques, including enzyme-linked immunosorbent assay, immunoblotting, and immunohistochemistry. In contrast, different properties apply to antibodies against neuronal cell surface proteins which should be considered when it comes to assay design and interpretation of results. Discovery of antineural antibodies is a rapidly evolving field and several new autoantigens in
289
autoimmune encephalitis have been reported recently. For discovery reasons in research it is best to use a sensitive assay which may be less specific. In a clinical setting, assays need to be specific and robust. In the field of specific antibody testing three different methods have emerged which are used in different settings: (1) immunohistochemistry/indirect immunofluorescence on adult rat or primate brain slices; (2) immunocytochemistry on living cultured rat hippocampal neurons; and (3) cellbased assays (CBA) for neuronal membrane proteins, as shown in Table 17.5. Most CBAs are commercially available and therefore fit for purpose in clinical laboratories. In a CBA a recombinant antigen is expressed by mammalian cells. The transfected cells are stained with patient serum or CSF using immunofluorescence. When the patient sample contains antibodies directed at this specific antigen, staining of the transfected cells is enhanced when compared to nontransfected cells (Fig. 17.1). In CBAs the antigen mostly maintains its tertiary structure and appropriate posttranslational modifications. This allows for the detection of antibodies directed at conformational epitopes. Most CBAs use human embryonic kidney cells, which are well suited for membrane protein expression (Chaudhary et al., 2011). Some other cell lines for protein expression have also been used, e.g., Chinese hamster ovaries. There is an unresolved issue about use of live cells versus a priori fixed cells. In live cell assays incubation takes place before fixation, whereas in other formats cells are fixed and permeabilized before immunostaining, which is obviously the preferred setting in commercial assays. Comparing these approaches, one study found a higher sensitivity of the fixed CBA (Gresa-Arribas et al., 2014), although theoretically one would not have expected this result. However, different receptors might perform differently depending on native or fixed cell systems (Leite et al., 2008; Irani et al., 2010). In immunohistochemistry the CSF/serum is applied to rat brain slices, meaning that all possible antigens are available and accessible. This method is standard for the detection of onconeural antibodies detecting intracellular antigens. Mostly, clinical laboratories use immunofluorescence on primate cerebellum, with the advantage that commercial kits are available. For the detection of synaptic surface antibodies, pretreatment of rat brain tissue is different from the methods described above (Ances et al., 2005; Dalmau et al., 2007), which leads to stable and well-preserved antigens. Using diaminobenzidine peroxidase or detection antibodies that are fluorescently labeled, antineural antibodies can be visualized. Onconeural antibodies appear with typical patterns (Graus et al., 1997; Sillevis et al., 2002). Cell surface antibodies usually stain
Table 17.4 Classification of encephalitis groups and commonly associated clinical features Encephalitis groups in the present study
Antigen
Number of patientsa
(A) NMDAR encephalitis (n ¼ 53)
NMDAR
(B) Non-NMDAR cell surface antigens (n ¼ 24)
Psychiatric symptoms
Additional symptoms
Typical patient
n ¼ 53 (53%)
Psychosis, schizophreniform illness, catatonia, hallucinations, aggression
Young women, association with ovarian teratomas
Caspr2
n ¼ 4 (4%)
Insomnia, panic attacks, schizophreniform illness, depression
Epileptic seizures, dyskinesia, autonomic instability, speech dysfunction, decreased consciousness Morvan syndrome, neuromyotonia, muscle spasms, fasciculations
LGI1
n ¼ 14 (14%)
Amnesia, confusion, memory deficits, depression
Metabotropic glutamate receptor 5
n ¼ 2 (2%)
Glycine receptor
n ¼ 1 (1%)
Behavioral changes, emotional instability, memory deficits Behavioral changes, schizophreniform syndrome
Metabotropic glutamate receptor 1 GABAA-receptor
Limbic encephalitis, faciobrachial dystonic seizures, hyponatremia, bradycardia Limbic encephalitis, Ophelia syndrome
Cerebellar degeneration
Stiff-person syndrome (SPS) or progressive encephalomyelitis with rigidity and myoclonus, hyperekplexia Hodgkin lymphoma
Encephalitis, seizures
Comatose state
Middle-aged or elderly patients, may be associated with thymoma Middle-aged or elderly patients, male:female (2:1), may be associated with thymoma Young adults, may be associated with Hodgkin lymphoma Middle-aged or elderly patients, may be associated with thymomas and lymphomas Not applicable Not applicable, broad age range, no particular sex preference
GABAB-receptor
Limbic encephalitis
Seizures, ataxia
AMPA receptor
Limbic encephalitis
Sometimes pure psychosis or RPD
DPPX
Unexplained gastrointestinal dysfunction, diarrhea, and loss of weight followed by confusion, seizures, tremor, myoclonus, nystagmus Sleep apnea, REM sleep behavior disorders, ataxia, dysphagia, diplopia Schizophreniform illness, autism, attention-deficit/ hyperactivity disorder
Hyperekplexia
Behavioral changes
Limbic encephalitis, cerebellar degeneration, sensory neuropathy, encephalomyelitis, uveitis, retinopathy, optic neuropathy, chorea
IgLon5
(C) Antibodies against intracellular antigens (n ¼ 23)
Synaptic antigens: anti-GAD antibodies
n ¼ 9 (9%)
Onconeuronal antigens: anti-Yo, -Hu, -CV2, -Ri, Tr2/DNER Ma2 antibodies
n ¼ 14 (14%)
Adult, balanced sex distribution, >50% associated with tumour (SCLC, thymoma), coexisting onconeural antibodies Adult, balanced sex distribution, >50% associated with tumor (SCLC, thymoma), coexisting onconeural antibodies Adult, 4th to 7th decade, severe prodromal weight loss
Not applicable
Adult >50 years, balanced sex distribution
Limbic encephalitis, seizures, SPS, brainstem dysfunction, ataxia
Middle-aged or elderly patients, might be associated with SCLC, tumor screening recommended Elderly patients, often with malignant tumors (SCLC, Hu; testicular seminoma, Ma2)
a Sections A–C refer to the study published by Herken and Pr€uß (2017). The descriptions of other autoantibody-associated diseases (DPPX: anti-dipeptidyl-peptidase-like protein-6, IgLON5, metabotropic glutamate receptor 1, GABAB-receptor, AMPA receptor, DNER) were added by the authors of the present chapter. Caspr2, contactin-associated protein 2; GAD, glutamate decarboxylase; LGI1, leucine-rich glioma inactivated 1; NMDAR, N-methyl-D-aspartate receptor; REM, rapid eye movement; RPD, rapidly progressive dementia; SCLC, small cell lung carcinoma.
