| Abstract|| |
Autoimmune encephalitis is a group of non-infectious immune-mediated inflammatory disorders manifesting with epilepsy and encephalitis syndromes that are associated with autoantibodies in the serum and/or cerebrospinal fluid (CSF). Pathogenic autoantibodies have been discovered against intracellular onconeural antigens, surface neuronal, or synaptic antigens with distinctive pathogenesis that underlie differences in response to immunotherapy. The onconeural antigens incite cytotoxic T-cell-mediated neuronal destruction, whereas surface antigens trigger direct damage by autoantibodies via complement mediated pathways, and hence respond well to immunomodulatory therapy, in contrast to poor response in the former. Neuroimaging, electroencephalogram, and CSF findings being non-specific, detection of autoantibodies is essential for a confirmatory diagnosis. Detection methods available include tissue-based assay, cell-based assays, immunoblot, cell culture, flow cytometry, and enzyme-linked immunosorbent assays. In this review, we discuss the various testing modalities available for onconeural and cell surface antibodies, their sensitivity and specificity and the emerging role of the pathologist in the diagnosis of autoimmune encephalitis. Early diagnosis is crucial for instituting treatment and preventing morbidity and mortality.
Keywords: Assays, autoantibody, autoimmune, encephalitis
|How to cite this article:|
Rao S, Netravathi M, Mahadevan A. Role of the pathologist in the diagnosis of autoimmune encephalitis. Indian J Pathol Microbiol 2022;65, Suppl S1:198-206
|How to cite this URL:|
Rao S, Netravathi M, Mahadevan A. Role of the pathologist in the diagnosis of autoimmune encephalitis. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 May 28];65, Suppl S1:198-206. Available from: https://www.ijpmonline.org/text.asp?2022/65/5/198/345056
| Introduction|| |
Autoimmune encephalitis (AE) is an immune-mediated inflammatory disorder which is non-infectious. They predominantly involve the grey matter (cortical and deep); and white matter, meninges or spinal cord may be involved. Pathogenic autoantibodies have been discovered against intracellular onconeural antigens, surface neuronal, or synaptic antigens. The diagnosis of AE is based primarily on clinical suspicion. Magnetic resonance imaging (MRI) abnormalities are found only in a proportion of cases and hence confirmatory diagnosis relies on the demonstration of disease-specific antibodies in serum/cerebrospinal fluid (CSF). The role of brain biopsy is also limited, as the histopathological findings are non-specific. With widespread availability of commercially available tests for detection of autoantibodies with high sensitivity and specificity, the role of a pathologist in the diagnosis of AE is increasing day by day.
AE can be classified based on the specificity of autoantibody, the etiology, or the neuroanatomical area of involvement.
- AE with onconeural antibodies
- AE with antibodies to surface antigens
- Seronegative AE.
A high index of clinical suspicion is critical for diagnosing AE. Several of these disorders have characteristic clinical features that provide the clinical clue to diagnosis. The patients usually present with an acute or subacute presentation of less than three months duration. A relapsing course may be seen in some patients following inadequate treatment or interruption of immunotherapy. In some, the symptoms may be precipitated by viral infections like herpes simplex encephalitis, Japanese encephalitis, dengue, and more recently following Coronavirus 19 (COVID-19) infection. Some of the strong clinical indicators for AE and its association for antibody type is provided in [Table 1].,,
|Table 1: Shows clinical characteristics and immunofluorescence patterns of various autoimmune encephalitis|
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Graus F et al. have proposed criteria for clinical diagnosis of AE.
Definite autoimmune limbic encephalitis
All four of the following criteria have to be met
- Subacute onset (rapid progression of less than three months) of working memory deficits (short-term memory loss), altered mental status, or psychiatric symptoms suggesting involvement of the limbic system
- Bilateral brain abnormalities on T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI restricted to the medial temporal lobes
- At least one of the following:
- CSF pleocytosis (white blood cell count of more than five cells per mm3)
- EEG with epileptic or slow-wave activity involving the temporal lobes
- Reasonable exclusion of alternative causes.
