Background

Schizophrenia and other psychotic disorders are severe and frequent conditions characterized by delusions, hallucinations, disorganization, formal thinking changes, catatonia, and different negative symptoms typically occurring for the first-time during adolescence and early adulthood [65]. Primary schizophreniform psychoses are caused by a complex interaction between multiple genes and environmental factors [81]. Large, genome-wide studies have identified over 100 distinct gene sites that contribute to the relative risk of psychotic symptoms [73]. Secondary forms are based on clearly identifiable causes in the sense of etiology or according to recognizable pathogenesis [45, 81]. Such secondary forms can be linked to autoantibody (Ab)-associated autoimmune processes such as anti-N-Methyl-d-aspartate receptor [NMDA-R] encephalitis [44]. In 2007, the field of autoimmune encephalitis (AE) was redefined with the first description of anti-NMDA-R encephalitis [16, 18, 19]. Since then, a large number of other antineuronal Abs against cell surface antigens and their associated syndromes have been identified [15, 17, 31, 89, 90]. Because these syndromes can be accompanied by polymorphic psychotic symptoms, immunological concepts of schizophreniform psychoses have gained considerable attention since [1, 6, 15, 22, 36, 67, 68, 76, 77, 78, 84]. In a German case series of 100 patients with different forms of AEs with Abs against antineuronal antigens, over half of the patients (60%) presented with psychotic symptoms [36]. In most cases that are positive for antineuronal Abs, patients develop clear neurological symptoms in the course of the disease, such as dystonic movement disorders or epileptic seizures [31, 36, 51]. For AE with predominant psychotic symptoms, the term “autoimmune psychosis” (AP) was recently suggested [21, 61, 67]. The changing nomenclature for autoimmune neuropsychiatric phenomena is summarized in Box 1.

Rationale

The awareness of the fact that psychotic syndromes may have autoimmune, Ab-associated causes opens up a new field in psychiatry for a small but probable relevant subgroup of patients. For clinicians, this raises the question as to how far the diagnostic workup and immunomodulating therapy attempts should be advanced in individual cases. This article investigates this question by illustrating constellations in which extended organic diagnostic procedures, especially Ab analyses, should be carried out.

Clinical symptomatology

The syndrome of possible autoimmune encephalitis

In a current consensus article, experts in the field of neurology and neuroimmunology described the syndrome diagnosis of a possible AE. Accordingly, an autoimmune etiology should be considered if the following criteria are present:

  1. 1.

    Subacute onset (less than 3 months) of deficits in working memory, altered mental state (changes in consciousness, changes in personality, or lethargy) or psychiatric (e.g., psychotic) symptoms.

  2. 2.

    One of the following findings:

    • New focal neurological symptoms.

    • New epileptic seizures.

    • Magnetic resonance imaging (MRI) signs of “encephalitis” (temporal FLAIR hyperintensities, multifocal demyelinating or inflammatory lesions).

    • Cerebrospinal fluid (CSF) pleocytosis (> 5 per mm3).

  3. 3.

    Exclusion of other causes (see Table 4; [31]).

Established neuropsychiatric syndromes

From a clinical perspective, different established Ab-associated neuropsychiatric syndromes with generally mixed psychiatric and neurological symptoms can be identified (Table 1). In particular, limbic and anti-NMDA-R encephalitis are established central nervous system (CNS) syndromes that can go along with psychotic syndromes [31]. Various Ab-associated immunological systemic diseases, such as the prototype of neuropsychiatric systemic lupus erythematosus (NP-SLE), but also antiphospholipid syndrome, Sjögren’s syndrome, scleroderma, or (ANCA associated) vasculitis may also be associated with psychotic syndromes [63].

Table 1 Main neuropsychiatric autoimmune encephalitides associated with psychotic symptoms
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  • Limbic encephalitis (LE): LE is characterized by the subacute development of deficits in working memory, paranoid symptoms, hallucinations, irritability, affective symptoms including emotional instability, and epileptic seizures with leading temporal semiology [68]. LE is often associated with specific Abs against cell surface antigens (e.g., LGI-1, GABAB-R, and AMPA-R) or intracellular antigens (e.g., GAD65, Hu, and Ma2 [31, 52]).