Table 17.5 Methods of auto-antibody detection Number of patients reported IHC
ICC of living neurons
NMDAR
>1000
Surface labeling of excitatory Specific staining synapses pattern hippocampus (Hughes et al., 2010) (AIE protocol) (Dalmau et al., 2007) and (Gresa-Arribas et al., 2014)
LGI1
250
Specific staining pattern of hippocampus (AIE protocol) (Lai et al., 2010)
Caspr2
100
GlyR
75
Surface labeling of neurons, Diffuse neuropil not further specified staining (Lancaster et al., 2011a) (AIE protocol) (Lancaster et al., 2011a) Neuropil of brainstem Not published and spinal cord (PNS protocol) (Carvajal-González et al., 2014)
Surface labeling of neurons, not further specified (Lai et al., 2010)
CBA Fixed (Dalmau et al., 2008) and (Gresa-Arribas et al., 2014)
Commercial CBA available Yes
Yes Fixed (with ADAM22/23 coexpression) (Lai et al., 2010) Fixed with added transmembrane part (van Sonderen et al., 2016c) Live (Irani et al., 2010a) Yes Fixed (Lancaster et al., 2011a) Live (Irani et al., 2012) No Live (Carvajal-González et al., 2014)
Sensitivity and specificity Sensitivity IHC: CSF 100%, serum 92% (Gresa-Arribas et al., 2014) Sensitivity fixed CBA: CSF 100%, serum 86% (Gresa-Arribas et al., 2014) Sensitivity IHC plus fixed CBA: CSF 100%, serum 86% (Gresa-Arribas et al., 2014) Specificity IHC plus fixed CBA: CSF 100%, serum 100% (Gresa-Arribas et al., 2014) Sensitivity IHC: CSF 88%, serum 100% (van Sonderen et al., 2016c) Sensitivity fixed CBA: CSF 53%, serum 100% (van Sonderen et al., 2016c) Sensitivity fixed CBA: CSF 100%, serum 100% (van Sonderen et al., 2016a) Sensitivity live CBA: CSF: PERM 100% (Carvajal-González et al., 2014), SPS-spectrum 0% (Martinez-Hernandez et al., 2016), serum: PERM 100% (Carvajal-González et al., 2014) Sensitivity fixed CBA: Serum 92–94% (disease controls) (Martinez-Hernandez et al., 2015) (Martinez-Hernandez et al., 2016)
GABABR
67
DNER
65
AMPAR
64
DPPX
28
DopamineR∗
26
mGluR1
16
IgLon5
10
mGluR5
3
Diffuse neuropil staining (AIE protocol) (Lancaster et al., 2010) and (H€oftberger et al., 2013) PC cytoplasm, punctate staining of molecular layer cerebellum (PNS protocol) (Graus et al., 1997) and (de Graaff et al., 2012) Diffuse neuropil staining (AIE protocol) (Lai et al., 2009) Diffuse neuropil staining (AIE protocol) (Boronat et al., 2013); (Balint et al., 2014); and (Tobin et al., 2014) Staining of basal ganglia (Dale et al., 2012) PC cytoplasm, molecular layer cerebellum (PNS protocol) (Sillevis Smitt et al., 2000) and (Lopez-Chiriboga et al., 2016) Diffuse neuropil staining (AIE protocol) (Sabater et al., 2014) Diffuse neuropil staining (AIE protocol) (Lancaster et al., 2011b)
Surface labeling of neurons, not further specified (Lancaster et al., 2010)
Fixed (Lancaster et al., 2010)
Yes
Sensitivity fixed CBA: CSF 100%, serum 67–93% (Lancaster et al., 2010); (H€ oftberger et al., 2013); and (Jeffery et al., 2013)
Surface labeling of neurons overexpressing DNER (de Graaff et al., 2012)
Fixed (de Graaff et al., 2012) Live (Greene et al., 2014)
Yes
Sensitivity fixed CBA: Serum 100% (Probst et al., 2015) Specificity fixed CBA: Serum 100% (Probst et al., 2015)
Surface labeling of excitatory synapses (Lai et al., 2009)
Fixed (Lai et al., 2009) and (H€ oftberger et al., 2015)
Yes
Specificity fixed CBA: CSF 100%, serum 70% (H€ oftberger et al., 2015)
Surface labeling of both excitatory and inhibitory synapses (Piepgras et al., 2015)
Fixed (Boronat et al., 2013); (Balint et al., 2014); and (Tobin et al., 2014)
Yes
Not available
Surface labeling of neurons, not further specified (Dale et al., 2012) Not published
Live (Dale et al., 2012)
No
Not available
Fixed (Lopez-Chiriboga et al., 2016) and (Iorio et al., 2013)
Yes
Not available
Surface labeling of neurons, not further specified (Sabater et al., 2014)
Live (Sabater et al., 2014)
No
Not available
Surface labeling of neurons, not further specified (Lancaster et al., 2011b)
Fixed (Lancaster et al., 2011b)
Yes
Not available
294
K. BECHTER AND F. DEISENHAMMER
hippocampal synapses, referred to as neuropil (Dalmau et al., 2011; Montojo et al., 2015). However, this approach requires highly experienced and skilled experts to interpret the test results correctly. The advantage is that the method is sensitive and one might detect a broader range of antibodies compared to CBAs, where only the specifically expressed and clearly defined antigens can be recognized. When screening for novel neuronal antigens it needs to be noted that differences between species exist and some human epitopes may be missed in rodents. Live CBAs require neuronal cultures which need to be grown for longer than 14 days and kept alive for the assay procedure (Hughes et al., 2010) – the advantage is selective binding of antibodies, thereby reducing background signals. Obviously, this method is restricted to highly specialized laboratories.
OUTLOOK There is an open issue about definitions of encephalitis and encephalopathy (Venkatesan et al., 2013). The definition of encephalitis includes cases presenting with normal CSF findings, whereas the definition of encephalopathy includes cases with inflammatory CNS disease. The term encephalopathy appears to be mainly based on traded assumptions, though with long-standing observations of an association between systemic inflammation, and the term inflammatory encephalopathy misses a clear pathogenetic concept. Obviously, there is a need for better terms and definitions with respect to primary and secondary CNS diseases leading to psychiatric manifestations. Secondly, exploring the pathomechanism in primary psychotic disorders will be an important challenge, not least to develop more targeted therapies. Given the fact that CSF alterations at a molecular and cellular level can be found in a substantial number of patients, this body fluid plays a pivotal role in this field of research. The rapidly growing number of distinct molecular targets in autoimmune encephalopathies will very likely further increase. Although the proportion of inflammatory/autoimmune diseases is relatively small in acuteonset psychiatric patients, this clearly underscores the importance of CSF in the diagnostic workup of such cases, with clear therapeutic consequences. In turn, a broader use of CSF will increase research activities, leading to a better understanding of psychiatric diseases. Recent developments in laboratory techniques, such as mass spectrometry or electrochemoluminescence, which are becoming more broadly available, will be supportive of new developments in the field.
REFERENCES Ahn S-M, Byun K, Cho K et al. (2008). Human microglia cells synthesize albumin in brain. PLoS One 3. e2829. American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders, 5th ed.American Psychiatric Association, Washington, DC. Ances BM, Vitaliani R, Taylor RA et al. (2005). Treatmentresponsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates. Brain 128: 1764–1777. Anderson G, Berk M, Dodd S et al. (2013). Immunoinflammatory oxidative and nitrosative stress and neuroprogressive pathways in the etiology, course and treatment of schizophrenia. Prog. Neuro-Psychopharmacol Biol Psychiatry 42: 1–4. Bachmann S, Degen C, Geider FJ et al. (2014). Neurological soft signs in the clinical course of schizophrenia: results of a meta-analysis. Front Psychiatry 5: 185. Bay-Richter C, Linderholm KR, Lim CK et al. (2015). A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor in depression and suicidality. BBI 43: 110–117. Bechter K (2012). Diagnosis of infectious or inflammatory psychosyndromes. The Open Neurology Journal 6 (Suppl 1-M6): 113–118. Bechter K (2013). Updating the mild encephalitis hypothesis of schizophrenia. Progr NP&BP 42: 71–91. Bechter K (2016). CSF diagnostics in psychiatry – present status – future developments. Neurol Psychiatry Brain Res 22: 69–74. Bechter K, Reiber H, Herzog S et al. (2010). Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: identification of subgroups with immune responses and blood–CSF barrier dysfunction. J Psychiatr Res 44: 321–330. Benros ME, Mortensen PB, Eaton WW (2012). Autoimmune diseases and infections as risk factors for schizophrenia. Ann N Y Acad Sci 1262: 65–66. Benros ME, Waltoft BL, Nordentoft M et al. (2013). Autoimmune diseases and severe infections as risk factors for mood disorders: a nationwide study. JAMA Psychiatry 70: 812–820. Cannon TD (2016). Microglial activation and the onset of psychosis. Am J Psychiatry 173: 3–4. Cannon TD, Chung Y, He G et al. (2015). Progressive reduction in cortical thickness as psychosis develops: a multisite longitudinal neuroimaging study of youth at elevated clinical risk. Biol Psychiatry 77: 147–157. Chaudhary S, Pak JE, Pedersen BP et al. (2011). Efficient expression screening of human membrane proteins in transiently transfected human embryonic kidney 293S cells. Methods 55: 273–280. Dalmau J, Tuzun E, Wu HY et al. (2007). Paraneoplastic antiN-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 61: 25–36. Dalmau J, Lancaster E, Martinez-Hernandez E et al. (2011). Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 10: 63–74.