Brain MRI commonly showhyperintense signals on T2 weighted image in the hippocampus which may be unilateral or bilateral. These lesions are usually accompanied by extrahippocampal involvement of the cortical or subcortical regions., Cortical/subcortical, striatal, diencephalic, brainstem, encephalomyelitis, and meningoencephalitis can support possible or probable AE. Presence of inflammation may result in contrast enhancement, however intense enhancement favours alternative diagnosis. In chronic course, hippocampal atrophy may be seen. In a few cases, changes on MRI may appear later in the disease course. Brain MRI also helps in excluding other differential diagnoses.
Electroencephalogram (EEG) in patients with suspected AE serves to exclude non-convulsive status epilepticus in patients in altered sensorium and monitor response to anti-epileptic drugs (AEDs) in patients with seizures. It can also differentiate AE from Creutzfelt-Jacob disease (CJD). EEG findings are however nonspecific and include focal slowing, lateralised periodic discharges. An extreme delta brush has been reported in N-methyl D aspartate receptor (NMDAR)-antibody encephalitis., In Leucine-rich glioma inactivated 1 (LGI1)-antibody encephalitis, subclinical seizures are commonly reported, although a normal EEG has also been seen in classical faciobrachial dystonic seizures.,
Findings are non-specific in AE. There can be mild to moderate lymphocytic pleocytosis with cell count in the range of 20–200 cells/mm3. High CSF proteins or elevated IgG index and positive oligoclonal bands has been reported but is not specific to AE.,,
AE are characterised by epilepsy and encephalitis syndromes that are associated with serum and CSF autoantibodies. Neuroimaging, EEG, and CSF findings are non-specific and do not provide a confirmatory diagnosis in AE. Hence, the detection of autoantibodies is essential for a confirmatory diagnosis.
Various techniques are available for the detection of autoantibodies. These include tissue-based assay, cell-based immunoassay, and immunoblotting.
The tissue-based assay is used as a screening method in all suspected cases of AE. Hippocampal (for cell surface antigens) or cerebellar sections (for intracellular antigens) from mouse brain are used and the antibody detection is by indirect immunofluorescence method. In tissue-based assay, unknown antibodies can also be detected.
Cell-based assay is more useful in detection of cell-surface or synaptic antibodies such as NMDA-R or LGI1 and others. This method identifies conformation dependent antibodies and has a high sensitivity for surface antibodies. In this method, human or murine cells are transfected with plasmid with human complementary deoxyribonucleic acid (DNA) and these express the target antigen on the surface which reacts with the antibodies present in the patients' serum or CSF. Further, the detection of specific antibodies is by indirect immunofluorescence [Figure 1]. Commercial kits are available for the cell-based assay. These include several autoantibodies within one test run [NMDAR, AMPAR, GABA(B)R, LGI1, CASPR2, and DPPX] or individual tests (IgLON5).
|Figure 1: 8-year-old girl with seizures, behavioural abnormalities, and choreoathetosis. MRI revealed left medial temporal hypointensities on T1WI (a), hyperintensities in T2WI (b) and FLAIR (c). Cell-based assay with transfected cell lines show positivity for NMDAR (d), CASPR2 (e), LGI1 (g); (f) negative. [Indirect immunofluorescence, cell-based assay. Magnification = 40x objective]|
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False negatives can be avoided by replacing fixed cells with live cells to avoid damage to epitopes as a result of fixation. The other methods employ clustering proteins which cluster antigen at high density or enhance the number of recognizable antigens by adding subunits of a receptor such as the gamma 2 subunit of the GABA(A)R.
For detection of intracellular onconeural antigens, the detection methods available include tissue based assay, immunoblot (line assay), western blot analysis, enzyme-linked immunosorbent assay, cell-based assays, or radioimmunoassay. Of these, the most commonly used in routine practice are the immunoblot and tissue-based assays. In immunoblotting, antibody binds to a specific protein from a mixture of several proteins. Purified recombinant proteins are transferred onto a membrane, and incubated with patient's sample followed by epitope specific secondary antibodies, and detection by enzymes or radioisotopes.
