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Clinical characteristics, treatments, outcome and prognostic factors of severe autoimmune encephalitis in the intensive care unit: standard treatment and the value of additional plasma cell depleting escalation therapies for treatment-refractory patients

40 patients participated in the present study.

Conclusions: Our findings suggest that treatment-refractory AE patients with nsAb in the ICU can reach similarly good outcomes after plasma cell-depleting escalation therapy as patients already responding to standard first- and/or second-line therapies.

Simplified regimen of combined low-dose rituximab for autoimmune encephalitis with neuronal surface antibodies

18 patients participated in the present study, the 3 main findings about rituximab treatment for AE are that: (1) our simplified regimen of low-dose rituximab (100 mg once) combined with common first-line therapy significantly accelerates comprehensive short-term recovery within 1 year, as well as markedly contributing to long-term improvement even after at least 1 year. (2) Our refined protocol of rituximab infusions leads to faster oral prednisolone gradual taper and withdrawal, in parallel with markedly sustained clinical remission and reduced relapses. (3) Opportunity of rituximab schedule shows earlier initiation with better improvement, while frequency of first-line therapy has no influence on satisfactory outcome with rituximab combination.

CONCLUSIONS: Our simplified regimen of combined low-dose rituximab firstly showed significantly accelerating short-term recovery and long-term improvement for AE with NSAbs, in parallel with markedly reduced prednisone dosage and clinical relapses. Moreover, opportunity of protocol showed earlier initiation (≤ 3 months) with better long-term improvement.

Cytokine dynamics and targeted immunotherapies in autoimmune encephalitis

Recent improvements in cytokine identification and quantification provide new insights into the immune mechanism underlying neuroinflammation. In this review, we summarized several studies that explored their dynamics and suitability as prognostic and therapeutic biomarkers in AE, chiefly anti-NMDAR and anti-LGI1 encephalitis, reflecting the synergic pathogenic role of humoral and cellular immunity.

The CSF/serum cytokine gradient and BBB dysfunction were rarely reported despite being crucial to determine intrathecal production. Hence, future studies should study cytokines in paired CSF/serum samples at similar time-points, as the concentration and location of cytokines may change during the course of the disease and after the administration of immunomodulators. Otherwise, the results obtained may lead to misinterpretations that might explain the high heterogeneity observed so far.

The increasing knowledge on the cytokine dynamics summarized in this review offers a promising opportunity to treat patients in a personalized manner that could change the present paradigm of AE management.

Therapeutic Potential of Intravenous Immunoglobulin in Acute Brain Injury

There is growing evidence that the rapid activation of the immune system in response to acute sterile tissue damage can be detrimental for the affected organ. Particularly, postischemic inflammation following stroke has been investigated extensively and multiple preclinical studies emphasize beneficial IVIg effects in models of acute brain injury, i.e., ischemic stroke, spinalcord, and traumatic brain injury. The already established use of IVIg in various neurological diseases is a major advantage. Furthermore, available data suggest that IVIg are specifically modulating harmful inflammatory processes, without relevant immunosuppressive side effects.

In general, IVIg exert protective effects in autoimmune disease via multiple mechanisms. Similarly, in acute brain injury, it is most likely that IVIg protection is mediated by the interaction with different targets concomitantly, which merge to a mutual effect. In this context, immunomodulatory pathways are among the most promising candidates. IVIg can target microglia as resident immune cells of the CNS as well as immune cells from the systemic immune compartment and endothelial cells. Furthermore, it is important to mention that IVIg can stabilize the BBB and even facilitate direct neuroprotection. Eventually, it currently remains concealed if IVIg effects are Fc or F(ab)2 fragment dependent and if IVIg can modulate cells indirectly, which are not expressing Fc receptors in this context. Although the currently existing data are promising, further research is needed to gain more insight into protective IVIg-dependent mechanisms and to explore the therapeutic potential of IVIg in acute brain injury.

Advances in Potential Cerebrospinal Fluid Biomarkers for Autoimmune Encephalitis: A Review

Recently, AE has received increasing attention, and the level of AE diagnosis and treatment has dramatically improved. However, there are drawbacks for clinical diagnosis based solely on antibodies; therefore, additional biomarkers are needed to guide diagnosis and treatment. Considering the primary role of the immune mechanism in the pathogenesis of AE, this review summarizes the relevant research progress in identifying CSF biomarkers with a focus on cytokines/chemokines, demyelination, and nerve damage (Table 1). Furthermore, we also provide the latest information to aid the diagnosis and treatment of the disease. 

Fluctuations in quality of life and immune responses during intravenous immunoglobulin infusion cycles

In summary, in this study, the QOL “wear off effect” following IVIG infusion was confirmed, and although several potentially relevant factors were identified, a clear role for these factors in this effect remain elusive. In this cohort, increases in Treg levels and various serum chemokines and cytokines did not correlate with reported improvement and subsequent deterioration in QOL throughout the IVIG cycle. Nonetheless, novel findings regarding replacement-dose IVIG infusions were discovered particularly relating to the differential response of IVIG-naïve vs. IVIG-experienced subjects. This constellation of findings provides a framework for future work exploring the non-infectious physiologic alterations induced by IVIG infusions and how they relate to the feeling of well-being among the highly burdened PIDD patient population.

Update on the use of immunoglobulin in human disease: A review of evidence

Review of all the ways IVIG is used – and it includes expert consensus support for use of IVIG in autoimmune encephalitis.Examples of positive reports
include those describing IVIG treatment in patients with acute disseminated encephalomyelitis, demyelinative brain stem encephalitis, subacute rhombencephalitis optica, and autoimmune encephalitis.

Neuronal and Neuroaxonal Damage Cerebrospinal Fluid Biomarkers in Autoimmune Encephalitis Associated or Not with the Presence of Tumor

A total of 31 adults was included in the study. The patterns of CSF biomarkers of neuronal and neuroaxonal damage in autoimmune neurological syndromes associated with antibodies against extracellular antigens showed distinct features compared to those associated with antibodies against intracellular antigens—a finding that implicates a difference in pathogenetic mechanisms between them. Our findings suggest that CSF-NFL could potentially be used as a diagnostic biomarker of encephalitis with underlying malignancies. In the CSF of antibody-mediated encephalitis, the relative maintenance of biomarkers of synaptic and/or neuroaxonal integrity (CSF-tau and NFL), possibly reflects distinct antibody-mediated effects. Future studies with larger cohorts are warranted to validate the benefit of NFL and total tau measures in clinical practice.