PSYCHIATRIC SYNDROMES OTHER THAN DEMENTIA Davis J, Moylan S, Harvey BH et al. (2014). Neuroprogression in schizophrenia: pathways underpinning clinical staging and therapeutic corollaries. Aust N Z J Psychiatry 48: 512–529. Deakin J, Lennox BR, Zandi MS (2014). Antibodies to the N-methyl-D-aspartate receptor and other synaptic proteins in psychosis. Biol Psychiatry 75: 284–291. Debnath M, Berk M (2016). Functional implications of the IL-23/IL-17 immune axis in schizophrenia. Mol Neurobiol. (epub ahead of print). Doorduin J, deVries EF, Willemsen AT et al. (2009). Neuroinflammation in schizophrenia-related psychosis: a PET study. J Nucl Med 50: 1801–1807. Ehrenreich H, Castillo-Gomez E, Oliveira B et al. (2016). Circulating NMDAR1 autoantibodies of different immunoglobulin classes modulate evolution of lesion size in acute ischemic stroke. Neurol Psychiatry Brain Res 22: 9–10. Endres D, Perlov E, Baumgartner A et al. (2015). Immunological findings in psychotic syndromes: a tertiary care hospital’s CSF sample of 180 patients. Front Hum Neurosci 9: 476. Fernandes BS, Steiner J, Molendijk ML et al. (2016). C-reactive protein concentrations across the mood spectrum in bipolar disorder: a systematic review and metaanalysis. Lancet Psychiatry 3: 1147–1156. Gaig C, Graus F, Compta Y et al. (2017). Clinical manifestations of the anti-IgLON5 disease. Neurology 88: 1736–1743. Graus F, Dalmau J, Valldeoriola F et al. (1997). Immunological characterization of a neuronal antibody (anti-Tr) associated with paraneoplastic cerebellar degeneration and Hodgkin’s disease. J Neuroimmunol 74: 55–61. Gresa-Arribas N, Titulaer MJ, Torrents A et al. (2014). Antibody titres at diagnosis and during follow-up of antiNMDA receptor encephalitis: a retrospective study. Lancet Neurol 13: 167–177. Hales RE, Yudofsky SC (2005). Textbook of clinical psychiatry, APP, Arlington. Hammer C, Stepniak B, Schneider A et al. (2013). Neuropsychiatric disease relevance of circulating antiNMDA receptor autoantibodies depends on blood-brain barrier integrity. Mol Psychiatry 19: 1143–1149. Hammer C, Zerche M, Schneider A et al. (2014). Apolipoprotein E4 carrier status plus circulating antiNMDAR1 autoantibodies: association with schizoaffective disorder. Mol Psychiatry 19: 1045–1056. Herken J, Pr€uss H (2017). Red flags: clinical signs for identifying autoimmune encephalitis in psychiatzric patients. Front Psych. https://doi.org/10.3389/fpsyt.2017.00025. Houenou J, d’Albis MA, Daban C et al. (2014). Cytomegalovirus seropositivity and serointensity are associated with hippocampal volume and verbal memory in schizophrenia and bipolar disorder. Prog NeuroPsychopharmacol Biol Psychiatry 48: 142–148. Hughes EG, Peng X, Gleichman AJ et al. (2010). Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci 30: 5866–5875.
295
Irani SR, Bera K, Waters P et al. (2010). N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly nonparaneoplastic disorder of both sexes. Brain 133: 1655–1667. Lang K, Pr€ uß H (2016). Anti-NMDA-Rezeptor-Enzephalitis – eine wichtige Differenzialdiagnose. InFo Neurologie & Psychiatrie 18: 7–8. Leboyer M, Tamouza R, Charron D et al. (2013). Human endogenous retrovirus type W (HERV-W) in schizophrenia: a new avenue of research at the gene-environment interface. World J Biol Psychiatry 14: 80–90. Leite MI, Jacob S, Viegas S et al. (2008). IgG1 antibodies to acetylcholine receptors in ‘seronegative’ myasthenia gravis. Brain 131: 1940–1952. Lennox BR, Coles AJ, Vincent A (2012). Antibody-mediated encephalitis: a treatable cause of schizophrenia. Br J Psychiatry 200: 92–94. Leypoldt F, Armangue T, Dalmau J (2015). Autoimmune encephalopathies. Ann N Y Acad Sci 1338: 94–114. Maxeiner HG, Schneider M, Kurfiss S-T et al. (2014). Cerebrospinal fluid and serum cytokine profiling to detect immune control of infectious and inflammatory neurological and psychiatric diseases. Cytokine 69: 62–67. Maxeiner HG, Rojewski MT, Schmitt A et al. (2009). Flow cytometric analysis of T cell subsets in paired samples of cerebrospinal fluid and peripheral blood from patients with neurological and psychiatric disorders. Brain Behav Immun 23: 134–142. Meyding-Lamade U, Bechter K (2005). Meningoenzephalitis als Ursache psychiatrischer Syndrome – psychisch krank durch Mikroben im Hirn. Info NL&PS 7: 38–45. Montojo MT, Petit-Pedrol M, Graus F et al. (2015). Clinical spectrum and diagnostic value of antibodies against the potassium channel related protein complex. Neurologia 30: 295–301. M€ uller N, Riedel M, Blendinger C et al. (2004). Mycoplasma pneumoniae infection and Tourette’s syndrome. Psychiatry Res 129: 119125. Myint AM, Kim YK (2014). Network beyond IDO in psychiatric disorders: revisiting neurodegeneration hypothesis. Progress NP&BP 48: 304–313. Najjar S, Pearlman D, Devinsky O et al. (2013). Neuropsychiatric autoimmune encephalitis without VGKC-complex, NMDAR, and GAD autoantibodies: case report and literature review. Cogn Behav Neurol 26: 36–49. Perry VH, Teeling J (2013). Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration. Semin Immunopathol 35: 601–612. Schwarz E, van Beveren NJM, Ramsey J et al. (2014). Identification of subgroups of schizophrenia patients with changes in either immune or growth factor and hormonal pathway. Schizophr Bull 40: 787–795. Sekar A, Al Bialas, de Rivera H et al. (2016). Schizophrenia risk from complex variation of complement component. Nature 530: 177–183.
296
K. BECHTER AND F. DEISENHAMMER
Sillevis SP, Grefkens J, de LB et al. (2002). Survival and outcome in 73 anti-Hu positive patients with paraneoplastic encephalomyelitis/sensory neuronopathy. J Neurol 249: 745–753. Steiner J, Walter M, Glanz W et al. (2013). Increased prevalence of diverse N-methyl-D-aspartate glutamate receptor antibodies in patients with an initial diagnosis of schizophrenia: specific relevance of IgG NR1a antibodies for distinction from N-methyl-D-aspartate glutamate receptor encephalitis. JAMA Psychiatry 70: 271–278.
Tandon R, Gaebel W, Barch DM et al. (2013). Definition and description of schizophrenia in the DSM-5. Schizophr Res 150: 3–10. Titulaer MJ, McCracken L, Gabilondo I et al. (2013). Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 12: 157–165. Venkatesan A, Tunkel AR, Bloch KC et al. (2013). Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the International Encephalitis Consortium. Clin Infect Dis 57: 1114–1128.