Immunoblot, also known as line assays, are commercially available as strips with combination of well-characterized autoantibodies that are screened within one test run. In tissue based assays, patients' serum or CSF reacts with paraformaldehyde-fixed mouse or rat or monkey tissue (from cerebellum and enteric nervous system), that express the intracellular antigen. Based on the pattern of staining and the cell types reacting, the autoantibody is detected [Table 1], [Figure 2]. This requires further confirmation by the immunoblot assay. Both these tests are qualitative assays. The recommendation in an ideal setting is to use tissue based assay as screening and immunoblot for confirmation to achieve higher sensitivity and specificity. The drawback of tissue-based assay is that accompanying antibodies such as anti-nuclear antibodies may obscure the immunohistochemical staining pattern.
|(a and b) Anti-Hu antibodies-nuclear IF in Purkinje and internal granule neurons of the cerebellum (a) and intestinal ganglion cells (b). c: Ma2 antibodies – nucleolar IF in Purkinje cells. d and e: Anti Yo antibodies-cytoplasmic IF of Purkinje cells (d) confirmed on immunoblot (e). f and g: Anti GAD antibodies – tigroid pattern of IF in internal granular layer of cerebellum (f) confirmed on immunoblot (g) [Indirect immunofluorescence, magnification = Obj. 40x] [IF-immunofluorescence, P-Purkinje cell, M-molecular layer, IGL- internal granular layer, GC-ganglion cell]|
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Immunoassays are a rapid method which can quantify levels of antigen-specific antibody. Radioactive immunoassays (RIAs) use a radioactively labeled substance. Principle of RIA is identification of the antibody by radiolabelling the antigen of interest. Antibody in the patient's serum or CSF binds to the antigen, and forms a complex on addition of antihuman antibody. The reading is taken with a gamma counter. Titration can be performed by using serial dilutions to obtain accurate titres. More recently, Fluorescence immunoprecipitation assay (FIPA) which uses detergent extracted green fluorescent protein (GFP)-tagged target protein as the substrate has been developed. Although this technique is less sensitive compared to the cell-based techniques, this quantitative method is ideal for longitudinal follow-up of seropositive patients. It is also safer when compared to RIA, and two or more tags can be used simultaneously. Although sensitive and specific, the main disadvantage of immunoblot technique is that only known antigens can be detected.
Neuronal cell culture
Live neuronal cell cultures are used as a research platform to detect autoantibodies in human serum/CSF with binding capability to neuronal surface antigens. Most often, rat hippocampus is used for the detection of surface antibodies. The disadvantage being that all human antigens may not be represented on the rat neurons. Other cell lines used include glioneuronal, dorsal root ganglia, and retinal cell cultures to identify specific antibodies. Anti-contactin1 and anti-CASPR1 antibodies react with rat hippocampal neurons and dorsal root ganglion cells., In contrast, anti-AQP4-antibodies may be specifically seen in glioneuronal cell cultures and rat retinal cell cultures that contain Mueller cells., In addition, live cell cultures are useful to identify unknown antibodies recognised on the tissue-based assay. After confirming the reactivity on the cultured cells, the target antigen can be identified by immunoprecipitation of the patient's serum together with the cell cultures, followed by identification of the co-precipitated target antigen by mass spectrometry. Live cell cultures can be used to discover novel autoantibodies in seronegative AE. Overexpressing cell lines can then be developed for the detection of novel antibody.
Other less commonly used technique is the flow cytometry assay which use transfected cells which are trypsinised to form a solution and mixed with serum or CSF. Fluorescent secondary anti-human antibodies are used to detect surface-bound antibody and the level of binding is measured quantitatively. Although expensive and not freely available, it is a highly sensitive technique that also provides quantitation.
ELISA (Enzyme-linked immunosorbent assay)
ELISA can be used to detect antibodies in the serum or CSF of the patients. It is a simple technique where enzymes such as alkaline phosphatase or horseradish peroxidase is used to detect antibodies in patient serum or CSF that bind to the antigen target which in turn produce a complex with an anti-human secondary antibody. The colour change in the substrate in samples with antibodies provides a quantitative measure of the autoantibodies in the patient's serum or CSF.