  • Anti-NMDA-R encephalitis: This is the most common form of AE, and case series with > 500 patients are published [86]. Tumor association depends on age and gender: in children, tumor association is rare. By contrast, 58% of women from 18 to 45 years suffered from paraneoplastic forms, most commonly with ovarian teratomas [15, 86]. The symptoms usually develop in similar phases including psychotic/catatonic symptoms ([14, 15]; Fig. 1) or in case of relapses [44].

    Fig. 1
    figure 1

    Typical course of anti-NMDA-R encephalitis [14, 15, 18, 22, 52, 70]

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  • Hashimoto’s encephalopathy/steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT): This is a nosologically unclear, probably etiologically heterogeneous syndromatic diagnosis based on the detection of antibodies against specific thyroid antigens (TPO, TG), non-specific paraclinical findings [e.g., blood–brain barrier (BBB) dysfunction in CSF, electroencephalography (EEG) slowing, MRI white matter lesions, after exclusion of antineuronal Abs in serum and CSF (including tissue-based assay)], and steroid responsiveness [22, 48]. Most authors argue that the thyroid Abs have no functional relevance, are rather indicators of an increased autoimmune susceptibility and that, therefore, this diagnosis will decrease with the further discovery of new, specific antineuronal Abs. In line with these observations, a recent study indicates that the current criteria (see Table 1) do not allow a prediction of steroid responsiveness [57]. Better additional clinical, laboratory or instrumental-based diagnostic parameters as predictors of steroid response need to be explored; the criteria of Hashimoto’s encephalopathy must, therefore, be viewed critically [57].

  • Neuropsychiatric SLE (NP-SLE): The clinical picture of NP-SLE is usually a mixed neurological and psychiatric presentation, with systemic signs often providing decisive diagnostic indications. However, rare cases may present primarily with a classical schizophreniform phenotype [54]. The American College of Rheumatology (ACR) criteria are well established (Table 1), newer classification criteria such as the Systemic Lupus Collaborating Clinics (SLICC) criteria take laboratory findings more into account (https://www.rheumatology.org/Practice-Quality/Clinical-Support/Criteria/ACR-Endorsed-Criteria; [66]).

Predominant and isolated autoimmune psychosis

In addition to the established main neuropsychiatric syndromes, milder Ab-associated autoimmune disorders with predominant or even isolated schizophreniform psychosis have been described in individual cases [23,24,25, 27,28,29, 44, 54, 56, 83]. For a subgroup of 23 out of 571 (4%) patients with anti-NMDA-R encephalitis, Kayser and colleagues described episodes with purely psychiatric presentations. Five patients developed an initial encephalitis with isolated psychotic symptoms (0.9%), and 18 patients (3.2%) had isolated psychiatric symptoms during a relapse [44]. In the meantime, cases with isolated anti-NMDA-R Ab detection in the serum and typical [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) alterations were published [28]. In a case collection of 46 classic psychiatric Hashimoto encephalopathy cases, 12 patients suffered from acute psychosis (26.1%), and one patient met the criteria for schizophrenia (2.2%) [59]. Abs against intracellular antigens also may be associated with classical schizophreniform syndromes in rare individual cases [24, 60]. Tissue-based assays helped to detect new antineuronal Abs with neuropil pattern and yet unspecified target epitopes [27]. For such psychiatric manifestations of AE, the concept of AP was suggested and consensus criteria for possible, probable, and definite AP have recently been proposed for the first time ([67]; Table 2).

Table 2 The criteria of possible, probable, and definite autoimmune psychosis [67]
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Red flags that should lead to antibody diagnostics

The relatively rapid development of a psychotic syndrome, atypical and often polymorphic clinical symptoms and the presence of other neurological and/or medical symptoms are typical signs in autoimmune pathogenesis and thus should prompt broad Ab analyses [22]. Certain constellations in the course of the disease and typical additional findings should also trigger clinicians to consider the possibility of an AE/AP (Fig. 2; [2, 22, 36, 67, 76, 77, 84, 85]).