Update on the diagnosis of encephalitis

This continuing education aims to present in a clear and easy-to-understand way, the clinical features of autoimmune encephalitis, the difficulties in clinical diagnosis and the patterns seen on MRI and 18F-FDG PET/CT.

Immunotherapy in autoimmune encephalitis

Recent findings: We highlight acute and long-term treatments used in specific AE syndromes, exemplify how understanding disease pathogenesis can inform precision therapy and outline challenges of defining disability outcomes in AE.

Summary: Early first-line immunotherapies, including corticosteroids and plasma exchange, improve outcomes, with emerging evidence showing second-line immunotherapies (especially rituximab) reduce relapse rates. Optimal timing of immunotherapy escalation remains unclear. Routine reporting of outcome measures which incorporate cognitive impairment, fatigue, pain, and mental health will permit more accurate quantification of residual disability and comprehensive comparisons between international multicentre cohorts, and enable future meta-analyses with the aim of developing evidence-based therapeutic guidelines.

Paraneoplastic encephalitis: clinically based approach on diagnosis and management

Main messages
⇒ The updated criteria for paraneoplastic neurological
syndromes help to standardise the clinical approach towards
diagnosis.
⇒ Specific knowledge of the caveats of commercial antibody
testing methods is required to avoid under/overdiagnosis of
these syndromes.
⇒ Early tumour detection, removal and concomitant
immunomodulation are necessary to ensure better outcomes.

CONCLUSIONS AND FUTURE PERSPECTIVES
PE comprises a small subset of autoimmune disorders associated
with a growing number of neuronal Abs and a heterogeneous
pathophysiology. Despite major advances in the knowledge of
PNS pathogenesis and the recent update of their diagnostic
criteria, a deeper understanding is still required to promote their
diagnosis and optimal management. The development of novel
targeted therapies is crucial to improve PNS outcomes while
preserving the beneficial antitumour immunity

[18F]FDG brain PET and clinical symptoms in different autoantibodies of autoimmune encephalitis: a systematic review

Results: After two-step reviewing, 22 studies with a total of 332 participants were entered into our qualitative synthesis. In anti-NMDAR encephalitis, decreased activity in the occipital lobe was present, in addition, to an increase in frontal, parietal, and specifically medial temporal activity. Anti-VGKC patients showed altered metabolism in cortical and subcortical regions such as striata and cerebellum. Abnormal metabolism in patients with anti-LGI1 has been reported in diverse areas of the brain including medial temporal, hippocampus, cerebellum, and basal ganglia all of which had hypermetabolism. Hypometabolism in parietal, frontal, occipital lobes, temporal, frontal, and hippocampus was observed in AE patients with anti-GAD antibodies.

Conclusion: Our results indicate huge diversity in metabolic patterns among different AE subtypes and it is hard to draw a firm conclusion. Moreover, the timing of imaging, seizures, and acute treatments can alter the PET patterns strongly. Further prospective investigations with specific inclusion and exclusion criteria should be carried out to identify the metabolic defect in different AE subtypes.

Editorial: Antibody-Mediated Autoimmune Diseases of the CNS: Challenges and Approaches to Diagnosis and Management

In summary, this collection of articles provides novel scientific evidence that advance our understanding of clinical presentation, neuroimaging, antibody analysis, and disease mechanisms of antibody-mediated autoimmune CNS diseases. Moreover, these papers highlight enormous recent progress of diagnostic approaches and therapeutic regimens, as well as the remaining challenges.

The safety and efficacy of intravenous immunoglobulin in autoimmune encephalitis

18 of 23 patients completed the study.

Interpretation: IVIG improved neurological functional outcomes, and the improvement was evident by day 8. Adverse effects were tolerable. These data provide the prospective evidence regarding the efficacy of IVIG in improving the functional outcomes of autoimmune encephalitis.

Low Recruitment in a Double-Blind, Placebo-Controlled Trial of Ocrelizumab for Autoimmune Encephalitis: A Case Series and Review of Lessons Learned

Among 16 eligible patients, only three enrolled in the study, which closed due to poor recruitment. Two participants were randomized to the ocrelizumab arm and one to the placebo arm. The single patient in the placebo arm (NMDAR+) met the primary endpoint at 12 weeks and received open-label ocrelizumab with improvement. In the ocrelizumab arm, one participant (NMDAR+) demonstrated marked improvement, and the second (LGI1+) remained clinically stable. There were no serious adverse events associated with ocrelizumab.

Antibody Therapies in Autoimmune Encephalitis

Highly Recommended

Antibodies targeting the CD20 epitope on the surface of B cells are the cornerstone of second-line treatment in AE, originally combined with cyclophosphamide. They have a favorable side effect profile compared to second-line treatments with a different mode of action. Moreover, rituximab has shown to be effective in anti-NMDAR encephalitis as well as in many other AE cases when first-line therapies fail. However, anti-CD20 mAb do not deplete long-lived plasma cells which might underlie treatment-refractory cases and the occurrence of (early) relapses. Therefore, there is an emerging repertoire of mAb that aim to directly (inebulizumab, daratumumab) or indirectly (tocilizumab, sartralizumab) target long-lasting plasmablasts or plasma cells with or without additional B cell depletion. Alternatively, the plasma cell products (i.e. pathogenic antibodies) can be removed with mAb targeting the FcRn (efgartigimod, rozanolixizumab). mAbs that disrupt the complement cascade (eculizumab) are also explored but have fewer biological underpinnings. Future trials are needed to understand whether these third-line treatments are effective, when they need to be initiated and whether they have an acceptable safety profile in combination with previous rituximab administration.

 

Immunomodulation in the acute phase of autoimmune encephalitis

This review aimed to clarify the diagnostic and therapeutic approach during the acute phase, i.e. during the first weeks or months after symptom onset, of patients with AE and related disorders.

