MicroRNAs (miRNAs) are non-coding RNAs originally involved in RNA silencing and post-transcriptional regulation of gene expression. We have shown in previous work that the miRNA let-7b can act as a signalling molecule for Toll-like receptor 7, thereby initiating innate immune pathways and apoptosis in the central nervous system. Here, we investigated whether different members of the miRNA family let-7, abundantly expressed in the brain, are released into the human cerebrospinal fluid (CSF) and whether quantitative differences in let-7 copies exist in neurodegenerative diseases. RNA isolated from CSF of patients with Alzheimer´s disease (AD) and from control patients with frontotemporal lobe dementia (FTLD), major depressive episode (MDE) without clinical or neurobiological signs of AD, and healthy individuals, was reverse transcribed with primers against nine let-7 family members, and miRNAs were quantified and analyzed comparatively by quantitative PCR. let-7 miRNAs were present in CSF from patients with AD, FTLD, MDE, and healthy controls. However, the amount of individual let-7 miRNAs in the CSF varied substantially. CSF from AD patients contained higher amounts of let-7b and let-7e compared to healthy controls, while no differences were observed regarding the other let-7 miRNAs. No increase in let-7b and let-7e was detected in CSF from FTLD patients, while in CSF from MDE patients, let-7b and let-7e copy levels were elevated. In CSF from AD patients, let-7b and let-7e were associated with extracellular vesicles. let-7 family members present in the CSF mediated neurotoxicity in vitro, albeit to a variable extent. Taken together, neurotoxic let-7 miRNAs are differentially and specifically released in AD, but also in MDE patients. Thus, these miRNAs may mirror common neuropathological paths and by this serve to unscramble mechanisms of different neurodegenerative diseases.

Background and ObjectivesTo determine the real-world use of rituximab in autoimmune encephalitis (AE) and to correlate rituximab treatment with the long-term outcome.MethodsPatients with NMDA receptor (NMDAR)-AE, leucine-rich glioma-inactivated-1 (LGI1)- AE, contactin-associated protein-like-2 (CASPR2)-AE, or glutamic acid decarboxylase 65 (GAD65) disease from the GErman Network for Research on AuToimmune Encephalitis who had received at least 1 rituximab dose and a control cohort of non–rituximab-treated patients were analyzed retrospectively.ResultsOf the 358 patients, 163 (46%) received rituximab (NMDAR-AE: 57%, CASPR2-AE: 44%, LGI1-AE: 43%, and GAD65 disease: 37%). Rituximab treatment was initiated significantly earlier in NMDAR- and LGI1-AE (median: 54 and 155 days from disease onset) compared with CASPR2-AE or GAD65 disease (median: 632 and 1,209 days). Modified Rankin Scale (mRS) scores improved significantly in patients with NMDAR-AE, both with and without rituximab treatment. Although being more severely affected at baseline, rituximab-treated patients with NMDAR-AE more frequently reached independent living (mRS score ≤2) (94% vs 88%). In LGI1-AE, rituximab-treated and nontreated patients improved, whereas in CASPR2-AE, only rituximab-treated patients improved significantly. No improvement was observed in patients with GAD65 disease. A significant reduction of the relapse rate was observed in rituximab-treated patients (5% vs 13%). Detection of NMDAR antibodies was significantly associated with mRS score improvement. A favorable outcome was also observed with early treatment initiation.DiscussionWe provide real-world data on immunosuppressive treatments with a focus on rituximab treatment for patients with AE in Germany. We suggest that early and short-term rituximab therapy might be an effective and safe treatment option in most patients with NMDAR-, LGI1-, and CASPR2-AE.Class of EvidenceThis study provides Class IV evidence that rituximab is an effective treatment for some types of AE.

Background: Antibody-mediated and paraneoplastic autoimmune encephalitides (AE) present with a broad spectrum of clinical symptoms. They often lead to progressing inflammatory changes of the central nervous system with subacute onset and can cause persistent brain damage. Thus, to promptly start the appropriate and AEspecific therapy, recognition of symptoms, initiation of relevant antibody diagnostics and confirmation of the clinical diagnosis are crucial, in particular as the diseases are relatively rare. Aim: This standard operating procedure (SOP) should draw attention to the clinical presentation of AE, support the diagnostic approach to patients with suspected AE and guide through the necessary steps including therapeutic decisions, tumour screening and exclusion of differential diagnoses. Method: Based on existing diagnostic algorithms, treatment recommendations and personal experiences, this SOP gives an overview of clinical presentation, diagnostic procedures and therapy in AE. Additional information is provided within an accompanying text and a table describing the most important autoantibodies and their characteristics. Results: The initial steps of the AE flow chart are based on clinical symptoms and the patient's history. Assignment to paraneoplastic or antibody-mediated AE is sometimes clinically possible. Diagnostics should include MRI, EEG and CSF analysis with antibody panel diagnostic. Definite AE can be diagnosed if the underlying antibody is compatible with the clinical presentation. Classification of probable AE may be possible even with negative antineuronal autoantibodies if the clinical presentation and laboratory abnormalities are highly suggestive of AE. The confirmed AE diagnosis requires immediate initiation of immunotherapy. Conclusion: The SOP facilitates the recognition of patients with AE and presents the necessary diagnostic and therapeutic steps.

Autoimmune encephalitis (AE) is a rapidly progressive inflammatory neurological disease. Underlying autoantibodies can bind to neuronal surfaces and synaptic proteins resulting in psychiatric symptoms, focal neurological signs, autonomic dysfunction and cognitive decline. Early and effective treatment is mandatory to reduce clinical symptoms and to achieve remission. Therapeutic apheresis, involving both plasma exchange (PE) and immunoadsorption (IA), can rapidly remove pathogenic antibodies from the circulation, thus representing an important first-line treatment in AE patients. We here review the most relevant studies regarding therapeutic apheresis in AE, summarizing the outcome for patients and the expanding clinical spectrum of treatment-responsive clinical conditions. For example, patients with slowly progressing cognitive impairment suggesting a neurodegenerative dementia can have underlying autoantibodies and improve with therapeutic apheresis. Findings are encouraging and have led to the first ongoing clinical studies assessing the therapeutic effect of IA in patients with anti-neuronal autoantibodies and the clinical presentation of dementia. Therapeutic apheresis is an established and well tolerated option for first-line therapy in AE and, potentially, other antibody-mediated central nervous system diseases.

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Autoimmunenzephalitiden bilden eine heterogene Gruppe neurologischer und psychiatrischer Erkrankungen. Es werden Antikörper-vermittelte Enzephalitiden von den häufig paraneoplastisch auftretenden Antikörper-assoziierten Enzephalitiden unterschieden. Während die Antikörper im ersten Fall direkt krankheitsverursachend sind, dienen sie im zweiten Fall als diagnostischer Biomarker mit hoher Aussagekraft für einen zugrunde liegenden Tumor.

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