Background
Box 1: Different nomenclature [6, 22]
Rationale
Clinical symptomatology
The syndrome of possible autoimmune encephalitis
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New focal neurological symptoms.
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New epileptic seizures.
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Magnetic resonance imaging (MRI) signs of “encephalitis” (temporal FLAIR hyperintensities, multifocal demyelinating or inflammatory lesions).
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Cerebrospinal fluid (CSF) pleocytosis (> 5 per mm3).
Established neuropsychiatric syndromes
Limbic encephalitis | Anti-NMDA-R encephalitis | Hashimoto encephalopathy | Neuropsychiatric SLE | |
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Age and gender | Mostly elderly patients, but in all ages possible | Especially in girls/young women and children | More common among women; average age 52 years (large range) | Most common in young/middle-aged women |
Clinical symptoms and para-clinical findings | 1. Subacute onset of working memory deficits, epileptic seizures, or psychiatric symptoms indicating involvement of the limbic system 2. Temporal MRI or FDG-PET pathologies 3. One of the following findings: CSF pleocytosis Temporal EEG pathologies 4. Exclusion of other causes | 1. Subacute onset with at least four of the following symptoms: Behavioral or cognitive deficits Speech dysfunction Epileptic seizures Movement disorders, dyskinesia, or rigidity Disturbances of consciousness Autonomic dysfunction or central hypoventilation 2. One of the following findings: EEG changes (incl. extreme delta brush) CSF pleocytosis or oligoclonal bands 3. Exclusion of other causes | 1. Encephalopathy with hallucinations, myoclonus, epileptic seizures or stroke-like episodes 2. Subclinical or mild thyroid dysfunction (often hypothyroidism) 3. Normal MRI or nonspecific changes 4. Elevated thyroid Abs in serum 5. No evidence of currently established antineuronal Abs in CSF or serum (incl. “screening” using tissue-based assays) 6. Exclusion of other causes | 1. Malar rash 2. Discoid rash 3. Photosensitivity 4. Oral ulcers 5. Non-erosive arthritis 6. Pleuritis/pericarditis 7. Kidney involvement 8. Epileptic seizures or psychosis 9. Hematological involvement, (hemolytic anemia, leukopenia, lymphopenia, thrombopenia) 10. Immunological markers (anti-ds-DNA, Anti-Sm, antiphospholipid Abs) 11 ANA detection |
Diagnostic criteria | All four criteria must be fulfilled for diagnosis. If one of criteria 1–3 is not met, the diagnosis can be made only if currently established antineuronal Abs are detected | If all three criteria are met, a syndrome diagnosis can be made. Only three groups of symptoms are required after the detection of a teratoma. The diagnosis is confirmed by Ab detection; in cases of Ab detection, one symptom (under heading 1) is sufficient for diagnosis | All six criteria must be fulfilled (the authors recommend speaking of Hashimoto encephalopathy only when improvement of treatment with steroids or other immunosuppressive procedures was documented → according to the idea of steroid-responsive encephalopathy) | Four criteria (at least one clinical and one immunological criterion) must be fulfilled |
EEG | Mostly temporal or frontal epileptic activity and rhythmic delta/theta activity in the EEG | Delta slowing, dysrhythmias, partial epileptic activity/beta-delta complexes, special pattern: the specific finding of “extreme delta brush” | Frequent EEG pathologies with slowing or less often epileptic activity | EEG alterations in approx. 80%, often diffuse theta or delta slowing or epileptic activity |
Imaging | Mostly uni- or bilateral mesiotemporal T2/FLAIR hyperintensities; in 10–20% of cases, the MRI remains inconspicuous (in such cases, an FDG-PET might help to objectify the mesiotemporal pathology) | MRI mostly normal, abnormalities only in 33%! T2/FLAIR hyperintensities in the hippocampi, cerebellar, or cerebral cortex, frontobasal, in the insular cortex, in the basal ganglia, and in the brain stem were described | In about half of the patients MRI pathologies, mostly non-specific white matter lesions | MRI changes in 30-75%, mostly T2w hyperintense lesions in the subcortical and deep white matter and around the lateral ventricles, as well as atrophy and cerebral infarction |
CSF/serum | Often mild to moderate pleocytosis (i.e., 6–100 cells per mm3; in 60–80%, but only in 41% of cases with anti-LGI1 Abs); OCBs in approx. 50% of cases | Moderate pleocytosis, increased total protein concentration, and OCBs (CSF abnormalities in approx. 79%). | Mostly increased anti-TPO and anti-TG Abs (in 69%); less often, isolated increased anti-TPO/TG Abs; often, increased protein concentrations in CSF (82%), and slight CSF pleocytosis in 20% | Increased ANA titers, anti-dsDNA Abs/anti-Sm/anti-rib. P/anti-nucleosome Abs; increased antiphospholipid Abs; CSF pleocytosis in approx. 30%, increased total protein in approx. half of the patients, and OCBs in one-third of those affected |
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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]).