Chapter 17
Psychiatric syndromes other than dementia 1
KARL BECHTER1* AND FLORIAN DEISENHAMMER2 Clinic for Psychiatry and Psychotherapy II, Ulm University, Bezirkskrankenhaus G€ unzburg, G€ unzburg, Germany 2
Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
Abstract 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.
INTRODUCTION There is wide variability 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 (Hales and Yudofsky, 2005), 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,
*Correspondence to: Professor Dr Karl Bechter, Clinic for Psychiatry and Psychotherapy II, Bezirkskrankenhaus G€ unzburg, Ludwig-Heilmeyer-Str. 4, G€unzburg, D-89312, Germany. Tel: +49-8221-96-2869, E-mail: [email protected]
286
K. BECHTER AND F. DEISENHAMMER
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 (Bechter, 2012; Bachmann et al., 2014). 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 (Lang and Pr€ uß, 2016), 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 rarely to the surprise of the psychiatric doctors (Lennox et al., 2012; Endres et al., 2015; Bechter, 2016). Overall, an increasing number of psychiatrists believe that CSF is too rarely examined in psychiatric patients (Bechter, 2013). 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.
ETIOLOGIC AND PATHOPHYSIOLOGIC CONSIDERATIONS Currently, the etiology and pathogenesis of SMI remain unclear (Tandon et al., 2013), although important general risk factors have been identified. Among these, a genetic contribution was the most relevant and has been best investigated for schizophrenia and affective spectrum disorders. Also, genetic causes (mostly single genes) were identified, but such cases remained rare and were therefore not listed in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-V: American Psychiatric Association, 2013) as a specific
diagnostic category. Nevertheless, differential diagnosis in SMI, especially in new-onset cases, includes a long list of biologic causes, all of which are rare. Apparently, the lack of specificity of psychopathologic symptoms due to diverse biologic etiologies demonstrates the major factor complicating differential diagnostic approaches in SMI. A new scenario now emerges with differential diagnosis of autoimmune encephalitis, so the conundrum of unknown etiologies of SMI (Endres et al., 2015) is currently subject to important changes. Attempts at biologic subgrouping of depression, schizophrenia, or bipolar disorder by, for example, proteomics (in blood and in CSF) have been multiple but only partly successful. The differential diagnostic sensitivity of these approaches remains limited and has not yet provided a basis for differential therapies. Previous disease models involved genetic, neurodevelopmental, and neurotransmitter alterations, a vulnerability stress model, as well as immunologic factors. As for present knowledge, the involvement of immune growth factors, hormonal pathways (Schwarz et al., 2014), or inflammatory pathways (Myint and Kim, 2014) has been indicated. Attempts to improve the outcome of depression or schizophrenia with anti-inflammatory therapy (M€uller et al., 2004) have indeed been successful and even though effect sizes were small, it points to immune involvement in this syndrome. In addition, many findings indicate an immunopathologic involvement in SMI, for example, of human endogenous retrovirus type W in schizophrenia (Leboyer et al., 2013), or inflammatory metabolites as modulators of N-methyl-D-aspartate receptor (NMDAR) in depression and suicidality (Bay-Richter et al., 2015). All these findings add to an overall scenario of a large subgroup of SMI patients presenting a variety of immunoinflammatory abnormalities which likely have some poorly understood pathogenic relevance. Markers of inflammation and stress may distinguish subsets of individuals with schizophrenia versus bipolar disorder. The brain atrophy observed in a subgroup of schizophrenia may be explained by neurodegeneration related to cytokine signaling and oxidative stress and linked to chronicity of disease (Davis et al., 2014), as well as with minor systemic inflammatory signs (Cannon et al., 2015) and microglia activation (Cannon, 2016). Lastly, systemic C-reactive protein appears to be moderately increased in bipolar disorder, though meta-analysis showed only minor associations with disease stages and severity (Fernandes et al., 2016). Infections and autoimmune disorders additively and strongly increase the risk of SMI, an important validated finding, and major schizophrenia (and broader psychosis) risk genes are located in the major histocompatibility complex and involve complement gene, which is also active in parallel in the
PSYCHIATRIC SYNDROMES OTHER THAN DEMENTIA CSF pathologies in therapy-resistant schizophrenias n = 39
CSF pathologies in therapy-resistant depression n = 24 10%
33%
31%
Neopterin Inflammation
17%
Neopterin
31%
13%
Normal
25%
Inflammation BCBD
BCBD
23%
287
17%
Systemic Infl. Normal
Fig. 17.1. Summarized data obtained from author’s own cerebrospinal fluid (CSF) studies (Bechter, 2016).
brain itself (Benros et al., 2012; Sekar et al., 2016). A study showed clear associations in between mood disorders, infections, and autoimmune disorders (Benros et al., 2013). Microglia activation appears to be generally involved in chronic neurodegeneration and a relationship to systemic inflammation exists. Microglia activation can take place independently of the function of the blood–brain barrier; however a disturbed blood–brain barrier is associated with more severe consequences for brain functioning and brain structural changes (Perry and Teeling, 2013). Microglia activation and onset of psychosis seem to coincide (Cannon, 2016) and can be responsible for local albumin production and consequent elevated CSF albumin levels (Ahn et al., 2008). Systemic inflammation may be linked to environmental factors. For example, cytomegalovirus infection may be involved in localized brain atrophy in schizophrenia and bipolar disorder (Houenou et al., 2014). Low-grade inflammation has been linked to schizophrenia, but how the immune axis may be functionally involved remains to be explored (Doorduin et al., 2009; Anderson et al., 2013; Deakin et al., 2014; Debnath and Berk, 2016). Overall, many open questions exist with regard to the etiology and pathogenesis of SMI.
THE CSF IN DISEASES WITH ACUTE PSYCHIATRIC SYMPTOMS AT ONSET The potential misdiagnosis of SMI as a so-called primary psychiatric disorder versus neurologic disorders presenting with psychiatric symptoms constitutes a diagnostic challenge (Bechter, 2016), particularly since the many potential differential diagnoses of infectious and autoimmune causes are rare or unknown (Meyding-Lamade and Bechter, 2005). With the recent advent of emerging new methods to detect CNS autoantibodies in blood and CSF, the prevalence of SMI cases rediagnosed as a type of limbic encephalitis or autoimmune encephalitis has increased. In addition, an emerging number of cases have presented with limbic encephalitis without CNS
autoantibodies; diagnosis requires combined clinical methods and possibly brain biopsy. It has been suggested that up to 10% of cases of new-onset psychosis may causally be related to neuro-(auto-) inflammation (Bechter et al., 2010; Najjar et al., 2013). As shown in Figure 17.1, about 30–40% of new-onset cases of schizophrenia and affective disorders present with minor CSF pathologies (Bechter et al., 2010). When new CSF markers such as neopterin are included, in a population of therapy-resistant SMIs some minor CSF pathology was found in 70% of patients (Bechter, 2016). Analyzing results from research projects investigating CSF and serum cytokines, it appears that all therapy-resistant psychiatric cases on the affective and schizophrenic spectrum presented with some cytokine CSF abnormalities (Maxeiner et al., 2009, 2014). In another study determining surface markers of CSF cells by flow cytometry, affective and schizophrenic spectrum cases presented with normal CSF cell numbers but about one-third of cases demonstrated inflammatory activation similar to the activated status found in CSF cells from patients with defined neuroinflammatory disorders (Maxeiner et al., 2009). Although results of a standard CSF examination (including protein and glucose and/or lactate concentrations, cell counts, and determination of intrathecal immunoglobulin synthesis) may be slightly abnormal in many primary psychotic disorders, such as schizophrenia or depression (Table 17.1), there is a substantial lack of specificity. However, CSF investigation plays a pivotal role in differential diagnosis, as shown in Table 17.2. CSF changes in infectious and malignant diseases are dealt with in other chapters. Psychiatric symptoms due to endocrine, metabolic, genetic, or systemic disorders usually do not require CSF examination unless the symptoms are poorly explained by the underlying disease, e.g., sudden onset of psychiatric symptoms in long-lasting metabolic disorders. We will next expand on autoimmune encephalitis because an increasing number of specific CSF markers, i.e., autoantibodies, are often present in patients
288
K. BECHTER AND F. DEISENHAMMER
Table 17.1 Reported minor cerebrospinal fluid (CSF) abnormalities in severe mental illness Albumin increase/total protein increase Intrathecal immune response (OCBs, Igs) CSF cell increases Elevated cytokine concentrations
+++ ++ + +
Patient cohorts varied with regard to psychiatric diagnosis, disease duration, and medication, in part also with regard to methods in these CSF studies, which hampered comparability. Nevertheless an idea about replicated findings can be given; replication of abnormal findings respectively indicated by +, ++, +++. Igs, immunoglobulins; OCBs, oligoclonal bands.
