2017-18Research/Highly-Recommended/HR

In that algorithmic assessment, to meet at least possible AE criteria, patients require subacute onset (rapid progression of less than 3 months) of working memory deficits (short-term memory loss), altered mental status (altered level of consciousness, lethargy, or personality change) or psychiatric symptoms with at least 1 of new focal CNS findings, new-onset seizures, CSF pleocytosis, and supportive MRI. These tests are complemented by AE-specific IgG antibody testing, CSF IgG index and oligoclonal bands, EEG, and brain biopsy to further refine diagnostic certainty. Specificity is assured by the requirement for reasonable exclusion of other diagnoses and differing levels of diagnostic certainty (possible, probable, and definite). Discerning the characteristics and relative frequencies in the clinical practice of different AE disorder subcategories (possible, probable, definite, and seropositive or seronegative) and related encephalopathies not meeting at least possible AE criteria (e.g., those with primarily seizure disorders without encephalopathy, brainstem disorders without altered awareness, and atypical presentations) would be informative for clinical treatment decisions, epidemiologic studies, and clinical trial design.

In this study, we applied the AE guidelines to 538 adult patients diagnosed with diverse autoimmune encephalopathies within our practice (Autoimmune Neurology Clinic, Mayo Clinic, Rochester, MN).⁴ The scope of this assessment did not include pure ataxias, stiff-person syndrome, or other pure movement disorders.

This is an update to the 2015 review.

This paper reviews the most common types of AE in detail, treatments, outcomes and new advances, and monitoring the disease. 

The field of autoimmune encephalitis has witnessed a number of advances in our understanding of the underlying biology and the correlation of this with more refined clinical observations. Our hope is that by the time of our next review, the use of early, targeted immunotherapies is commonplace in these conditions and has had an appreciable impact on the long-term outcomes of patients. To integrate the emerging biological insights with our progress around patient-relevant outcomes and the limitations of currently available therapies, the field now needs to embrace experimental medicine approaches. Some classical clinical trials are underway but may be hampered by difficulty recruiting immunotherapy-naïve patients. Nevertheless, a large pipeline of exciting new treatments will likely enter clinical trials in the near future. If incorporated with further dissection of the underlying biology, these trials are likely to provide a foundation for patient treatments over the next decade.

CONCLUSIONS AND RELEVANCE When evaluating for autoimmune encephalitis, a broad differential diagnosis should be considered and misdiagnosis occurs in many settings including at specialized centers. In this study, red flags suggesting alternative diagnoses included an insidious onset, positive nonspecific serum antibody, and failure to fulfill autoimmune encephalitis diagnostic criteria. Autoimmune encephalitis misdiagnosis
leads to morbidity from unnecessary immunotherapies and delayed treatment of the correct diagnosis.

Conclusion and Future Directions

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.

Autoantibody encephalitis involves distinct clinical syndromes that can be recognized in many cases. In other patients, cancer screening and rational antibody testing can lead to a precise diagnosis. Our knowledge about the optimal treatments is still hampered by the lack of randomized treatment trials, but new information from retrospective studies has provided important new information on treatment of anti-LGI1 and anti-NMDAR syndromes. In selecting treatments it is important to understand the underlying disease mechanisms and the evidence supporting treatment. There will almost certainly be additional autoantibody syndromes discovered in the coming year. Each disease teaches us about the neuroscience of the target antigens. It is not reasonable to expect a general neurologist to memorize the associations of each new antibody. Rather, the goal should be to read and review the cancer associations and treatment guidance for a specific antibody when encountering a case.

In conclusion, this study presents comprehensive longitudinal data for the cognitive outcome in NMDAR encephalitis. All patients had cognitive deficits about 2 years after disease onset, mainly affecting memory and executive function. After 4 years, moderate or severe cognitive deficits persisted in 2/3 of patients despite good functional neurological outcome, indicating that cognitive function is an important outcome measure in addition to the functional neurological scales. Impaired cognitive outcome was predicted by delayed treatment and higher disease severity. However, continued improvement of cognitive function was observed for several years after disease onset in some patients.