The identification of antibodies associated with AE and the understanding of its pathogenesis has revolutionized the diagnosis and management of these conditions. Moreover, the definition of diagnostic criteria for possible AE and probable seronegative AE has encouraged many physicians to promptly initiate empirical immunotherapy, since this approach is associated with better long-term outcomes. Accordingly, first-line therapies should be initiated as soon as criteria for possible AE are confirmed.

Clinical Sensitivity, Specificity, and Predictive Value of Neural Antibody Testing for Autoimmune Encephalitis

Neural antibody testing plays a major role in the diagnostic evaluation of patients with suspected autoimmune encephalitis. Through reviewing the diagnostic measures of clinical sensitivity, specificity, and predictive value, it becomes apparent that a neural antibody test result cannot be considered in isolation. An understanding of how the disease state is defined in relation to the neural antibody, knowledge of the test methodology implemented, and estimation of the pretest probability that the patient’s presentation is autoimmune are all required in each case to ensure appropriate test interpretation.

Subcortical Hypermetabolism Associated With Cortical Hypometabolism Is a Common Metabolic Pattern in Patients With Anti-Leucine-Rich Glioma-Inactivated 1 Antibody Encephalitis

Brain 18F-fluorodeoxyglucose positron emission tomography (FDG PET) is a sensitive technique for assisting in the diagnosis of patients with anti-leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis. The purpose of this study aimed to explore the glucose metabolic patterns of this disorder based on PET voxel analysis.This retrospective study enrolled 25 patients with anti-LGI1 encephalitis.

Conclusion

Subcortical hypermetabolism associated with cortical hypometabolism presented with a common metabolic pattern in patients with anti-LGI1 encephalitis in the present study. The resolution of the metabolic gradient of the hippocampal hypermetabolism and neocortical hypometabolism may bring about improved clinical neurologic disability.

Ketogenic Diet Therapy for the Treatment of Post-encephalitic and Autoimmune-Associated Epilepsies

In addition to its potential role in the treatment of acute refractory status epilepticus in patients with PE and AE, ketogenic diet therapies may be feasible and safe in the management of chronic post-encephalitic and autoimmune-associated epilepsy. Patients with prior history of SE might respond better to KDT. Further studies are needed to explore the efficacy of KDT in managing seizures in patients with PE and AE. Moreover, whether the early use of KDT can alter the pathophysiology, prognosis, and outcome of patients with encephalitis warrants further exploration.

Progressive hippocampal sclerosis after viral encephalitis: Potential role of NMDA receptor antibodies

NMDA Ab in context of progressive hippocampal sclerosis after VZVE (varicella zoster virus encephalitis)

This case series of 4 patients presents the first tentative evidence in support of chronic autoimmune inflammation driving disease progression after viral encephalitis beyond the known acute immune-mediated relapses. The anecdotal nature of the data does not, however, permit conclusive judgement on causality. Should our findings be replicated in larger cohorts, the treatment of post-infectious epilepsy could potentially be expanded to include immunosuppressive strategies in antibody-positive cases.

Autoimmune encephalitis after Japanese encephalitis in children: A prospective study

In addition to anti-NMDAR antibodies, anti-GABABR antibodies and antibodies against unknown neuronal surface antigens can trigger autoimmune encephalitis following JE. Patients who developed autoimmune encephalitis had a poorer prognosis at the one-year follow-up. Serum CXCL13 may represent a predictor of autoimmune encephalitis after JE.

Relevance of Brain 18F-FDG PET Imaging in Probable Seronegative Encephalitis With Catatonia: A Case Report

Cerebral 18F-fluorodeoxyglucose PET imaging could be considered a relevant biomarker in the assessment of possible/probable seronegative autoimmune encephalitis associated with psychiatric manifestations that is an infrequent but complex clinical presentation in child and adolescent psychiatry, as it may be the only abnormal paraclinical exam. This noninvasive imaging test could help guide the diagnosis and early treatment of AIE, significantly impacting the prognosis of this serious illness.

Leucine Zipper 4 Autoantibody: A Novel Germ Cell Tumor and Paraneoplastic Biomarker

LUZP4‐IgG represents a novel serological biomarker of PNS and has high predictive value for germ cell tumors. This study was undertaken to describe a novel biomarker of germ cell tumor and associated paraneoplastic neurological syndrome (PNS).

Leucine zipper 4 (LUZP4)–immunoglobulin G (IgG) was detected in 28 patients’ sera, 26 of whom (93%) were men. The median age at neurological symptom onset was 45 years.

Leucine zipper 4 (LUZP4)–immunoglobulin G (IgG) was detected in 28 patients’ sera, 26 of whom (93%) were men. The median age at neurological symptom onset was 45 years (range = 28–84). Median titer (ELISA) was 1:300 (1:50 to >1:6,400, normal value < 1:50). Coexistent kelchlike protein 11–IgG was identified in 18 cases (64%). The most common presenting phenotype was rhombencephalitis (17/28, 61%). Other presentations included limbic encephalitis (n = 5, 18%), seizures and/or encephalitis (n = 2, 7%), and motor neuronopathy/polyradiculopathy (n = 4, 14%). The most common malignancy among cancer‐evaluated PNS patients was seminoma (21/27, 78%). Nine of the 21 seminomas detected by whole‐body fluorodeoxyglucose positron emission tomography scan (43%) were extratesticular. Both female patients had ovarian teratoma. Regressed testicular germ cell tumors were found in 4 patients.

ASL MRI and 18F-FDG-PET in autoimmune limbic encephalitis: clues from two paradigmatic cases

Arterial spin labeling (ASL) and 18F-FDG-PET may highlight brain metabolism abnormalities in a very early stage of Limbic encephalitis.
Fluorine-18 fluorodeoxyglucose (18F-FDG-PET) has recently proved to be an important diagnostic tool in Autoimmune limbic encephalitis (LE), a neurological condition characterized by seizures and cognitive dysfunction.
Two main 18F-FDG-PET patterns have been described: the mixed hypermetabolic/hypometabolic and the neurodegenerative one. Arterial spin labeling (ASL) is an MRI technique showing brain perfusion, rarely used in autoimmune neurological conditions. The aim of the present study was to study patients with LE with both techniques, in order to compare their results.
Conclusion: ASL and 18F-FDG-PET findings are strongly concordant in LE. ASL imaging was able to detect the two main 18F-FDG-PET patterns previously described in patients with LE.