with predominantly psychiatric symptoms and permit a definite diagnosis. In a systematic study on the prevalence of CNS autoantibodies, where a schizophrenia cohort was retrospectively reanalyzed, the authors found anti-NMDAR autoantibodies in about 10% of cases Table 17.2 Differential diagnosis of acute psychosis regularly or potentially requiring cerebrospinal fluid (CSF) examination (Meningo-) Encephalitis of infectious etiologiesa Viruses: adeno-, arenaviruses, herpesviruses, myxoviruses, enteroviruses Bacteria: Mycoplasma tuberculosus, Borrelia burgdorferi, pneumococci, streptococci Parasites/protozoa/fungi: Plasmodium falciparum, Toxoplasma gondii, Babesia spp., Trypanosoma, and others CNS autoantibody-associated encephalitis: see Table 17.3b Neoplastic disorders, e.g., carcinomatous leptomeningitis, metastases Metabolic disorders, e.g., porphyria, electrolyte disturbances Endocrine disorders, e.g., hyperthyroidism Systemic disorders, e.g., adrenoleukodystrophy, collagenosis, sarcoidosis, lupus erythematosus Toxic and allergic encephalopathies Genetic disorders, e.g., Huntington disease, Wilson disease Genetic a
Some patients may present with various psychiatric syndromes, including delirium, in the early stages of these specific types of meningoencephalitis. Such patients frequently are admitted to psychiatric hospitals. The diagnostic procedures that should be performed, including CSF examination, are identical to those recommended in meningoencephalitis with neurologic symptoms (see respective chapters in this book). b Most cases of central nervous system (CNS) autoantibody encephalitis present with various and varying psychiatric syndromes in prodromal (or initial) stages; neurologic symptoms typically emerge later in more advanced disease stages. In addition, there is emerging evidence of CNS autoantibody-negative types of limbic encephalitis presenting with similar symptoms to CNS autoantibody-positive cases. For details see Meyding-Lamade and Bechter (2005), and other chapters in this book.
diagnosed with schizophrenia. In addition, in 2 cases the minor neurologic signs noticed in the charts were in retrospect considered to fulfill diagnostic criteria of NMDAR encephalitis, meaning 2 cases had to be reclassified (Steiner et al., 2013). The possible meaning of NMDAR autoantibodies in nearly 10% of remaining cases, though intriguing, was difficult to interpret in relation to the pathophysiology of schizophrenia. In another study, a similarly high prevalence of anti-NMDAR antibodies in schizophrenia patients was found; these authors suggested that CNS autoantibodies were pathogenic only when blood–brain barrier function was disturbed (Hammer et al., 2013, 2014; Ehrenreich et al., 2016). In most patients with autoimmune encephalopathies the respective autoantibodies can be detected in serum, but CSF is more sensitive (Herken and Pr€uss, 2017). In the spectrum of autoimmune encephalitis, NMDAR-associated disease is relatively distinct. It affects mostly patients younger than 45 years (95%), and 37% are even younger than 18 years. The ratio of female-to-male patients is roughly 4:1. In children younger than 12 years and adults older than 45 years the sex distribution is more balanced. Typical symptoms are abnormal behavior (psychosis, delusions, hallucinations, agitation, aggression, or catatonia) with or without insomnia, followed by dysfunction of speech, dyskinesia, memory deficits, autonomic instability, and disturbance of consciousness (Dalmau et al., 2011). Epileptic seizures may occur at any time. In a large study it was found that, 1 month after onset, 87% of patients had four or more of the following symptoms: abnormal behavior and cognition; memory deficit; speech disorder; seizures; abnormal movements (orofacial, limb, or trunk dyskinesias); loss of consciousness or autonomic dysfunction; central hypoventilation; and cerebellar ataxia or hemiparesis (Titulaer et al., 2013). Other forms of autoimmune encephalitis are associated with a variety of autoantibodies (Table 17.4), but a specific antibody may not be present, although the clinical syndrome is suggestive. For this reason, a consensus group recently suggested diagnostic criteria that do not include detection of autoantibodies (Table 17.3). These syndromes are frequently dominated by limbic encephalitis, but other features may hint at a particular antibody type. However, caution is advisable because there is overlap of clinical presentations between different entities and sometimes unusual or unexpected symptoms may occur as antibody testing becomes more widely available. Also, one should always be aware of the fact that a tumor might be the underlying cause. Antibodies against the antigens Ma2, LGI1, GABAB receptor, AMPA receptor, and glutamate decarboxylase are also predominantly associated with limbic encephalitis
PSYCHIATRIC SYNDROMES OTHER THAN DEMENTIA Table 17.3 Proposed diagnostic criteria for autoimmune encephalitis Diagnosis can be made when all four of the following criteria have been met: 1. Subacute onset (rapid progression of less than 3 months) of working-memory deficits, seizures, or psychiatric symptoms suggesting involvement of the limbic system 2. Bilateral brain abnormalities on T2-weighted fluidattenuated inversion recovery magnetic resonance imaging highly restricted to the medial temporal lobes 3. At least one of the following: ● Cerebrospinal fluid pleocytosis (white blood cell count of more than 5 cells per mm3) ● Electroencephalogram with epileptic or slow-wave activity involving the temporal lobes 4. Reasonable exclusion of alternative causes (Lancet Neurol. 2016; 15(4): 391–404).
(Leypoldt et al., 2015), whereas other antigens are more often associated with different syndromes (Table 17.4). Anti-IgLon5-associated disease frequently presents with sleep disorders, mostly sleep apnea and rapid eye movement sleep behavior disorders, and gait instability, mostly ataxia, dysphagia, and diplopia (Gaig et al., 2017). The clinical hallmark of patients with DPPX antibodies is unexplained diarrhea and weight loss followed by encephalopathic symptoms. In patients with antiGABAaR antibodies, the predominant syndrome is encephalitis with a high risk of seizures or status epilepticus, sometimes leading to a comatose state. In general, specific antibodies in autoimmune encephalitis can be detected in CSF and blood. However, there is evidence that investigation of CSF is slightly more sensitive (Gresa-Arribas et al., 2014), which is why CSF should always be analyzed in suspected cases, particularly when serum antibodies cannot be detected. In the following the individual entities will be discussed with respect to particular CSF findings.