Comprehensive article on Autoimmune Encephalitis. The first to be published in Finnish. We hope this leads to increased awareness, accurate diagnosis and treatment for patients in Finland. Advocacy for this article was done by long time IAES Member who established the non-profit

Suomen Ultraharvinaiset

KEY POINTS

• AE is an umbrella term for a group of inflammatory central nervous system disorders associated with neuronal autoantibodies or other biomarkers of central nervous system autoimmunity.

• Common clinical presentations include progressive neurocognitive symptoms with concomitant movement disorders, seizures, and autonomic dysfunction that worsens over weeks to months.

• Objective clinical findings are needed to make the diagnosis of AE, including changes on magnetic resonance imaging, electroencephalography, and cerebrospinal fluid analysis.

• Paper contains a detailed section on differential diagnosis we highly recommend

The identification of neural autoantibodies in patients with new-onset seizures of unknown etiology has led to the concept of acute symptomatic seizures secondary to autoimmune encephalitis (ASSAE) and autoimmune-associated epilepsy (AAE). In these patients, antiseizure medication (ASM)-resistant seizures occur as an early and prominent feature. When combined with other symptoms suggestive of immune-mediated seizures, urgent consultation with neurology is recommended. Early treatment with immunotherapy can drastically alter the course of the disease. First-line immunotherapies include intravenous steroids, intravenous immunoglobulin, and PLEX. In the case of insufficient response, cyclophosphamide and rituximab can be considered appropriate second-line treatments. Treatment also includes adjunct ASM therapy and non-CNS tumor resection (if paraneoplastic etiology is suspected) when found on screening.

As we continue to advance our knowledge in AAE and ASSAE, we need to clarify its definition and diagnostic criteria and promote recognition of relevant symptoms (detailed in Table 2) that would lead to early neurology referral and timely diagnosis. The recently developed APE2 and ACES scores have helped build a foundation for diagnosing ASSAE and AAE; however, there remains much ambiguity.

Supplemental video is included at the end of the paper. Downloadable .mp4

This review aimed to discuss the different ways anti-NMDAR encephalitis could present and manifest on the psychological, mainly, and the neurological spectrum of signs and symptoms. The signs and symptoms expressed by anti-NMDAR encephalitis patients can be categorized into psychosis (represented by delusions and hallucinations), catatonia, seizures, speech and movement abnormalities, and autonomic instability, in addition to cognitive dysfunction.

The temporal association between those signs and symptoms varied among cases; first presentations tend to overlap with psychiatric diagnoses, especially on the schizophrenic spectrum. Catatonia is one of the disease hallmarks as well. Movement disorders are commonly seen among the anti-NMDAR encephalitis pediatric population. The autoimmune link between anti-NMDAR encephalitis and schizophrenia has been described before; antibody-positive patients go on to develop neurological manifestations later on. Anti-NMDAR encephalitis can also present with affective manifestations. Narcolepsy and hypersomnia as manifestations of anti-NMDAR encephalitis have been described, as well as the association between alcohol or drug abuse and NMDAR encephalitis. There are some clinical red flags that could be of use to make the diagnosis.

Hence, for physicians trying to familiarize themselves with this diagnosis, this is a good place to start. The review included a general scheme that covers almost all aspects of the psychiatric presentation, similarities, and differences in contrast to other differential diagnoses, in addition to clinical pearls that aid diagnosis. However, this paper did not discuss the different ways this disorder presents in pediatrics; hence, this remains an area future reviews might be more inclusive of.