Fig. 2
figure 2

Red flags that should lead to antibody diagnostics (according to [2, 5, 22, 36, 53, 55, 61, 67, 74, 76, 77, 85]). EEG electroencephalography, MRI magnetic resonance imaging

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Pathophysiology

Established antineuronal antibodies

Abs against neuronal epitopes can be divided into Abs against cell surface antigens, which are most frequently associated with schizophreniform psychoses, and those against intracellular antigens [15, 36, 67].

  • Abs against cell surface antigens These Abs bind to synaptic receptors, ion channels, or other cell surface proteins. This enables pathogenic Abs to lead to functional changes in electrophysiological signaling or synaptic transmission [8, 47, 68]. Therefore, they can have a direct pathogenic meaning. The exact pathophysiological processes are partly understood. Ab formation can be tumor-triggered. In addition, herpes simplex or other infections can act as triggers of the pathogenic process [4, 42]. Apart from that, Ab production can be the expression of autoimmune predisposition [15]. The initial hope that the anti-NMDA-R Abs at disease onset could provide an explanation for the glutamate hypothesis of schizophrenia [75, 87] could not be confirmed. Some of the largest Ab studies to date (with > 1000 schizophrenia patients), which were limited to blood serum examinations, have shown similar prevalence rates of different Abs (across all Ab classes, especially IgA and IgM isotypes) in the serum of patients with schizophrenia and controls, predominantly with very low Ab titers [13, 33]. At the same time, Ab detection in CSF appears to be less frequently [26, 64]; in a study of 124 patients with schizophrenia spectrum disorders, even all CSF tests were negative for antibodies against NMDAR, AMPAR, CASPR2, LGI1, and GABAA/BR [64].

  • Abs against intracellular antigens Abs against non-synaptic intracellular antigens (e.g., Hu) typically occur paraneoplastically and have no direct pathogenic effect. They merely represent an epiphenomenon of a systemic tumor-triggered immune process. The cause of the inflammatory brain damage is a misguided response of cytotoxic T cells [51, 79]. There are often early and irreversible structural neuronal damages [79]. Abs against synaptic intracellular antigens are the “stiff-person spectrum” Abs against GAD65 and amphiphysin [51]. Anti-GAD65 Abs are more common idiopathically, and it has not been conclusively determined whether they have a pathogenetic significance or are only an epiphenomenon of another immune process [15].

Systemic “possibly antineuronal” antibodies

These Abs do not bind exclusively to neuronal structures and can also be found together with antineuronal Abs in the context of an autoimmune predisposition [52]. Antinuclear antibodies (ANAs) can bind to ubiquitous nuclear structures (e.g., ds-DNA), but also to NMDA receptors and activate them. Therefore, excitotoxicity mediated by an acute NMDA receptor as well as subacute activation of microglia cells can lead to the destruction of synapses [62]. Thyroid Abs also occurs in about 13% of the healthy population [31], and serum Ab titers do not clearly correlate with symptom expression [48]; therefore, most authors have regarded them as an epiphenomenon [22].

Diagnostic approach

Indication for antibody analyses

The indication for serum and CSF Ab analyses results from the above-mentioned red flags (Fig. 2). The following considerations and operationalizations represent a kind of clinical consent among the authors who are all active in clinical diagnosis and management of new onset psychiatric and in particular psychotic patients. In the authors’ opinion, Ab measurements should be performed at least in the following constellation (compare with [36, 61, 67, 76, 77, 82, 85]):

The combination of acute or peracute onset of a first schizophreniform psychotic episode OR psychotic symptoms after AE in the past AND according to Fig. 2:

 at least one typical clinical finding OR

 at least one sign of typical autoimmune course OR

 at least one typical examination finding [82, 85].