Methods of detection of specific antibodies to neural cell surface antigens Classic onconeuronal antibodies targeting intracellular proteins with linear epitopes can be detected with various techniques, including enzyme-linked immunosorbent assay, immunoblotting, and immunohistochemistry. In contrast, different properties apply to antibodies against neuronal cell surface proteins which should be considered when it comes to assay design and interpretation of results. Discovery of antineural antibodies is a rapidly evolving field and several new autoantigens in
289
autoimmune encephalitis have been reported recently. For discovery reasons in research it is best to use a sensitive assay which may be less specific. In a clinical setting, assays need to be specific and robust. In the field of specific antibody testing three different methods have emerged which are used in different settings: (1) immunohistochemistry/indirect immunofluorescence on adult rat or primate brain slices; (2) immunocytochemistry on living cultured rat hippocampal neurons; and (3) cellbased assays (CBA) for neuronal membrane proteins, as shown in Table 17.5. Most CBAs are commercially available and therefore fit for purpose in clinical laboratories. In a CBA a recombinant antigen is expressed by mammalian cells. The transfected cells are stained with patient serum or CSF using immunofluorescence. When the patient sample contains antibodies directed at this specific antigen, staining of the transfected cells is enhanced when compared to nontransfected cells (Fig. 17.1). In CBAs the antigen mostly maintains its tertiary structure and appropriate posttranslational modifications. This allows for the detection of antibodies directed at conformational epitopes. Most CBAs use human embryonic kidney cells, which are well suited for membrane protein expression (Chaudhary et al., 2011). Some other cell lines for protein expression have also been used, e.g., Chinese hamster ovaries. There is an unresolved issue about use of live cells versus a priori fixed cells. In live cell assays incubation takes place before fixation, whereas in other formats cells are fixed and permeabilized before immunostaining, which is obviously the preferred setting in commercial assays. Comparing these approaches, one study found a higher sensitivity of the fixed CBA (Gresa-Arribas et al., 2014), although theoretically one would not have expected this result. However, different receptors might perform differently depending on native or fixed cell systems (Leite et al., 2008; Irani et al., 2010). In immunohistochemistry the CSF/serum is applied to rat brain slices, meaning that all possible antigens are available and accessible. This method is standard for the detection of onconeural antibodies detecting intracellular antigens. Mostly, clinical laboratories use immunofluorescence on primate cerebellum, with the advantage that commercial kits are available. For the detection of synaptic surface antibodies, pretreatment of rat brain tissue is different from the methods described above (Ances et al., 2005; Dalmau et al., 2007), which leads to stable and well-preserved antigens. Using diaminobenzidine peroxidase or detection antibodies that are fluorescently labeled, antineural antibodies can be visualized. Onconeural antibodies appear with typical patterns (Graus et al., 1997; Sillevis et al., 2002). Cell surface antibodies usually stain
Table 17.4 Classification of encephalitis groups and commonly associated clinical features Encephalitis groups in the present study
Antigen
Number of patientsa
(A) NMDAR encephalitis (n ¼ 53)
NMDAR
(B) Non-NMDAR cell surface antigens (n ¼ 24)
Psychiatric symptoms
Additional symptoms
Typical patient
n ¼ 53 (53%)
Psychosis, schizophreniform illness, catatonia, hallucinations, aggression
Young women, association with ovarian teratomas
Caspr2
n ¼ 4 (4%)
Insomnia, panic attacks, schizophreniform illness, depression
Epileptic seizures, dyskinesia, autonomic instability, speech dysfunction, decreased consciousness Morvan syndrome, neuromyotonia, muscle spasms, fasciculations
LGI1
n ¼ 14 (14%)
Amnesia, confusion, memory deficits, depression
Metabotropic glutamate receptor 5
n ¼ 2 (2%)
Glycine receptor
n ¼ 1 (1%)
Behavioral changes, emotional instability, memory deficits Behavioral changes, schizophreniform syndrome
Metabotropic glutamate receptor 1 GABAA-receptor
Limbic encephalitis, faciobrachial dystonic seizures, hyponatremia, bradycardia Limbic encephalitis, Ophelia syndrome
Cerebellar degeneration
Stiff-person syndrome (SPS) or progressive encephalomyelitis with rigidity and myoclonus, hyperekplexia Hodgkin lymphoma
Encephalitis, seizures
Comatose state
Middle-aged or elderly patients, may be associated with thymoma Middle-aged or elderly patients, male:female (2:1), may be associated with thymoma Young adults, may be associated with Hodgkin lymphoma Middle-aged or elderly patients, may be associated with thymomas and lymphomas Not applicable Not applicable, broad age range, no particular sex preference
GABAB-receptor
Limbic encephalitis
Seizures, ataxia
AMPA receptor
Limbic encephalitis
Sometimes pure psychosis or RPD
DPPX
Unexplained gastrointestinal dysfunction, diarrhea, and loss of weight followed by confusion, seizures, tremor, myoclonus, nystagmus Sleep apnea, REM sleep behavior disorders, ataxia, dysphagia, diplopia Schizophreniform illness, autism, attention-deficit/ hyperactivity disorder
Hyperekplexia
Behavioral changes
Limbic encephalitis, cerebellar degeneration, sensory neuropathy, encephalomyelitis, uveitis, retinopathy, optic neuropathy, chorea
IgLon5
(C) Antibodies against intracellular antigens (n ¼ 23)
Synaptic antigens: anti-GAD antibodies
n ¼ 9 (9%)
Onconeuronal antigens: anti-Yo, -Hu, -CV2, -Ri, Tr2/DNER Ma2 antibodies
n ¼ 14 (14%)
Adult, balanced sex distribution, >50% associated with tumour (SCLC, thymoma), coexisting onconeural antibodies Adult, balanced sex distribution, >50% associated with tumor (SCLC, thymoma), coexisting onconeural antibodies Adult, 4th to 7th decade, severe prodromal weight loss
Not applicable
Adult >50 years, balanced sex distribution
Limbic encephalitis, seizures, SPS, brainstem dysfunction, ataxia
Middle-aged or elderly patients, might be associated with SCLC, tumor screening recommended Elderly patients, often with malignant tumors (SCLC, Hu; testicular seminoma, Ma2)
a Sections A–C refer to the study published by Herken and Pr€uß (2017). The descriptions of other autoantibody-associated diseases (DPPX: anti-dipeptidyl-peptidase-like protein-6, IgLON5, metabotropic glutamate receptor 1, GABAB-receptor, AMPA receptor, DNER) were added by the authors of the present chapter. Caspr2, contactin-associated protein 2; GAD, glutamate decarboxylase; LGI1, leucine-rich glioma inactivated 1; NMDAR, N-methyl-D-aspartate receptor; REM, rapid eye movement; RPD, rapidly progressive dementia; SCLC, small cell lung carcinoma.