Tofacitinib treatment for refractory autoimmune encephalitis

A total of eight patients were treated with tofacitinib; two had good responses (clinical global impression-improvement score [CGI-I] = 1 or 2), three had partial responses (CGI-I = 3), and three showed no significant improvements (CGI-I = 4) in response to tofacitinib. The two good responders showed the improvement of chronic autoimmune meningoencephalitis and the cessation of the new-onset refractory status epilepticus in anti-myelin oligodendrocyte glycoprotein (MOG)-associated disorder, which was previously intractable to anesthetics and the other immunotherapies. No patients had serious side effects. Our findings suggest the potential of tofacitinib as a therapeutic option for central nervous system autoimmune diseases.

Autoimmune encephalitis: proposed recommendations for symptomatic and long-term management Part 1

This is part 1 of a two-part paper

In this first part of the best practice recommendations, we covered the clinical presentation, diagnostic workup and acute management of AE.

The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. 

Autoimmune encephalitis: proposed recommendations for symptomatic and long-term management Part 2

This is part 2 of a two-part paper.

In this second part, we will cover symptomatic, bridging, and maintenance immunotherapy of AE.

The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. 

18F-FDG PET/CT in Initial Diagnosis and Treatment Response Evaluation of Anti-NMDAr and Anti-GAD Dual Antibody Autoimmune Encephalitis

Case report underwent F-FDG PET for a suspicion of encephalitis, which revealed increased FDG uptake in the bilateral parietotemporal lobes (right more than left), anterior cingulate cortex, bilateral basal ganglia, thalami, and cerebellum. This atypical pattern did not conform to any known pattern of encephalitis, which was later attributed to the presence of both anti-NMDAr and anti-GAD antibodies in blood and cerebrospinal fluid.

Antibody-negative autoimmune encephalitis as a complication of long-term immune-suppression for liver transplantation

Autoimmune encephalitis is a rare spectrum of disease that can be a complication of chronic immunosuppression. Diagnosis often requires the presence of antineuronal antibodies, but many causative antibodies have not yet been identified. Antibody-negative autoimmune encephalitis (AbNAE) is especially difficult to diagnose and must rely largely on exclusion of other causes. In chronically immune-suppressed transplant recipients, the differential is broad, likely resulting in underdiagnosis and worse outcomes. Here, we present a 58-year-old liver transplant recipient taking tacrolimus for prevention of chronic rejection who presented with 5 days of confusion, lethargy and lightheadedness. He was diagnosed with AbNAE after an extensive workup and recovered fully after high-dose corticosteroids. Our case highlights the importance of recognising the association between chronic immunosuppression and autoimmune encephalitis. Autoimmune encephalitis, even in the absence of characterised antibodies, should be considered when transplant recipients present with central neurologic symptoms.

Intelligent cell-based therapies for cancer and autoimmune disorders

Highlights

Emerging strategies to develop smart and controllable CAR T-cells.

Devising CAR T-cells to overcome immunosuppressive tumor microenvironment.

CAR engineering in natural killer cells and macrophages to expand immunotherapy.

Engineered immune cells used to target autoimmune disorders.

Delta brush variant: A novel ictal EEG pattern in anti‐NMDAR encephalitis

Key Points

  • Delta brush variance is a novel ictal electroencephalogram pattern in anti‐NMDAR encephalitis.

  • Delta brush variance is characterized as generalized delta rhythm with fast spike activity riding on it.

  • Delta brush variance is derived from extreme delta brush in the florid phase of the disease.

  • Cortex‐subcortical area interaction may contribute to the evolution between delta brush variance and extreme delta brush.

Apheresis in Autoimmune Encephalitis and Autoimmune Dementia

Discusses autoimmune dementia, which might be considered a sub-form of AE with predominant cognitive deficits. It is a course of autoimmune encephalitis believed to occur slowly over time but caused by some of the same antibodies.
Predictors for beneficial outcomes after treatment with apheresis in patients with AE include the start of the treatment early in the disease before substantial irreversible brain damage has occurred. Nevertheless, after longer periods from symptom onset to therapy initiation, apheresis can also result in symptom improvement. Immunotherapy with steroids or IVIG prior to apheresis does not seem to have an effect on the overall outcome. Especially in patients with severe disease courses apheresis is a major treatment option and should be initiated early, possibly together with other immune therapies.
For selected patient groups such as children and pregnant women as well as patients requiring ICU treatment, the safety and efficacy of apheresis could also be shown.

Update on the diagnosis and management of autoimmune encephalitis

Key points~

Autoimmune encephalitis should be a key part of the differential diagnosis in patients with alterations in cognition,  consciousness, personality or behaviour.

Antibody testing should be guided by recognisable clinical syndromes, but also should account for the expanding numbers of recognised antibodies and overlapping phenotypes.

Autoimmune encephalitis may present sub-acutely with normal or subtly abnormal cerebrospinal fluid findings and neuroimaging.

Despite severe symptoms and long intensive treatment, unit stays, the outcome of autoimmune encephalitis is good in most cases if early immune therapy is given.

The optimum first- and second-line treatment strategy for autoimmune encephalitis is unclear and well-designed clinical trials are needed.

The Clinical Value of 18 F-FDG-PET in Autoimmune Encephalitis Associated With LGI1 Antibody

Results: The initial 18F-FDG-PET scan indicated a significant abnormal metabolic pattern in 31 LGI1 AE patients (91%), whereas only 20 patients (59%) showed an abnormal MRI. The 18F-FDG-PET metabolic pattern was reversible after treatment; most of the patients showed an almost normal uptake of 18F-FDG-PET after discharge.