All serum-Ab findings should be interpreted in the context of extended history data, the clinical syndrome, and the examination findings (especially including CSF Ab testing; [51, 82, 85]). The following investigations are suggested for patients with potential immunological genesis [82, 85]:

  • Extended history: Infections/infectious prodroms and tumors should be looked for as possible triggers of Ab production. Attention should also be paid to a predisposition for immunological systemic diseases (presence of rheumatological diseases, inflammatory skin diseases, etc.). In addition, risk factors (such as earlier epileptic seizures, earlier episodes with encephalitides, infections), systemic signs (e.g., CNS or gastrointestinal symptoms), patient’s medication history (e.g., tolerability of antipsychotics), and family history should be inquired into.

  • Medical and neurological physical examination: The medical examination should focus on possible signs for autonomic dysfunction or feverish conditions. In addition, attention should be paid to newly occurring neurological symptoms such as dyskinesia, or myoclonus.

  • Neuropsychological testing: Neuropsychological testing should be considered to objectify more subtle cognitive deficits and to establish an objective follow-up parameter. The corresponding diagnostics can be based on standards of the established German GENERATE network (https://generate-net.de/generate-sops.html), which recommends carrying out bedside screening tests such as the Montreal Cognitive Assessment and extended tests such as the Test Battery for Attention Testing, Verbal Learning and Memory Test, Ray Rey-Osterrieth Complex Figure Test, or Frontal Assessment Battery, etc.

  • Laboratory measurements: The basic parameters of CSF are very important for differential diagnostic considerations. Pleocytosis or CSF-specific OCBs provide information about a possible inflammatory process in the CNS. Based on the level of pleocytosis, autoimmune and infectious inflammations can often be distinguished [69]. Autoimmune genesis is usually accompanied by mild pleocytosis (from ≥ 5 to 100 per mm3; [31]), and the albumin quotient CSF/serum informs about the blood-CSF-barrier function, which should be assessed using the Reiber scheme [39, 72]. Serological analyses should exclude hyponatremia, which can be associated with anti-LGI1 Abs [88]. Box 2 puts forward a proposal for a two-step Ab diagnostic approach (compare with [82]). The determination of CSF is more sensitive for some Abs against established neuronal surface antigens; up to 14% of patients with anti-NMDA-R encephalitis had anti-NMDA-R Abs only in CSF [32]. The determination of Abs in serum and CSF enables the calculation of Ab indices (normalized to the total IgG ratio CSF/blood and the BBB function; [92]). Infectious (e.g., viral encephalitis), toxic, and other causes should be excluded.

  • EEG: It is a sensitive, although not very specific, tool in the diagnosis of AEs [48, 86]. EEG examinations should, therefore, be carried out on a low-threshold basis [82, 85].

  • Imaging: In LEs, MRI diagnostics usually show mesiotemporal hyperintensities in the T2 or FLAIR sequences [35]. In AEs with Abs against neuronal cell surface antigens, MRI often remains inconspicuous [35, 86]. The following sequences are suggested by the German GENERATE network: FLAIR axial + FLAIR coronary hippocampal view, T2 coronary, DWI axial and coronary, T2* axial or SWI, T1 + contrast agent axial, T1-MPRAGE (1 × 1 × 1 mm; before contrast agent; https://generate-net.de/generate-sops.html). If the findings remain unclear, an FDG-PET examination can be considered for specific questions. Compared to MRI, FDG-PET possibly has higher sensitivity for inflammatory changes ([5, 28, 35]; Fig. 3).

    Fig. 3
    figure 3

    (©Endres et al., 2019, Front Neurol. Nov 5 [28]: https://www.frontiersin.org/articles/10.3389/fneur.2019.01086/full)

    Findings of a 21-year-old female patient with probable anti-NMDA-R encephalitis. Magnetic resonance imaging depicted only a few slight, nonspecific bifrontal white matter lesions. [18F]fluorodeoxyglucose positron emission tomography showed pronounced relative hypermetabolism of her association cortices and a relative hypometabolism of the primary cortices (at baseline), which quickly improved during the follow-up examination after anti-inflammatory treatment

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  • Tumor screening Tumor screening is essential in the event of the detection of paraneoplastic, onconeural antineuronal Abs.

Organic differential diagnosis

Primary forms of schizophreniform psychoses must be distinguished not only from secondary Ab-mediated AEs but also from other CNS diseases (Table 4).