Table 17.5 Methods of auto-antibody detection Number of patients reported IHC
ICC of living neurons
NMDAR
>1000
Surface labeling of excitatory Specific staining synapses pattern hippocampus (Hughes et al., 2010) (AIE protocol) (Dalmau et al., 2007) and (Gresa-Arribas et al., 2014)
LGI1
250
Specific staining pattern of hippocampus (AIE protocol) (Lai et al., 2010)
Caspr2
100
GlyR
75
Surface labeling of neurons, Diffuse neuropil not further specified staining (Lancaster et al., 2011a) (AIE protocol) (Lancaster et al., 2011a) Neuropil of brainstem Not published and spinal cord (PNS protocol) (Carvajal-González et al., 2014)
Surface labeling of neurons, not further specified (Lai et al., 2010)
CBA Fixed (Dalmau et al., 2008) and (Gresa-Arribas et al., 2014)
Commercial CBA available Yes
Yes Fixed (with ADAM22/23 coexpression) (Lai et al., 2010) Fixed with added transmembrane part (van Sonderen et al., 2016c) Live (Irani et al., 2010a) Yes Fixed (Lancaster et al., 2011a) Live (Irani et al., 2012) No Live (Carvajal-González et al., 2014)
Sensitivity and specificity Sensitivity IHC: CSF 100%, serum 92% (Gresa-Arribas et al., 2014) Sensitivity fixed CBA: CSF 100%, serum 86% (Gresa-Arribas et al., 2014) Sensitivity IHC plus fixed CBA: CSF 100%, serum 86% (Gresa-Arribas et al., 2014) Specificity IHC plus fixed CBA: CSF 100%, serum 100% (Gresa-Arribas et al., 2014) Sensitivity IHC: CSF 88%, serum 100% (van Sonderen et al., 2016c) Sensitivity fixed CBA: CSF 53%, serum 100% (van Sonderen et al., 2016c) Sensitivity fixed CBA: CSF 100%, serum 100% (van Sonderen et al., 2016a) Sensitivity live CBA: CSF: PERM 100% (Carvajal-González et al., 2014), SPS-spectrum 0% (Martinez-Hernandez et al., 2016), serum: PERM 100% (Carvajal-González et al., 2014) Sensitivity fixed CBA: Serum 92–94% (disease controls) (Martinez-Hernandez et al., 2015) (Martinez-Hernandez et al., 2016)
GABABR
67
DNER
65
AMPAR
64
DPPX
28
DopamineR∗
26
mGluR1
16
IgLon5
10
mGluR5
3
Diffuse neuropil staining (AIE protocol) (Lancaster et al., 2010) and (H€oftberger et al., 2013) PC cytoplasm, punctate staining of molecular layer cerebellum (PNS protocol) (Graus et al., 1997) and (de Graaff et al., 2012) Diffuse neuropil staining (AIE protocol) (Lai et al., 2009) Diffuse neuropil staining (AIE protocol) (Boronat et al., 2013); (Balint et al., 2014); and (Tobin et al., 2014) Staining of basal ganglia (Dale et al., 2012) PC cytoplasm, molecular layer cerebellum (PNS protocol) (Sillevis Smitt et al., 2000) and (Lopez-Chiriboga et al., 2016) Diffuse neuropil staining (AIE protocol) (Sabater et al., 2014) Diffuse neuropil staining (AIE protocol) (Lancaster et al., 2011b)
Surface labeling of neurons, not further specified (Lancaster et al., 2010)
Fixed (Lancaster et al., 2010)
Yes
Sensitivity fixed CBA: CSF 100%, serum 67–93% (Lancaster et al., 2010); (H€ oftberger et al., 2013); and (Jeffery et al., 2013)
Surface labeling of neurons overexpressing DNER (de Graaff et al., 2012)
Fixed (de Graaff et al., 2012) Live (Greene et al., 2014)
Yes
Sensitivity fixed CBA: Serum 100% (Probst et al., 2015) Specificity fixed CBA: Serum 100% (Probst et al., 2015)
Surface labeling of excitatory synapses (Lai et al., 2009)
Fixed (Lai et al., 2009) and (H€ oftberger et al., 2015)
Yes
Specificity fixed CBA: CSF 100%, serum 70% (H€ oftberger et al., 2015)
Surface labeling of both excitatory and inhibitory synapses (Piepgras et al., 2015)
Fixed (Boronat et al., 2013); (Balint et al., 2014); and (Tobin et al., 2014)
Yes
Not available
Surface labeling of neurons, not further specified (Dale et al., 2012) Not published
Live (Dale et al., 2012)
No
Not available
Fixed (Lopez-Chiriboga et al., 2016) and (Iorio et al., 2013)
Yes
Not available
Surface labeling of neurons, not further specified (Sabater et al., 2014)
Live (Sabater et al., 2014)
No
Not available
Surface labeling of neurons, not further specified (Lancaster et al., 2011b)
Fixed (Lancaster et al., 2011b)
Yes
Not available
294
K. BECHTER AND F. DEISENHAMMER
hippocampal synapses, referred to as neuropil (Dalmau et al., 2011; Montojo et al., 2015). However, this approach requires highly experienced and skilled experts to interpret the test results correctly. The advantage is that the method is sensitive and one might detect a broader range of antibodies compared to CBAs, where only the specifically expressed and clearly defined antigens can be recognized. When screening for novel neuronal antigens it needs to be noted that differences between species exist and some human epitopes may be missed in rodents. Live CBAs require neuronal cultures which need to be grown for longer than 14 days and kept alive for the assay procedure (Hughes et al., 2010) – the advantage is selective binding of antibodies, thereby reducing background signals. Obviously, this method is restricted to highly specialized laboratories.
OUTLOOK There is an open issue about definitions of encephalitis and encephalopathy (Venkatesan et al., 2013). The definition of encephalitis includes cases presenting with normal CSF findings, whereas the definition of encephalopathy includes cases with inflammatory CNS disease. The term encephalopathy appears to be mainly based on traded assumptions, though with long-standing observations of an association between systemic inflammation, and the term inflammatory encephalopathy misses a clear pathogenetic concept. Obviously, there is a need for better terms and definitions with respect to primary and secondary CNS diseases leading to psychiatric manifestations. Secondly, exploring the pathomechanism in primary psychotic disorders will be an important challenge, not least to develop more targeted therapies. Given the fact that CSF alterations at a molecular and cellular level can be found in a substantial number of patients, this body fluid plays a pivotal role in this field of research. The rapidly growing number of distinct molecular targets in autoimmune encephalopathies will very likely further increase. Although the proportion of inflammatory/autoimmune diseases is relatively small in acuteonset psychiatric patients, this clearly underscores the importance of CSF in the diagnostic workup of such cases, with clear therapeutic consequences. In turn, a broader use of CSF will increase research activities, leading to a better understanding of psychiatric diseases. Recent developments in laboratory techniques, such as mass spectrometry or electrochemoluminescence, which are becoming more broadly available, will be supportive of new developments in the field.
REFERENCES Ahn S-M, Byun K, Cho K et al. (2008). Human microglia cells synthesize albumin in brain. PLoS One 3. e2829. American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders, 5th ed.American Psychiatric Association, Washington, DC. Ances BM, Vitaliani R, Taylor RA et al. (2005). Treatmentresponsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates. Brain 128: 1764–1777. Anderson G, Berk M, Dodd S et al. (2013). Immunoinflammatory oxidative and nitrosative stress and neuroprogressive pathways in the etiology, course and treatment of schizophrenia. Prog. Neuro-Psychopharmacol Biol Psychiatry 42: 1–4. Bachmann S, Degen C, Geider FJ et al. (2014). Neurological soft signs in the clinical course of schizophrenia: results of a meta-analysis. Front Psychiatry 5: 185. Bay-Richter C, Linderholm KR, Lim CK et al. (2015). A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor in depression and suicidality. BBI 43: 110–117. Bechter K (2012). Diagnosis of infectious or inflammatory psychosyndromes. The Open Neurology Journal 6 (Suppl 1-M6): 113–118. Bechter K (2013). Updating the mild encephalitis hypothesis of schizophrenia. Progr NP&BP 42: 71–91. Bechter K (2016). CSF diagnostics in psychiatry – present status – future developments. Neurol Psychiatry Brain Res 22: 69–74. Bechter K, Reiber H, Herzog S et al. (2010). Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: identification of subgroups with immune responses and blood–CSF barrier dysfunction. J Psychiatr Res 44: 321–330. Benros ME, Mortensen PB, Eaton WW (2012). Autoimmune diseases and infections as risk factors for schizophrenia. Ann N Y Acad Sci 1262: 65–66. Benros ME, Waltoft BL, Nordentoft M et al. (2013). Autoimmune diseases and severe infections as risk factors for mood disorders: a nationwide study. JAMA Psychiatry 70: 812–820. Cannon TD (2016). Microglial activation and the onset of psychosis. Am J Psychiatry 173: 3–4. Cannon TD, Chung Y, He G et al. (2015). Progressive reduction in cortical thickness as psychosis develops: a multisite longitudinal neuroimaging study of youth at elevated clinical risk. Biol Psychiatry 77: 147–157. Chaudhary S, Pak JE, Pedersen BP et al. (2011). Efficient expression screening of human membrane proteins in transiently transfected human embryonic kidney 293S cells. Methods 55: 273–280. Dalmau J, Tuzun E, Wu HY et al. (2007). Paraneoplastic antiN-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 61: 25–36. Dalmau J, Lancaster E, Martinez-Hernandez E et al. (2011). Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 10: 63–74.