 

Regarding the abnormal metabolic pattern in LGI1 AE subjects exhibiting hypermetabolism was specifically located in the basal ganglia (BG) and medial temporal lobe (MTL). BG hypermetabolism was observed in 28 subjects (82%), and 68% of patients showed MTL hypermetabolism. A total of 17 patients (50%) exhibited faciobrachial dystonic seizures (FBDS), and the remaining subjects showed non-FBDS symptoms (50 and 50%). BG-only hypermetabolism was detected in seven subjects in the FBDS subgroup (7/16) but in only one subject in the non-FBDS subgroup

Even a Few Days of Steroids May Be Risky, New Study Suggests

Patients with a chronic inflammatory condition such as rheumatoid arthritis may benefit substantially from short-term steroids to treat a disease flare. “In that specific case, the benefits of short-term steroids may outweigh the risks.”

Extended use of corticosteroids for chronic inflammatory conditions puts patients at risk for serious adverse events (AEs), including cardiovascular disease, osteoporosiscataracts, and diabetes. Now, a growing body of evidence suggests that even short bursts of these drugs are associated serious risks.

Cerebrospinal Fluid Findings in Patients With Autoimmune Encephalitis—A Systematic Analysis

The different antibody-defined AIE subtypes might be highly distinct with regard to their immune pathophysiology, e.g., the pre-dominance of specific IgG subclasses, IgG1, or IgG4, or frequency of paraneoplastic compared to idiopathic origin. Thus, it is conceivable that the results of basic CSF analysis might also be very different. However, this has not been explored systematically. Here, we systematically reviewed the literature about the 10 most important AE subtypes, AE with antibodies against NMDA, AMPA, glycine, GABAA, and GABAB receptors as well as DPPX, CASPR2, LGI1, IgLON5, or glutamate decarboxylase (GAD), with respect to the reported basic CSF findings comprising CSF leukocyte count, total protein, and the presence of oligoclonal bands (OCB) restricted to the CSF as a sensitive measure for intrathecal IgG synthesis. Our results indicate that these basic CSF findings are profoundly different among the 10 different AE subtypes. Whereas, AEs with antibodies against NMDA, GABAB, and AMPA receptors as well as DPPX show rather frequent inflammatory CSF changes, in AEs with either CASPR2, LGI1, GABAA, or glycine receptor antibodies CSF findings were mostly normal.

Our findings suggest that different antibody-defined AE subtypes are associated with characteristic CSF findings. Rather non-paraneoplastic and IgG4 pre-dominant disease subtypes tend to have less CSF inflammatory activity compared to diseases with IgG1 pre-dominance, which more frequently are paraneoplastic. AE with NMDAR antibodies is the most frequent AE subtype at younger age and almost always associated with inflammatory CSF findings while anti-LGI1 AE, the most frequent AIE subtype in the elderly, in the majority of patients CSF is normal. We thus conclude that in suspected AE in the elderly, normal basic CSF findings should not lead to the decision against testing for antineuronal antibodies.

Utility of Brain Fluorodeoxyglucose PET in Children With Possible Autoimmune Encephalitis

We aimed to explore the utility and additional clinical contribution of brain fluorodeoxyglucose (FDG) PET imaging for the assessment of children with possible autoimmune encephalitis in comparison to brain MRI.

Conclusions: Our findings support the usage of fluorine-18-FDG PET/computed tomography (CT)/MRI with quantitative analysis early in the diagnostic work-up of possible autoimmune encephalitis, particularly in those with normal or nonspecific MRI findings

Efficacy and Safety of Rituximab in Autoimmune Encephalitis: A Meta-Analysis

Results: Good functional outcome at last follow-up following rituximab therapy occurred in 72.2% of patients (95% CI: 66.3%-77.4%). Mean mRS score decreased by 2.67 (95% CI: 2.04-3.3; p <0.001). Relapses following the rituximab therapy occurred in only 14.2% of patients (95% CI: 9.5%-20.8%). Infusion related reactions, pneumonia and severe sepsis were seen in 29 (15.7%), 11 (6.0%) and 2 patients (1.1%) respectively. The efficacy and side effect profile of rituximab is comparable to outcomes seen in rituximab use in other autoimmune and inflammatory CNS disease.

Conclusion: Our meta-analysis showed that rituximab is an effective second line agent for AE with an acceptable toxicity profile.

Diagnostic tools for immune causes of encephalitis

Mycophenolate mofetil in paediatric autoimmune or immune‐mediated diseases

Abnormal brain metabolism on FDG-PET/CT is a common early finding in autoimmune encephalitis

Conclusions: FDG-PET/CT was more often abnormal than initial EEG, MRI, and CSF studies in neurology inpatients with AE, with brain region hypometabolism the most frequently observed.

The diagnosis and treatment of Autoimmune Encephalitis - Lancaster

Glioblastoma as differential diagnosis of autoimmune encephalitis

Mayo Develops Test to Distinguish Demyelinating Diseases: NMO, ADEM, transverse myelitis

Improving the antibody-based evaluation of autoimmune encephalitis

Treatment strategies for autoimmune encephalitis

CT Scan (CAT Scan): How Do They Work?

The Laboratory Diagnosis of Autoimmune Encephalitis

Steroids vs Steroid sparing treatments

Tocilizumab in Autoimmune Encephalitis Refractory to Rituximab: An Institutional Cohort Study

CSF herpes virus and autoantibody profiles in the evaluation of encephalitis

Comparison of 18F-FDG PET-CT and MRI in the evaluation of patients with antibody positive autoimmune encephalitis

Modulatory effects of bortezomib on host immune cell functions

Treating Autoimmune Encephalitis

Aggressive course in encephalitis with opsoclonus, ataxia, chorea, and seizure

The Diagnostic Conundrum and Treatment Dilemma of a Patient With a Rapidly Progressive Encephalopathy

Mitochondrial diseases mimicking autoimmune diseases of the CNS and good response to steroids initially

Discussion: We would like to draw attention to a subset of patients with MD initially presenting with signs and symptoms mimicking neuroimmunological. The absence of CSF pleocytosis elevated CSF lactate and progressive, relapsing course should trigger further (genetic) investigations in search of mitochondrial diseases (MD) even in patients with good response initially to immunomodulating therapies.

