Autoimmune encephalitis as a differential diagnosis of schizophreniform psychosis: clinical symptomatology, pathophysiology, diagnostic approach, and therapeutic considerations

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


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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.

Box 1: Different nomenclature [6, 22]
Encephalopathy: Traditionally, this term has been used mainly for persistent brain damage. The term has also been used when secondary brain damage was assumed, but the exact mechanism of the disease remained unclear (e.g., hepatic or epileptic encephalopathy). Because antineuronal autoantibodies (Abs) can now be detected, cases of encephalopathy not previously recognized as neuroinflammatory can comply with the criteria of autoimmune encephalitis.
Limbic encephalitis (LE): LE has developed in the context of paraneoplastic encephalitis, which has been known for some time and has undergone a change in meaning in the discourse of the last decade. Originally, the term described a clinical focal point syndrome. Currently, the term is mainly used syndromally, as a description of a clinical syndrome [31].
Autoimmune encephalitis (AE): The term has largely established itself as an umbrella term for Ab-associated immune-mediated neuropsychiatric syndromes. It is also used to describe Ab-negative, probable AE. In an international consensus paper from global experts in the field of neurology and neuroimmunology, they have suggested a clinical approach to the diagnosis of autoimmune encephalitis [31].
Autoimmune psychosis (AP): AP describes a syndrome with predominant psychoses and a probable autoimmune pathophysiology [21,61,67]. Initially, a distinction among the following groups was suggested: (1) psychoses with detection of classical antineuronal Abs, (2) psychoses associated with systemic inflammatory and autoimmune diseases, and (3) Ab-negative AP [61]. The authors of a recent expert consensus paper defined criteria for a possible, probable, and definite AP [67].

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. 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. 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 mm 3 ). Table 4; [31]).
• 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, GABA B -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]. • 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].
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.rheum atolo gy.org/ Pract ice-Quali ty/Clini cal-Suppo rt/Crite ria/ACR-Endor sed-Crite ria; [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 [23-25, 27-29, 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 Fig. 1 Typical course of anti-NMDA-R encephalitis [14,15,18,22,52,70] 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 [ 18 F]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).

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]).

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 tumortriggered. 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 GABA A/B R [64]. • Abs against intracellular antigens Abs against nonsynaptic 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].

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].

Fig. 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 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] 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 mm 3 ; [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].

Box 2: Methodological aspects and suggestions for two-step antibody measurements
Basic measurement methods for the detection of antineuronal antibodies against cell surface antigens (especially against NMDA-R; [41,47,76,77,82,85]): • Screening tests: Commercially available cell-based assays (CBAs) using indirect immunofluorescence (IF) on fixed cells expressing synaptic or neuronal cell surface proteins (also called "biochip assays") are often used for screening. These tests might be less sensitive in patients with psychosis. However, they allow directly an exact detection of the target epitope. • CBAs on live mammalian cells (so-called live CBAs) might show higher sensitivity for some surface antibodies (e.g., AMPA-R-abs); however, they are currently available only in special laboratories. • Tissue-based assays: IF or immunohistochemical screening tests on brain sections of rodents can also detect previously unknown Abs. With their application, the percentage of "seronegative" cases is expected to decrease. Commercially available tissuebased tests are considered to be less sensitive than research laboratory approaches.

Basic antibody screening for patients with schizophreniform psychoses should contain at least the most common IgG antibodies against the following antigens
[82]: In the second step (in cases of negative screening and justified suspicion-compare Table 3), IgG antibodies against the following antigens can be added anticardiolipin Abs, lupus anticoagulant; in serum/ citrate tube).

Immunofluorescence screening tests on brain sections of rodents ("tissue-based assays") can also detect previously unknown antineuronal antibodies.
For the second step, CSF material can be stored and cooled at 4 °C for at least four to 6 weeks; alternatively, the CSF material can be deep-frozen at − 80 °C [82].
*In line with the authors' clinical experience, only the Abs most frequently associated with schizophreniform psychoses are mentioned.

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).

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).

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 Table 3 The most important known autoantibodies that can be associated with symptoms of schizophreniform psychoses [9,15,31,34,36,37,38,48,63,71,79,81,82,84,85,90] Antigen Established neuropsychiatric syndrome(s) 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 CSFresults and Ab-titers are needed to shed more light on the relationship between the Abs and the outcome of psychosis discussed here. No tumor association known a Directed against an extracellular neuronal antigen (delta/notch-like epidermal growth factor-related receptor). For a full list of abbreviations, see appendix 1 3 Table 4 The most important organic differential diagnoses [31,45,81,82,84,85] Inflammatory disorders Non-inflammatory disorders CNS infections (e.g., neuro-borreliosis, neuro-syphilis, Whipple's disease, Herpes simplex virus encephalitis, HIV infection, Creutzfeldt-Jakob disease) Demyelinating CNS diseases (e.g., multiple sclerosis, acute disseminated encephalomyelitis); neuromyelitis optica-spectrum diseases Other rheumatological diseases with brain involvement (e.g., neurosarcoidosis, Behcet's disease) Primary/secondary CNS vasculitis Other immunological diseases: Rasmussen encephalitis, CLIPPERS etc. Progressive multifocal leukoencephalopathy (JC-Virus infection) Intoxication (illegal drugs such as amphetamines or cannabis) Inborn Errors of Metabolism (e.g., Niemann-Pick type C, acute intermittent porphyria, phenylketonuria, glycogen storage disorders) Mitochondriopathies Congenital disorders (e.g., velocardiofacial syndrome, agenesis of corpus callosum) Seizure disorders (e.g., temporal lobe epilepsy, paraepileptic psychoses) Endocrinological diseases (e.g., Cushing's disease, hypoparathyroidism, hyperparathyroidism) Craniocerebral trauma Vitamin deficiency (e.g., B1, folic acid, B12) Toxic-metabolic causes (e.g., anticonvulsants, steroid treatment; hepatic/uremic encephalopathy) Vascular hypoxic damage (strategic stroke lesions) Neoplasias (e.g., gliomas, lymphomas, meningitis neoplastica) Basal ganglia diseases (e.g., Parkinson's disease, chorea minor, Wilson's disease, pantothenate-kinase associated neurodegeneration, Huntington's disease) Neurodegenerative-dementia syndromes (e.g., frontotemporal dementia, Lewy body dementia etc.) Creutzfeldt-Jakob disease  [11,51,58,76,77,79,82]. However, in individual cases, special features must be taken into account, depending on the individual autoan-tibodies/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 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/.