Although ELISA is a simple technique, it lacks sensitivity and specificity. False positive results are common when the sera bind to the plastic well rather than the specific target antigen. Sensitivity and specificity is dependent on the purification and immobilization of the specific protein. It is especially difficult to purify central nervous system (CNS) membrane proteins.
Common panels of neuronal surface autoantibodies include detection of IgG against NMDAR, Caspr2, LGI1, GABAbR, AMPAR, followed by mGluR5, glycine-R, and IgLON5. Panel for intracellular neuronal antibodies includes antibodies against Hu, Yo, Ri, PNMA2 (Ma2/Ta), CV2, amphiphysin, PCA2, TR, SOX1, Zic4, Recoverin, GAD, Myelin, Titin, MAG, and anti-glial nuclear antibodies as well as DPPX-antibodies. Different methods of testing are compared in [Table 2].
|Table 2: Shows comparison between different methods of testing for antibodies in autoimmune encephalitis|
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Sensitivity and specificity of CSF and serum for testing
The recommendation for testing for autoantibodies is to test both serum and CSF in any patient with suspected AE. The sensitivity of detection in serum vs CSF varies with different autoantibody types. CSF is more sensitive than serum in detecting antibodies against NMDAR, GABA(B)R, or AMPAR. In 14–20% of patients with anti-NMDAR encephalitis, antibodies are present in CSF only. In contrast, anti-AQP4 or anti-MOG-antibodies which are not synthesised intrathecally, antibodies are more prevalent in serum than in CSF. Rarely, the antibodies in serum and CSF may be of different types. In such situations, clinical correlation is essential. At times, predictive values of CSF autoantibodies are higher, for instance, in patients with GABA(A)R antibodies, levels of antibodies in CSF correlated better with neurological symptoms. Serum testing has additional disadvantages. The higher background staining and cross reactivity due to high protein content, results in false positive results. Hence, it is ideal to test both serum and CSF. Practical decision needs to be taken depending on the clinical suspicion due to cost constraints.
The immunoglobulin subclass varies with the antibody of interest, NMDAR is most often associated with IgG1 and LGI1 is the IgG4 subclass. However, the anti-human IgG antibody used to detect the antibodies is broad and tends to detect other immunoglobulin classes as well leading to false-positive results. In such cases, specific secondary antibodies may be necessary. False positive NMDAR antibodies can be seen in multiple sclerosis and neuromyelitis optica, similar to VGKC antibodies in Miller-Fisher syndrome and Bickerstaff encephalitis.,, Some of the antibodies may not be pathogenic, the patients being asymptomatic as in small cell lung cancer with anti-Hu antibody.
In a clinical setting of AE, auto-Abs may not be demonstrable in the serum or CSF. Possible explanations for seronegativity are declining serum antibodies and the existence of unidentified antibodies which are yet to be discovered. The other possibilities include antigen denaturation during tissue fixation, false-negative results due to the amount of antibody being insufficient for detection, differences between human and mouse epitopes, and the presence of T-cell-dominant autoimmune encephalitis. Lee et al. found that 44% of patients that are rituximab responders have autoimmune encephalitis without detectable antibodies.
Mechanism underlying neuronal damage in PNS vs AE is distinctly different. In PNS, cell mediated immune attack by cytotoxic T cells results in neuronal cell destruction.,,,, The initial trigger is the antigen (onconeural proteins) which is released from the tumor cells which undergo apoptosis when the innate immunity acts on it. The antigen presenting cells recognise these antigens and activate the CD4+ helper T cells through major histocompatibility complex class II (MHC II), which in turn activate antigen-specific B cells. The activated B cells produce onconeural antibodies in the serum and CSF that are detected by the autoantibody tests. However, these onconeural antibodies are not directly responsible for the neuronal destruction, but act via activating CD8+ cytotoxic T lymphocytes through MHC class I and the cytotoxic T cells act through perforin and granzyme.,,
In contrast, surface antigens trigger the production of autoantibodies which directly cause neuronal damage. The mechanism underlying the disease mediated by surface antibodies is either by activation of immune cells or the complement system which damage the neuronal cells. The differences in the mechanism of cell damage explain the good response of non-PNS AE in contrast to lack of response of PNS to immunomodulatory therapy. Alternate pathogenetic mechanisms have also been proposed. For instance, NMDAR antibodies may cross-link NMDARs, resulting in a reversible hypofunction in the absence of destruction of the nerve cells or synapses.