Positron emission tomography in autoimmune encephalitis: Clinical implications and future directions

18 F-fluoro-deoxyglucose position emission tomography (18 F-FDG-PET) has been proven as a sensitive and reliable tool for diagnosis of autoimmune encephalitis (AE). More attention was paid to this kind of imaging because of the shortage of MRI, EEG, and CSF findings. FDG-PET has been assessed in a few small studies and case reports showing apparent abnormalities in cases where MRI does not. Here, we summarized the patterns (specific or not) in AE with different antibodies detected and the clinical outlook for the wide application of FDG-PET considering some limitations. Specific patterns based on antibody subtypes and clinical symptoms were critical for identifying suspicious AE, the most common of which was the anteroposterior gradient in anti- N -methyl- d -aspartate receptor (NMDAR) encephalitis and the medial temporal lobe hypermetabolism in limbic encephalitis. And the dynamic changes of metabolic presentations in different phases provided us the potential to inspect the evolution of AE and predict the functional outcomes.

NMDAR autoantibodies in psychiatric disease - An immunopsychiatric continuum and potential predisposition for disease pathogenesis

Our findings might suggest that an autoimmunity continuum exists that ranges from NMDAR antibodies associated with psychiatric disease to probable to definitive NMDARE (Fig. 1). Thus, we postulate the following model depicted in Fig. 1: the psychiatric disease severity worsens when the autoinflammation increases and autoimmunity phenomena develop along with rising production of NMDAR antibodies. Two main phenomena can be distinguished such as psychiatric disease associated with NMDAR antibodies, and NMDAR antibody-mediated encephalitis. However, this model does not consider an initial attack on the brain induced by NMDAR encephalitis that later develops to an NMDAR antibody-associated chronic psychiatric disease like schizophrenia. Thus, we developed a second model (Fig. 2) that integrates an initial severe inflammation attack on the brain entailing a chronic psychiatric disease that appears later. Furthermore, there is evidence that an initial NMDARE might initiate an autoimmune attack that predisposes the brain to develop a psychiatric disease like schizophrenia later. Such a strong initial attack in the form of an NMDARE might be detected by specific brain morphology such as atrophy, ie, cerebellar atrophy.

Fluctuations in quality of life and immune responses during intravenous immunoglobulin infusion cycles

Paper supports that patients are not making up ivig ups and downs. This is addressing questions of people with humoral immunodeficiency. And it says that the following happens: “Multiple inflammatory chemokine and cytokine levels increased in the blood by 1 hour after infusion (CCL4 (MIP-1b), CCL3 (MIP-1a), CCL2 (MCP-1), TNF-α, granzyme B, IL-10, IL-1RA, IL-8, IL-6, GM-CSF, and IFN- γ). The largest changes in analytes occurred in subjects initiated on IVIG during the study. A significant decrease in IL-25 (IL-17E) following infusion was seen in most intervals among subjects already receiving regular infusions prior to study entry. These findings reveal several short-term effects of IVIG given in replacement doses to patients with humoral immunodeficiency: QOL consistently improves in the first week of infusion, levels of a collection of monocyte-associated cytokines increase immediately after infusion whereas IL-25 levels decrease, and Treg levels increase. Moreover, patients that are new to IVIG experience more significant fluctuations in cytokine levels than those receiving it regularly.”

Construction of an Assisted Model Based on Natural Language Processing for Automatic Early Diagnosis of Autoimmune Encephalitis

The assisted diagnostic model could effectively increase the early diagnostic sensitivity for AE compared to previous diagnostic criteria, assist physicians in establishing the diagnosis of AE automatically after inputting the HPI and the results of standard paraclinical tests according to their narrative habits for describing symptoms, avoiding misdiagnosis and allowing for prompt initiation of specific treatment.

Case Report: Triphasic Waves in a 9-Year-Old Girl With Anti-NMDAR Encephalitis

Triphasic waves (TWs) are not specific to metabolic encephalopathy, but can also occur in children with autoimmune encephalitis. This case achieved a good prognosis after the early initiation of immunotherapy.

Daratumumab for treatment-refractory antibody-mediated diseases in neurology

Our findings suggest that daratumumab provided a clinically relevant depletion
of autoreactive long-lived plasma cells, identifying plasma cell-targeted therapies as
promising escalation therapy for highly active, otherwise treatment-refractory autoantibodymediated neurological diseases.

Electroclinical biomarkers of autoimmune encephalitis

Significance: We have identified EEG biomarkers that differentiate NMDAR AIE from other subtypes. We have also demonstrated EEG biomarkers that are associated with poor functional outcomes.

The importance of tissue-based assay in the diagnosis of autoimmune encephalitis

Non-antigen-specific assays, such as IFA, can identify antibodies not detected in commercially available kits and therefore are recommended in the evaluation of autoimmune encephalitis.

Autoimmune/Paraneoplastic Encephalitis Antibody Biomarkers: Frequency, Age, and Sex Associations

This neuroimmunology laboratory cohort study provides a big-picture perspective of the distribution among samples that are positive for AE-Abs. This study also finds age and sex associations in patients evaluated for AE that can aid in clinical prognostication and provide inference to pathophysiologic processes.

The most frequent AE-Abs detected were NMDA-R-IgG, GAD65-IgG, LGI1-IgG, and MOG-IgG1. Age and sex associations may suggest paraneoplastic, or aging influences on neurologic autoimmunity.

Risk Classification to Differentiate Autoimmune from Viral Encephalitis

As compared to viral encephalitis, patients with autoimmune encephalitis were more likely to be younger (< 60 years old), have a subacute (6-30 days) or chronic ( >30 days) presentation, have seizures, and have psychiatric and/or memory complaints (P< 0.001). Furthermore, patients with autoimmune encephalitis were less likely to be febrile and to lack inflammatory cerebrospinal fluid (CSF) (defined as white blood cells < 50 per microliter or protein < 50 milligrams per deciliter) [See Table 1]. In the multivariable logistic regression model, subacute/chronic presentation, psychiatric and/or memory complaints, and lack of inflammatory CSF were significantly associated with autoimmune encephalitis. Using these 3 variables, patients were classified into 3 risk categories for autoimmune encephalitis: low risk (0-1 variables); 0%; intermediate risk (2 variables); 16%; and high risk (3 variables); 83% (P value < 0.001).