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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].×
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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].
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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
Possible autoimmune psychosis | Probable autoimmune psychosis | Definite autoimmune psychosis |
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Psychotic episode with abrupt onset (less than 3 months) with at least one of the following: 1. Tumor, 2. Movement disorder (catatonia/dyskinesia), 3. Adverse response to antipsychotics indicative of neuroleptic malignant syndrome, 4. Severe/disproportionate cognitive dysfunction, 5. Decreased level of consciousness, 6. New seizures 7. Significant autonomic dysfunction (pathological fluctuant blood pressure, temperature or heart rate) | Meeting the criteria for possible AP and At least one of the following: 1. CSF pleocytosis (> 5 per mm3) 2. Bilateral brain abnormalities on T2-weighted fluid-attenuated inversion recovery MRI highly restricted to the medial temporal lobes Or two of the following: 1. “Encephalopathic” EEG alterations (i.e., spikes, spike-wave activity, rhythmic slowing, focal changes or extreme delta brush) 2. CSF specific OCBs and/or increased IgG index 3. The presence of a serum anti-neuronal antibody detected by cell-based assay After exclusion of alternative causes | Meeting the criteria for probable AP and Evidence for IgG anti-neuronal antibodies in CSF. |
Red flags that should lead to antibody diagnostics
Pathophysiology
Established antineuronal antibodies
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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].
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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
Diagnostic approach
Indication for antibody analyses
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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.
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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.
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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.
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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.
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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).×
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Tumor screening Tumor screening is essential in the event of the detection of paraneoplastic, onconeural antineuronal Abs.
Box 2: Methodological aspects and suggestions for two-step antibody measurements
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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.
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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.
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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 tissue-based tests are considered to be less sensitive than research laboratory approaches.
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NMDA-R, CASPR2, LGI1, AMPA-R, GABAB-R, GAD65 (in serum and CSF).
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Hu, Ri, Yo, CV2/CRMP5, Ma2 [Ta], Amphiphysin (in serum, CSF testing can be added if the serum is positive).
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TPO, TG, ANA (in serum).