PSYCHIATRIC SYNDROMES OTHER THAN DEMENTIA Davis J, Moylan S, Harvey BH et al. (2014). Neuroprogression in schizophrenia: pathways underpinning clinical staging and therapeutic corollaries. Aust N Z J Psychiatry 48: 512–529. Deakin J, Lennox BR, Zandi MS (2014). Antibodies to the N-methyl-D-aspartate receptor and other synaptic proteins in psychosis. Biol Psychiatry 75: 284–291. Debnath M, Berk M (2016). Functional implications of the IL-23/IL-17 immune axis in schizophrenia. Mol Neurobiol. (epub ahead of print). Doorduin J, deVries EF, Willemsen AT et al. (2009). Neuroinflammation in schizophrenia-related psychosis: a PET study. J Nucl Med 50: 1801–1807. Ehrenreich H, Castillo-Gomez E, Oliveira B et al. (2016). Circulating NMDAR1 autoantibodies of different immunoglobulin classes modulate evolution of lesion size in acute ischemic stroke. Neurol Psychiatry Brain Res 22: 9–10. Endres D, Perlov E, Baumgartner A et al. (2015). Immunological findings in psychotic syndromes: a tertiary care hospital’s CSF sample of 180 patients. Front Hum Neurosci 9: 476. Fernandes BS, Steiner J, Molendijk ML et al. (2016). C-reactive protein concentrations across the mood spectrum in bipolar disorder: a systematic review and metaanalysis. Lancet Psychiatry 3: 1147–1156. Gaig C, Graus F, Compta Y et al. (2017). Clinical manifestations of the anti-IgLON5 disease. Neurology 88: 1736–1743. Graus F, Dalmau J, Valldeoriola F et al. (1997). Immunological characterization of a neuronal antibody (anti-Tr) associated with paraneoplastic cerebellar degeneration and Hodgkin’s disease. J Neuroimmunol 74: 55–61. Gresa-Arribas N, Titulaer MJ, Torrents A et al. (2014). Antibody titres at diagnosis and during follow-up of antiNMDA receptor encephalitis: a retrospective study. Lancet Neurol 13: 167–177. Hales RE, Yudofsky SC (2005). Textbook of clinical psychiatry, APP, Arlington. Hammer C, Stepniak B, Schneider A et al. (2013). Neuropsychiatric disease relevance of circulating antiNMDA receptor autoantibodies depends on blood-brain barrier integrity. Mol Psychiatry 19: 1143–1149. Hammer C, Zerche M, Schneider A et al. (2014). Apolipoprotein E4 carrier status plus circulating antiNMDAR1 autoantibodies: association with schizoaffective disorder. Mol Psychiatry 19: 1045–1056. Herken J, Pr€uss H (2017). Red flags: clinical signs for identifying autoimmune encephalitis in psychiatzric patients. Front Psych. https://doi.org/10.3389/fpsyt.2017.00025. Houenou J, d’Albis MA, Daban C et al. (2014). Cytomegalovirus seropositivity and serointensity are associated with hippocampal volume and verbal memory in schizophrenia and bipolar disorder. Prog NeuroPsychopharmacol Biol Psychiatry 48: 142–148. Hughes EG, Peng X, Gleichman AJ et al. (2010). Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci 30: 5866–5875.
295
Irani SR, Bera K, Waters P et al. (2010). N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly nonparaneoplastic disorder of both sexes. Brain 133: 1655–1667. Lang K, Pr€ uß H (2016). Anti-NMDA-Rezeptor-Enzephalitis – eine wichtige Differenzialdiagnose. InFo Neurologie & Psychiatrie 18: 7–8. Leboyer M, Tamouza R, Charron D et al. (2013). Human endogenous retrovirus type W (HERV-W) in schizophrenia: a new avenue of research at the gene-environment interface. World J Biol Psychiatry 14: 80–90. Leite MI, Jacob S, Viegas S et al. (2008). IgG1 antibodies to acetylcholine receptors in ‘seronegative’ myasthenia gravis. Brain 131: 1940–1952. Lennox BR, Coles AJ, Vincent A (2012). Antibody-mediated encephalitis: a treatable cause of schizophrenia. Br J Psychiatry 200: 92–94. Leypoldt F, Armangue T, Dalmau J (2015). Autoimmune encephalopathies. Ann N Y Acad Sci 1338: 94–114. Maxeiner HG, Schneider M, Kurfiss S-T et al. (2014). Cerebrospinal fluid and serum cytokine profiling to detect immune control of infectious and inflammatory neurological and psychiatric diseases. Cytokine 69: 62–67. Maxeiner HG, Rojewski MT, Schmitt A et al. (2009). Flow cytometric analysis of T cell subsets in paired samples of cerebrospinal fluid and peripheral blood from patients with neurological and psychiatric disorders. Brain Behav Immun 23: 134–142. Meyding-Lamade U, Bechter K (2005). Meningoenzephalitis als Ursache psychiatrischer Syndrome – psychisch krank durch Mikroben im Hirn. Info NL&PS 7: 38–45. Montojo MT, Petit-Pedrol M, Graus F et al. (2015). Clinical spectrum and diagnostic value of antibodies against the potassium channel related protein complex. Neurologia 30: 295–301. M€ uller N, Riedel M, Blendinger C et al. (2004). Mycoplasma pneumoniae infection and Tourette’s syndrome. Psychiatry Res 129: 119125. Myint AM, Kim YK (2014). Network beyond IDO in psychiatric disorders: revisiting neurodegeneration hypothesis. Progress NP&BP 48: 304–313. Najjar S, Pearlman D, Devinsky O et al. (2013). Neuropsychiatric autoimmune encephalitis without VGKC-complex, NMDAR, and GAD autoantibodies: case report and literature review. Cogn Behav Neurol 26: 36–49. Perry VH, Teeling J (2013). Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration. Semin Immunopathol 35: 601–612. Schwarz E, van Beveren NJM, Ramsey J et al. (2014). Identification of subgroups of schizophrenia patients with changes in either immune or growth factor and hormonal pathway. Schizophr Bull 40: 787–795. Sekar A, Al Bialas, de Rivera H et al. (2016). Schizophrenia risk from complex variation of complement component. Nature 530: 177–183.
296
K. BECHTER AND F. DEISENHAMMER
Sillevis SP, Grefkens J, de LB et al. (2002). Survival and outcome in 73 anti-Hu positive patients with paraneoplastic encephalomyelitis/sensory neuronopathy. J Neurol 249: 745–753. Steiner J, Walter M, Glanz W et al. (2013). Increased prevalence of diverse N-methyl-D-aspartate glutamate receptor antibodies in patients with an initial diagnosis of schizophrenia: specific relevance of IgG NR1a antibodies for distinction from N-methyl-D-aspartate glutamate receptor encephalitis. JAMA Psychiatry 70: 271–278.
Tandon R, Gaebel W, Barch DM et al. (2013). Definition and description of schizophrenia in the DSM-5. Schizophr Res 150: 3–10. Titulaer MJ, McCracken L, Gabilondo I et al. (2013). Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 12: 157–165. Venkatesan A, Tunkel AR, Bloch KC et al. (2013). Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the International Encephalitis Consortium. Clin Infect Dis 57: 1114–1128.