Neuropsychological Evaluations in Limbic Encephalitis

Limbic encephalitis (LE) can negatively affect cognition, mood and behavior. On the cognitive level, LE is primarily associated with different variants of mostly subacute episodic long-term memory dysfunction but also with impairments in attention and executive functions. On the behavioral level, patients with LE often show altered affective states, but other and partially severe psychiatric symptoms have been described as well. Cognition, affect and behavior can recover after immunomodulatory treatment as long as no persistent structural damage has been induced.
An evidence-based neuropsychological baseline assessment for supporting the diagnosis of LE should ideally be conducted before treatment initiation. Repeated assessments for demonstrating disease- or treatment-related disease dynamics should become an essential part of the diagnostic workup of patients with evident or suspected limbic encephalitis. Therefore, neuropsychology contributes to the diagnosis of LE, it is an important outcome parameter for monitoring the course of the disease and the success of therapeutic interventions, and therewith may guide treatment decisions.

The hippocampus as the switchboard between perception and memory

This paper discusses temporal lobe/ eeg/ and memory.

Rituximab Treatment and Long-term Outcome of Patients With Autoimmune Encephalitis-Real-world Evidence From the GENERATE Registry

Our results support the efficacy of early rituximab treatment in NMDAR-, LGI1-, and CASPR2-AE and suggest that short-term therapy could be a treatment option. They also suggest that patients with long-standing GAD65 disease are less likely to benefit from B-cell depletion than the other AE subgroups

Abnormal brain metabolism on FDG-PET/CT is a common early finding in autoimmune encephalitis

Highly Recommend ~includes outstanding graphs

The brain FDG-PET/CT was commonly abnormal in AE, most often demonstrating brain region hypometabolism. The frequency of metabolic abnormalities was greater than that of diagnostic studies currently included in consensus criteria for the diagnosis of AE. Overall, FDG-PET/CT may represent a sensitive and early biomarker for AE and could play a complementary role to currently proposed tests in the diagnosis of AE. 

The Diagnostic Challenge of Seronegative Autoimmune Encephalitis With Super-Refractory Status Epilepticus

Case study with  main concerning issue was super-refractory status epilepticus, requiring continuous anesthesia to suppress EEG burst activity. This poses a diagnostic challenge as present laboratory techniques lack specificity to identify this. There are many unidentified intracellular and extracellular protein receptors; hence, a negative serology panel for antibodies should not delay the initiation of primary immunomodulatory therapy (steroids, plasmapheresis). A strong clinical suspicion of disease, after a panel to rule out paraneoplastic and infectious serology, supported by MRI imaging, is the mainstay to identify seronegative autoimmune encephalitis. Primary therapy should be initiated to prevent disease progression. If the patient continues to have symptoms despite steroids and IVIG, then second-line immunotherapy with agents like rituximab can be used

Positive Predictive Value of Myelin Oligodendrocyte Glycoprotein Autoantibody Testing

Of 1260 consecutive patients tested for MOG-IgG1 at the Mayo Clinic over 2 years, 92 (7.3%) were positive, 26 (28%) of whom had their results independently designated as false positive by 2 neurologists.

Meaning  False-positive MOG-IgG1 results are encountered in clinical practice; caution is advised before assigning a MOG-IgG1–associated disorder diagnosis in patients with low-titer positive results and atypical phenotypes.

Brain 18F-FDG PET for the diagnosis of autoimmune encephalitis: a systematic review and a meta-analysis

Conclusion and relevance

Brain 18F-FDG PET has a high detection sensitivity and should be included in future diagnostic autoimmune encephalitis recommendations. Specific metabolic 18F-FDG PET patterns corresponding to the main autoimmune encephalitis autoantibody subtypes further enhance the value of this diagnostic

Effectiveness of Mycophenolate Mofetil in the Treatment of Pediatric Anti-NMDAR Encephalitis: A Retrospective Analysis of 6 Cases

Objective: To explore the effectiveness and safety of mycophenolate mofetil (MMF) as a second-line medication in the treatment of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, the most common and severe autoimmune encephalitis.

Results: Six children with anti-NMDAR encephalitis were treated with MMF in the 2nd or 3rd treatment disease event (3 cases vs. 3 cases). MMF initiation was mean 19.2 months (range 6–39 months) after disease onset at a mean dose of 25.6 mg/kg (range 19.6–28.4 mg/kg) for 14 months (range 6–26 months). Only two patients had transient mild diarrhea within 2 weeks of MMF application. During follow-up, one patient relapsed whilst on MMF, one patient discontinued MMF, and 4 cases were still on MMF.

Conclusion: The use of MMF in anti-NMDAR encephalitis may be effective and safe. MMF can be used as one of the relapse prevention options in patients who already have relapsed or possibly even after the first event. Delayed use may be the main reason for MMF failure.

The Diagnostic Challenge of Seronegative Autoimmune Encephalitis With Super-Refractory Status Epilepticus

In this case, the main concerning issue was super-refractory status epilepticus, requiring continuous anesthesia to suppress EEG burst activity. This poses a diagnostic challenge as present laboratory techniques lack specificity to identify this. There are many unidentified intracellular and extracellular protein receptors; hence, a negative serology panel for antibodies should not delay the initiation of primary immunomodulatory therapy (steroids, plasmapheresis). A strong clinical suspicion of disease, after a panel to rule out paraneoplastic and infectious serology, supported by MRI imaging, is the mainstay to identify seronegative autoimmune encephalitis. Primary therapy should be initiated to prevent disease progression. If the patient continues to have symptoms despite steroids and IVIG, then second-line immunotherapy with agents like rituximab can be used. Our patient recovered well after second-line immunotherapy and was discharged without any cognitive or neurological symptoms.

Therapy Approved for Rare Neurological Autoimmune Disorder

Satralizumab-mwge, marketed as Enspryng, was approved for adults with NMOSD who have antibodies against the aquaporin 4 (AQP4) protein. Binding of the antibodies with AQP4 activates the immune system and results in elevated, inflammation-promoting levels of interleukin 6 in cerebrospinal fluid. Satralizumab-mwge blocks interleukin 6 signaling pathways.