Antigen | Established neuropsychiatric syndrome(s) | Typical symptomatology | Tumor association |
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Antibodies against neuronal cell surface antigens | |||
AMPA-R (GluR1/2) | Limbic encephalitis | Atypical psychosis, memory deficits, confusion | In approx. 65%, mostly with small cell bronchial carcinoma or thymomas |
CASPR2 | Morvan syndrome; limbic encephalitis | Psychotic and depressive symptoms, memory disorder, sleep disorder, neuromyotonia | In approx. 20–50% of patients (with morvan syndrome) thymomas |
DPPX | Encephalitis, hyperekplexia, stiff-person spectrum | Delusion, hallucinations, cognitive deficits, confusion, diarrhea and other gastrointestinal symptoms, weight loss, hyperekplexia | Lymphoma in < 10% |
GABAA-R | Limbic encephalitis with refractory epileptic seizures, epileptic status | Catatonia, therapy-refractory seizures, epileptic status | Tumors are unusual, thymomas in < 5% |
GABAB-R | Limbic encephalitis with early and pronounced seizures | Memory deficits, seizures, orolingual dyskinesia | In approx. 50%, mostly with small cell bronchial carcinoma |
Glycine-R | Progressive encephalomyelitis with rigidity and myoclonus (PERM), Stiff-Person syndrome | Psychotic symptoms, behavioral changes, rigidity, myoclonus | In < 5%, there is an association with thymoma, bronchial carcinoma and lymphomas |
IgLON5 | Encephalitis with sleep disturbance | Hallucinations, depressiveness, sleep apnea, NREM + REM sleep behavior disorder and brainstem dysfunction (dysphagia, ataxia) | No tumor association known |
LGI1 | Limbic encephalitis | Polymorph psychotic symptoms, depression, REM sleep disorders, memory deficits up to dementia, confusion, faciobrachial dystonic seizures, hyponatremia | In 5–10% thymomas |
mGluR5 | Limbic encephalitis | Behavioral changes, emotional instability, memory deficits, confusion | In approx. 70% associated with Hodgkin lymphoma |
Neurexin-3-alpha | Encephalitis (compareable with anti-NMDA-R encephalitis) | Changes of behavior, agitation, prodromal symptoms (fever, headache, gastrointestinal symptoms), seizures, confusion, disturbed consciousness | No tumor association known |
NMDA-R (GluN1) | Anti-NMDA-R encephalitis | Psychosis, catatonia, epileptic seizures, movement disorders, autonomous instability, impaired consciousness | Depending on age and sex, total tumor association in approx. 40%, mostly ovarian teratomas |
Antibodies against synaptic intracellular antigens | |||
Amphiphysin | Stiff-Person syndrome, encephalomyelitis | Memory deficits, confusion, rigidity, spasms | In > 90%: breast cancer and small cell bronchial carcinomas |
GAD65 | Limbic encephalitis, Stiff-Person syndrome, epileptic seizures, cerebellar dysfunction | Psychotic syndromes, autism and ADHD symptoms (in atypical cases), bizarre movement disorders, muscle rigidity, spasms, seizures, ataxia | Isolated anti-GAD65 Abs are rarely paraneoplastic (otherwise in max. 25% thymomas, small-cell bronchial carcinoma) |
Antibodies against onconeuronal, non-synaptic intracellular antigens | |||
Hu, Ri, Yo, CV2 (CRMP5), Ma2 (Ta), SOX1, Tr/DNERa | Limbic encephalitis, cerebellar degeneration among others | Mixed neuropsychiatric symptoms, behavioral changes, neuropathies, gait disorders, seizures | In most cases (> 95%) tumor-associated, mostly SCLC and other neuroectodermal tumors, e.g. Merckel-Cell-Ca; testicular tumors in Ma2, breast/ovary in Yo, Hodgkin in Tr/DNER |
Antibodies against thyroid tissue | |||
TG/TPO | Hashimoto encephalopathy (SREAT) | Paranoia, hallucinations, depressiveness, memory problems, confusion, epileptic seizures, speech disorders, myoclonus | No tumor association known |
Rheumatic antibodies | |||
ANAs (anti-dsDNA/anti-Sm/anti-rib. P/anti-nucleosome antibodies), etc. | Neuropsychiatric SLE, etc. | Confusional states, anxiety, cognitive dysfunction, mood disorders, psychosis, headaches, seizures, stroke-like episodes, etc. | No tumor association known |
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GABAA-R, DPPX, mGluR5, Neurexin-3-alpha, IgLON5, Glycin-R (in serum and CSF).
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Additional rheumatological examinations:
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In the case of positive ANA screening: Abs against dsDNA/ENA-differentiation (specification for Sm,nucleosome, etc.; in serum).
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ANCA (specification for MPO and PR3; in serum).
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Antiphospholipid Abs (anti-β2-Glykoprotein-I Abs, anticardiolipin Abs, lupus anticoagulant; in serum/citrate tube).
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Organic differential diagnosis
Inflammatory disorders | Non-inflammatory disorders |
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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 |