Data on neuropathology of AE are limited as most cases do not require a biopsy for the diagnosis. Brain biopsy is rarely indicated in cases with an atypical presentation to exclude other differential diagnoses. Our current understanding is based on a few studies which have analysed the histopathological changes in biopsies or post-mortem tissues. In general, the pathological findings have been non-specific. The majority of AE cases show lymphocytic infiltrates in the parenchyma and perivascular regions. These infiltrates are most often T lymphocytes with B lymphocytes seen in occasional cases. This is accompanied by neuronal loss and secondary gliosis in the anatomical regions involved.
Vincent et al. described the changes in a stereotactic biopsy of a case of AE with VGKC-complex antibodies. They observed neuronal loss in the hippocampus and amygdala with a few T lymphocytes infiltrate and activated microglial cells. Similar changes were also described in the autopsy cases of limbic encephalitis by other authors., Khan et al. also observed loss of neurons in the hippocampus and amygdala with severe loss in the CA region with T lymphocytic infiltrates and perivascular B cells. They documented a diffuse background immunoreactivity of immunoglobulins which they considered nonspecific. However, later in 2012 in a study of 4 cases of AE with VGKC-complex and limbic encephalitis, immunoglobulin deposits were recognised on the neurons in addition to the background staining as well as deposition of complement C9neo on neurons in the CA4 region of hippocampus. The authors concluded that an antibody-mediated complement activation was responsible for neuronal loss in these cases. Kortvelyessy et al. also observed complement deposition in hippocampus of CASPR2-associated AE. Other studies in PNS have noted neuronal loss in cerebellum (Yo, Hu, Ri), olivary nucleus, dentate nucleus, and spinal cord. CD8+ T cells infiltrates vary from extensive to moderate in these cases.
In NMDA AE, the neuronal loss was detected in amygdala and hippocampus similar to other limbic encephalitis. However, T cell infiltrates and microglial activation was minimal. B cells and plasma cells were seen in the perivascular space of blood vessels.,, Neurons in the cortex, basal ganglia, and cerebellum were relatively preserved. Severe gliosis was observed in the hippocampus in these cases. A few authors also noted immunoglobulin deposits, but without complement deposition in contrast to that noted in VGKC-complex-associated AE., Neuronal death therefore is not complement mediated but secondary to dysfunction of NMDA receptors resulting in the neurological symptoms. This was supported by the finding of decreased NMDAR expression in the hippocampus of cases of NMDA AE.
NIMHANS as a tertiary referral centre dedicated to the care of patients with neurological, neurosurgical, and psychiatric disorders, has several patients referred for diagnosis and accurate treatment from throughout the country and from other South Asian Association for Regional Cooperation (SAARC) countries. As a novel initiative, the Autoimmune Lab, an advanced diagnostic facility for comprehensive diagnosis and management of neurological autoimmune disorders, was set up at NIMHANS, in 2014. This initiative was launched on a “self-sustaining mode” supported by a seed grant from NIMHANS to meet the initial expenditure involved in establishing new tests, recruit, and train personnel. The objective was to make available state of art, advanced diagnostic tests, at affordable price as well as to serve as a referral diagnostic centre for other hospitals in the country.
The laboratory provides panel of tests for AE and Neuromyelitis optica spectrum disorder (NMOSD), facilitating precision in clinical diagnosis and directing accurate treatment. There is an increasing demand for many of these diagnostic tests from the treating clinicians, for improving patient care and aid in therapeutic decision-making as several of these are not available anywhere in the country. A snapshot of number of samples tested till date and prevalence of various autoimmune disorders at our centre is tabulated [Table 3] (unpublished data). The lab is now a “referral centre” for the entire country with more than 70 hospitals across the country availing the facility including All India Institute of Medical Sciences (AIIMS) and AIIMS-like institutes.
|Table 3: Shows data from NIMHANS autoimmune laboratory for the period of August 2014 to December 2020|
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Early detection has had tremendous impact on management, reducing hospital stay, avoiding unnecessary additional investigations, and directing specific therapy thereby reducing mortality and morbidity.