Antibodies against glutamic acid decarboxylase (GAD), originally linked to stiff person syndrome (SPS), now denote the “GAD antibody-spectrum disorders” (GAD-SD). This review highlights that high-titer anti-GAD antibodies are associated with an array of distinct neurological syndromes including SPS, cerebellar ataxia, epilepsy, limbic encephalitis, abnormal eye movements. Although high anti-GAD antibodies in serum or their presence in CSF are important for diagnosis, the titers do not correlate with disease severity and do not generally predict response to immunotherapy. Despite considerable efforts, using both in vitro and in vivo preparations, the pathophysiological role of anti-GAD antibodies has not yet been clarified, suggesting that other autoantibodies affecting inhibitory neurotransmission might be of importance, because autoimmunity targeting inhibitory synaptic antigens point to a unifying theme of hyperexcitability as the underlying pathomechanism.

Collectively, the practicing neurologists need to be aware that anti-GAD antibody titers do matter: if high (>10,000 IU/mL), they are diagnostic for a true GAD-SD, necessitating immunotherapy; lower (<10,000 IU/mL) titers are associated with atypical or non-specific neurological disorders requiring further investigation, whereas very low titers (<2000 IU) are typically seen in DM-1 or are of unclear significance.⁷⁴ Importantly, GAD-Abs can also be detected within the various IVIg preparations and anti-GAD antibodies can be detected in patients receiving IVIg.⁸⁴ Most importantly, there is no association between GAD-Ab titer and disease severity or response to therapy without significant titer reduction after immunotherapies with either IVIg or rituximab based on two controlled studies we have performed.

Objective The contemporary diagnosis of paraneoplastic neurologic syndromes (PNSs) requires an increasing understanding of their clinical, immunologic, and oncologic heterogeneity. The 2004 PNS criteria are partially outdated due to advances in PNS research in the last 16 years leading to the identification of new phenotypes and antibodies that have transformed the diagnostic approach to PNS. Here, we propose updated diagnostic criteria for PNS.

Results The panel proposed to substitute “classical syndromes” with the term “high-risk phenotypes” for cancer and introduce the concept of “intermediate-risk phenotypes.” The term “onconeural antibody” was replaced by “high risk” (>70% associated with cancer) and “intermediate risk” (30%–70% associated with cancer) antibodies. The panel classified 3 levels of evidence for PNS: definite, probable, and possible. Each level can be reached by using the PNS-Care Score, which combines clinical phenotype, antibody type, the presence or absence of cancer, and time of follow-up. With the exception of opsoclonus-myoclonus, the diagnosis of definite PNS requires the presence of high- or intermediate-risk antibodies. Specific recommendations for similar syndromes triggered by immune checkpoint inhibitors are also provided.

Conclusions The proposed criteria and recommendations should be used to enhance the clinical care of patients with PNS and to encourage standardization of research initiatives addressing PNS.

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. 

Probably the best summary of how autoimmunity gets initiated is in this great review from Oxford Autoimmune Neurology Group,  which is generally a fantastic and up-to-date all-round primer for many of the clinical and mechanistic issues.

Outlines molecular observations with translational value. We focus on contemporary methodologies of autoantibody detection, the evolution and distinctive nature of the clinical phenotypes, generalisable therapeutic paradigms, and finally discuss the likely mechanisms of autoimmunity in these patients which may inform future precision therapies.

Existing consensus criteria for adult AE were refined for use in children. Provisional pediatric AE classification criteria and an algorithm to facilitate early diagnosis are proposed. There is also discussion about how to distinguish pediatric AE from conditions within the differential diagnosis.

See Correction to Figure 1

A syndrome-based diagnostic approach was published by Graus et al. (Lancet Neurol 15:391-404, 2016), but very little is known in the literature about its application in clinical practice.

AIM: Our aims are to test the feasibility of such approach in a real-world single-centre setting and to analyse the most relevant factors in criteria fulfilment.

Conclusion: Larger studies on prospective cohorts may be more helpful to explore possible important issues.

Many of the early clinical observations in AE have been further refined to permit the accurate recognition of distinctive clinical phenotypes.
AE is now identifed as an important and previously underrecognised cause of CNS infammation—it is highly treatable, and early diagnosis and initiation of immunotherapy are paramount to optimise outcomes.