2017-18Research/Diagnosis/DI

Conclusions

The beneficial effects of oral corticosteroid treatment may do not persist beyond 12 months and may even contribute to an increased incidence of adverse effects. In order to optimize the effectiveness and safety of treatment, we recommend a corticosteroid course of 3-12 months. Patients with reduced levels of consciousness may be more inclined to choose longer courses of corticosteroids for long-term treatment. Patients with an “overlapping syndrome” may require more intense immunotherapy to prevent relapse.

Catatonia is a severe neuropsychiatric syndrome that affects emotion, speech, movement and complex behaviour. It can occur in a wide range of psychiatric and neurological conditions, including depression, mania, schizophrenia, autism, autoimmune encephalitis (particularly NMDAR encephalitis), systemic lupus erythematosus, thyroid disease, epilepsy and medication-induced and -withdrawal states. This concise guideline highlights key recommendations from the British Association for Psychopharmacology (BAP) Catatonia Guideline, published in April 2023. Important investigations may include neuroimaging, electroencephalography and assessment for neuronal autoantibodies in serum and cerebrospinal fluid. First-line treatment comprises benzodiazepines and/or electroconvulsive therapy. The benzodiazepine of choice is lorazepam, which is sometimes used in very high doses. Multidisciplinary working between psychiatrists and physicians is often essential. The main limitation of the guidelines is the low quality of the underlying evidence, comprising mainly small observational studies and case reports or series.

Conclusions

During the acute/subacute stages of seropositive AE, alterations in standardized uptake value ratios (SUVRs) appear to be concentrated within physiologically significant regions, ultimately defining the general cerebral metabolic pattern. By incorporating these key regions into a new classification model, we have improved the overall diagnostic efficiency of AE.

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.

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.

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.

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.

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. 

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.

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.

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.

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.

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.

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

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.

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.

18 of 23 patients completed the study.

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.

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.

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.

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.

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.

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.

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.

In addition to anti-NMDAR antibodies, anti-GABA_BR 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.

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.

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.

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.

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. 

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. 

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.

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.

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 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.

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.

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

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

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.

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

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