Table 4 The most important organic differential diagnoses [31, 45, 81, 82, 84, 85]
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Therapeutic experiences and considerations

For the treatment of AE/AP, not only are the classical symptomatic therapy approaches available, but more causal therapy options also exist with immunosuppressive agents and in case of paraneoplastic disease with tumor treatment. Immunosuppressive and tumor therapy should be coordinated in a multidisciplinary setting [76, 77, 82]. Because controlled therapy studies are not yet available, immunosuppressive treatments have so far been carried out in the form of individual therapy trials [79, 90].

Symptomatic treatment

The risk for extrapyramidal motor side effects seems to be increased in patients with AEs [49, 67, 76, 77]. Therefore, psychotic symptoms in the context of AP can be symptomatically treated with antipsychotics with a low risk for motor side effects [76, 77]. Benzodiazepines can be used for anxiolysis and sedation and, in higher doses, for the treatment of catatonic symptoms [76, 77].

Causal immunosuppressive/tumor treatment

The first-line therapy for established AEs is high-dose steroids (e.g., 500–1000 mg methylprednisolone over three to five days; [11, 76, 77, 82, 84]). Possible steroid-induced affective, suicidality, psychotic, and other side effects must be explained in advance [30] and closely monitored. Based on previous experiences, intravenous immunoglobulins or plasmapheresis/immunoadsorption can also be used as a first-line treatment [31, 51, 58, 76, 77, 79]. Rituximab or cyclophosphamide are recommended as “escalation”/“second line” therapies [11, 31, 51, 58, 76, 77, 79]. If relapse prevention turns out to be necessary, azathioprine, mycophenolate mofetil, or methotrexate are often used ([51]; Fig. 4). The decision for immunomodulatory maintenance/relapse prevention therapies is often complicated, depending on several factors, and should, therefore, only be made after a multidisciplinary discussion and under regular follow-up investigations. Depending on the Ab type, slightly different approaches have been established, which cannot be discussed in detail here. The aim of tumor treatment in paraneoplastic syndromes is to switch off the ectopic antigen source that maintains the autoimmune process ([79], Table 3).

Fig. 4
figure 4

Therapeutic experiences and considerations for patients with autoimmune encephalitides and established antineuronal antibodies [11, 51, 58, 76, 77, 79, 82]. However, in individual cases, special features must be taken into account, depending on the individual autoantibodies/syndromes/circumstances. *Rituximab is increasingly used as a first-line therapy. **Treatment with cyclophosphamide should be used only with caution in young patients because of the relevant germ cell damage

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Limitations

The recommendations worked out here for Abs assessment and respective diagnostic and therapeutic consequences in schizophreniform psychoses were based on consensus from emerging clinical evidence rather than from systematic randomized studies as is the case with the present recommendations for diagnosis and treatment of AE [31]. Beyond, it should be recognized that indeed both well-established clinical terms (like encephalitis, encephalopathy, neuroinflammation) and newly proposed terms (such as AP, AE) are hardly exactly defined, thus for clinical use typically represent just clinical case definitions based on respective limited and steadily emerging clinical consensus [6, 12]. In addition, the possibility of underlying so far not identified new Abs is also limiting the whole issue. Finally, it should be pointed out again that low-positive serum antineuronal Ab titers without signs of brain involvement may occur nonspecifically and do not provide indication for treatment [13, 33, 50, 67].

Conclusion

AE/AP represent a new field for psychiatry. The exact prevalence and thus clinical relevance of classical psychotic manifestations of AEs cannot yet be clearly established. However, the fact that predominant and even isolated psychotic clinical pictures may arise as a result of such AEs in certain cases is casuistically proven for most of the subtypes discussed here and already led to the first immunological treatment trials in Ab seropositive patients with psychosis [50]. Additionally, the topic has been captured in the new German S3 guideline for schizophrenia [20]. Future randomized-controlled and multimodal trials also taking into consideration CSF-results and Ab-titers are needed to shed more light on the relationship between the Abs and the outcome of psychosis discussed here.