Note: 

*Some neuroimmunolgists specializing in AE feel this may be an appropriate treatment to consider as ‘off label use’ for Autoimmune Encephalitis patients when appropriate. 

18F-FDG-PET/MRI in the diagnostic work-up of limbic encephalitis

Conclusion
LE diagnosis remains challenging for imaging as it shows only subtle imaging findings in
most patients. Nevertheless, based on the simultaneous and combined analysis of morphologic and metabolic data, integrated PET/MRI may enable a dual platform for improved diagnostic confidence and overall detection of LE as well as whole-body imaging for the exclusion of
paraneoplastic LE.

Long-term efficacy of mycophenolate mofetil in myelin oligodendrocyte glycoprotein antibody-associated disorders

These findings provide a clinical evidence that MMF immunosuppression therapy may prevent relapse in patients with MOGAD.

Treatment of MOG-IgG-associated disorder with rituximab: An international study of 121 patients

Highlights  – The largest study of rituximab in MOG-IgG-associated disorder, includes both adults and children. Rituximab reduced relapse rates in MOG-IgG-associated disorder by 37%. Compared to similar studies in AQP4-IgG-associated NMOSD, the efficacy seems lower. Some patients relapsed despite apparent circulating B-cell depletion.

18F-FDG-PET Imaging Patterns in Autoimmune Encephalitis: Impact of Image Analysis on the Results

Conclusions: For the evaluation of patients with suspected AE, standard analysis of FDG-PET images benefits from voxel-based analysis, as it may lead to more comparable and accurate results. This study provides new evidence of the utility of FDG-PET for AE beyond the approach based on MRI, CSF sampling and EEG. Patients with AE may benefit from prompt diagnosis when brain FDG-PET is added to the traditional complementary tests.

Decreased occipital lobe metabolism by FDG-PET/CT An anti–NMDA receptor encephalitis biomarker

Brain FDG-PET/CT is commonly abnormal in anti–NMDA receptor encephalitis, most often demonstrating marked hypometabolism of the medial occipital lobes. This marked hypometabolism of the medial occipital lobes is relatively unique to anti–NMDA receptor encephalitis compared with other forms of definite AE, particularly in those with greatest neurologic disability. Among patients with anti–NMDA receptor encephalitis, marked lateral and medial occipital lobe hypometabolism is evident in those with severe neurologic disability compared with those less disabled. While detection of the anti–NMDA receptor antibody in the CSF serves as the diagnostic biomarker of choice, medial occipital hypometabolism could potentially serve as a unique, noninvasive, early biomarker of anti–NMDA receptor encephalitis, with utility in diagnosis as well as monitoring of clinical improvement.

Therapeutic plasma exchange as a life-saving therapy in a suspected case of autoimmune encephalitis: A case report from a tertiary health-care center

With early suspicion based on clinical features and rapid treatment initialization, even in the absence of detectable autoantibodies (due to lack of diagnostic kits and facilities), TPE plays an important role in the management of AE, as it can even remove some hitherto undetected autoantibodies. Compliance with TPE was excellent in our case.

Admission diagnoses of patients later diagnosed with autoimmune encephalitis

Autoimmune encephalitis with psychosis: Warning signs, step-by-step diagnostics and treatment

A clinical approach to diagnosis of Autoimmune Encephalitis

*Gold Standard paper.

We have shown that it is possible to proceed through a logical differential diagnosis of autoimmune encephalitis using criteria based on conventional clinical neurological assessment and standard diagnostic tests (MRI, EEG, and CSF studies). Through this approach, levels of evidence of probable and definite autoimmune encephalitis can be achieved early and therapies implemented quickly, with the possibility of fine-tuning the diagnosis and treatment when antibody results become available.

Role of ¹⁸F-FDG-PET imaging in the diagnosis of autoimmune encephalitis

¹⁸F-FDG-PET imaging has the potential to improve estimation of disease severity in patients with autoimmune encephalitis, with
implications for follow-up evaluation
and therapy monitoring.

¹⁸F-FDG-PET imaging might have a role in the
diagnosis of anti-NMDA receptor
encephalitis, an entity for which MRI
has poor sensitivity. Several ¹⁸F-FDGPET imaging studies in these patients have shown metabolic abnormalities in diff erent brain areas, including the frontal, temporal, and occipital lobes, and the basal ganglia, cerebellum, and brainstem.2,6 Again, the PET
fi ndings were more clearly associated
with the clinical picture (ie, basal ganglia involvement and presence of movement disorders), disease severity, and recovery after therapy than the MRI findings.

Diagnostic Value of 18F-FDG PET/CT Versus MRI in the Setting of Antibody-Specific Autoimmune Encephalitis

We believe that brain 18F-FDG PET/CT may serve as an important, early biomarker of AE. Current clinical recommendations do not include 18F-FDG PET/CT in their algorithms, with MRI remaining the standard imaging modality. Our results in a small group of antibody-positive AE patients show a much greater sensitivity for detection of an underlying abnormality with 18F-FDG PET/CT than with MRI. Because early intervention is paramount to optimal clinical outcome, our results suggest that 18F-FDG PET/CT of the brain be added to the clinical workup of patients with suspected AE, particularly in those with normal or nonspecific MRI findings

Side Effects of IVIG

Cytoxan - Generic Name: Cyclophosphamide

Encephalopathic EEG Patterns

Tocilizumab Effective in Refractory Autoimmune Limbic Encephalitis

MRI Scans: How Do They Work?

CD19 has emerged as a promising target for B cell depletion using Inebilizumab for AE patients

Introduction to Neuroplasticity and Cognitive Therapy

A new imaging technique may give researchers fresh insights into brain development and function with brain disease

Rituximab treatment for autoimmune limbic encephalitis in an institutional cohort

Glucocorticoid Therapy and Cushing Syndrome

The serum protein electrophoresis (SPEP) test

Successful immune moderation treatment for PERM with myoclonus

Autoimmune Dementia: Clinical Course and Predictors of Immunotherapy Response

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Autoimmune Encephalitis Trivia Playing Cards

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