Examples of a few classic cases encountered during routine practice are detailed below.
A 8-year-old girl presented with acute onset seizures, behavioural abnormalities, and choreoathetoid movements. Imaging revealed characteristic features of limbic encephalitis with hypointensities on T1WI in left medial temporal region, that was hyperintense in T2WI and FLAIR. Hence, cell-based assay of the serum was carried out, which revealed bright granular cytoplasmic fluorescence for NMDAR antibodies in transfected cell lines. This child was treated with plasmapheresis followed by immunomodulators and showed improvement in her symptoms.
A 40-year-old man presented with insomnia for a year. On examination, neuromyotonia was observed. Computed tomography of chest showed an enlarged thymus. Possibility of autoimmune encephalitis was considered and serum subjected to cell based assay, which revealed strong immunofluorescence for CASPR 2 antibodies in transfected cell lines.
A 45-year-old lady presented with a subacute onset of cognitive impairment and left-sided faciobrachial dystonic seizures. Due to the characteristic presentation, clinical diagnosis of LGI1-associated AE was considered. This was confirmed on cell-based assay of the serum which revealed a strong cytoplasmic fluorescence in transfected cells lines. The patient was treated with immunomodulators and responded well with resolution of symptoms.
A 59-year-old gentleman presented with persistent cough for two months duration and sudden onset imbalance while walking. Imaging of the brain revealed features of cerebellar hyperintensities. Serum tested for paraneoplastic antibodies by tissue-based assay showed granular fluorescence in the cerebellar neuronal nuclei and ganglion cells of the myenteric plexus of intestine, conforming to pattern of anti-Hu antibodies. The patient was also found to have carcinoma lung. Although treatment was initiated, the patient succumbed to his illness.
Quality and practice
Although various methods are available for the detection of autoantibodies, knowledge of the sensitivity, and specificity of each method allows accurate selection of appropriate test for the diagnosis. Onconeural antibodies are best detected by a combination of tissue-based assay and immunoblot to achieve high degree of sensitivity and specificity. Cell-based assay is recommended for the cellular and synaptic protein detection. Ideally testing both serum and CSF is suggested, however CSF has higher sensitivity for cellular antibodies such as NMDA-R whereas serum has better sensitivity for onconeural antibodies. All the tests need to be run along with positive and negative controls to avoid false positives and false negative results. In-house controls have the advantage of longer shelf life. It is also essential to recognise false positive patterns (artefacts) on immunofluorescence with tissue-based and cell-based assays. Knowledge of test characteristics and association with clinical presentation becomes essential in reporting of test results. If the results do not correlate with the clinical context, it is recommended to retest with the same sample and also test with a different assay or test in another laboratory to confirm or refute the result.
Precise diagnosis helps in timely initiation of treatment in AE. Immunomodulators are the mainstay of treatment with the use of plasmapheresis, cyclophosphamide, and rituximab.
| Conclusion|| |
The rapidly expanding repertoire of autoantibodies enables a more precise diagnosis of AIE. The easy availability of commercially available tests has enhanced the role of pathologist in the diagnosis of autoimmune disorders, and contributing to the decision-making and directing precise treatment. It is important for the pathologist to know available testing modalities and the ideal tests for each of AE. In general, the intracellular onconeuronal antibodies detection requires tissue based assays for screening and immunoblot/line assays for confirmation. In contrast, for detection of surface antibodies such as NMDAR/VGKC, cell based assays, and unfixed/postfixed tissue based assay is recommended. The highest sensitivity and specificity is achieved by validation of results employing more than one test method and the testing of both serum and CSF. It cannot be emphasised enough that all test results must be interpreted in context with the clinical presentation.
The authors wish to thank the team at Autoimmune laboratory – Mr Yashwanth G, Junior Scientific Officer, Mr Roshan Ahmed, Junior Technician, and Ms Bindu S, Data entry operator.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Professor, Department of Neuropathology National Institute of Mental Health & Neurosciences (NIMHANS), Bengaluru, Karnataka
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]