Autoimmune Encephalopathy Research Articles

Can Autoimmune Encephalitis Occur with Negative Markers? A Rare Case Report

In our case, we present a case of a 27-year-old male who presented with progressively worsening altered mental status and seizures. Over the course of his admission to the hospital and intensive care unit, laboratory testing failed to find an offending agent to his presentation. Testing did result in the diagnosis of encephalitis, but an underlying cause was not found. After careful exclusion of bacterial, viral, and other types of encephalopathy, autoimmune encephalopathy was diagnosed despite the absence of commonly used markers of autoimmune encephalopathy. The presentation and symptoms of our patient led to a wide range of differentials, and a high index of suspicion was needed throughout his admission in order to obtain the appropriate tests. Although appropriate testing might be ordered, due to the sensitivities and specificities of all laboratory tests, these objective tests do produce false negative results at times. It is in these times that one must weigh the physical exam, clinical judgment, and the process of elimination to diagnose an underlying pathology. Autoimmune Encephalitis diagnosis can be broken down into possible, probable, and definitive diagnoses based on antibody testing results. In this case, we present a patient with probable autoimmune encephalitis that failed to yield positive autoimmune markers after extensive testing of other possible causes of encephalitis.

The folate-centric concept of pathogenesis and GBINC personalized multidisciplinary approach to the clinical management of children with neuropsychiatric syndromes. Review

Solving the problem of children’s neuropsychiatric diseases is a priority task of modern medicine. The latest scientific achievements in the field of genetics, molecular biology and immunology, which demonstrate biochemical and immune‑dependent ways of formation of human neuropsychiatric disorders, shed light on the mechanisms of brain damage in children with ASD. These research give reason for optimism about overcoming this severe psychiatric pathology in the future thanks to the implementation of genetic, biochemical and immunodiagnostic approaches, as well as metabolic and immunotherapeutic interventions with neuroprotective effects. Currently, the folate‑centric concept of polygenic inheritance of predisposition to the development of neuropsychiatric syndromes in children with multisystem damage has been established. Biochemical and immune‑dependent (infectious, autoimmune, immunoinflammatory, and allergic) pathways of microbe‑induced autoimmune inflammatory encephalopathy with neuropsychiatric clinical manifestations are discussed in the context of the folate‑centric concept. Taking into account the new data, two personalized multidisciplinary approaches to the management of children with ASD and other neuropsychiatric syndromes are proposed. The first approach of J. J. Bradstreet et al. (2010) is based on the empirical analysis of a large group of laboratory biomarkers, the relevance of which has been demonstrated in clinical studies, and the targeted correction of abnormalities identified by biomarkers (so‑called biomarker‑guided interventions). In 2022, Frye R. developed a multidisciplinary personalized approach called BaS‑BiSTOR (collect Baseline data, search for Symptoms, measure Biomarkers, Select Treatment, Observe for Response), which systematizes and stratifies diagnostic and treatment interventions based on the assessment of biomarkers. In order to improve existing recommendations regarding specific subtypes of neuropsychiatric syndromes in children, this article proposes an improved personalized multidisciplinary approach to the clinical management of patients with autistic spectrum disorders and neuropsychiatric manifestations associated with genetic deficiency of the folate cycle, called GBINS (Genetic‑Biochemical‑Immunological‑Neurological‑Symptomatic evaluation). There are reasons to believe that the successful testing in clinical practice of evidence‑based personalized multidisciplinary diagnostic and treatment strategies will allow making a breakthrough in the clinical management of children with severe mental disorders in the near future, which will provide not only the possibility of recovery from a prognostically unfavorable and currently incurable neuropsychiatric disorder, but also and will contribute to stopping the large‑scale threatening epidemic of neuropsychiatric syndromes in the modern child population.

Anti-IgLON5 Disease with Isolated Hemichorea: A Case Report and Review of the Literature.

Anti-IgLON5 disease is an autoimmune encephalopathy with sleep disturbances as a hallmark in the majority of reported cases. Additional clinical symptoms are heterogenous and include movement disorders, bulbar dysfunction, autonomic disorders, and neurocognitive impairment. Here, we report the case of an 87-year-old woman presenting with isolated progressive hemichorea. An extensive diagnostic work-up revealed antibodies against IgLON5 in the serum. Neither history nor polysomnography (PSG) unveiled signs and features of sleep dysfunction typically reported in anti-IgLON5 disease. In an extensive literature review we identified twelve other studies reporting about patients with confirmed anti-IgLON5 disease and chorea as extrapyramidal movement disorder in their clinical phenotype. Subsequently, clinical characteristics of these patients were carefully evaluated. Our results support the diversity of clinical phenotypes in anti-IgLON5 disease, adding isolated hemichorea to the spectrum of presenting symptoms. As sleep-related disorders are often not the leading reason for consultation and only revealed by PSG examination, we suggest that screening for antibodies against IgLON5 should be considered in patients presenting with unexplained movement disorders, including isolated hemichorea.

Using RBANS to characterize cognitive treatment response in autoimmune encephalopathy

IntroductionAutoimmune encephalopathy (AE) is an increasingly recognized cause of cognitive impairment. This study investigates the use of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to characterize treatment response of AE cognitive symptoms in ambulatory clinical practice. MethodsRetrospective evaluation of 29 consecutive patients treated for AE at the University of Cincinnati Memory Disorders Clinic. All patients underwent RBANS before treatment and 4–5 weeks after treatment. The Reliable Change index and clinically meaningful improvement method were used to determine if changes in RBANS performance were clinically significant. ResultsClinically meaningful improvement was seen in 20 out of 29 (69 %) subjects on one or more RBANS domains and in 13 patients (45 %) for the global RBANS index. Measured improvement on one or more cognitive domain scores showed excellent agreement with clinical impression of change. ConclusionThe RBANS provided an efficient and effective means to document cognitive outcomes and treatment response in AE. The brief administration time, availability of normative data, and alternate versions make the RBANS useful in clinical practice and in clinical research related to AE.

Association of Microglial Activation With Spontaneous ARIA-E and CSF Levels of Anti-Aβ Autoantibodies.

Background and ObjectivesAmyloid-related imaging abnormalities suggestive of vasogenic edema or sulcal effusion (ARIA-E) are the most common adverse events complicating Alzheimer disease (AD) immunotherapy with anti–β-amyloid (Aβ) monoclonal antibodies. ARIA-E can also occur spontaneously in cerebral amyloid angiopathy–related inflammation (CAA-ri), a rare autoimmune encephalopathy associated with increased CSF levels of anti-Aβ autoantibodies. Although the pathophysiologic mechanisms of ARIA-E remain to be fully elucidated, experimental evidence from ex vivo studies suggests that gantenerumab and aducanumab enable microglial activation. However, the in vivo evidence for a direct association between neuroinflammation and ARIA-E in patients with high CSF anti-Aβ (auto)antibody levels has never been demonstrated.MethodsThe spatial distribution and temporal variations of microglial activation associated with levels of anti-Aβ autoantibodies at (sub)acute presentation of ARIA-E and after corticosteroid therapy were evaluated in a longitudinal case series of patients with CAA-ri, the spontaneous variant of the iatrogenic ARIA-E reported in Aβ-lowering immunotherapy with monoclonal antibodies. Multimodal and multiparametric MRI was used for CAA and ARIA-E severity quantification, according to validated scoring system; CSF testing for anti-Aβ autoantibodies and AD biomarkers; 11C-PK11195 PET for activated microglia.ResultsAt (sub)acute presentation, we found focal peaks of microglial activation having a greater spatial colocalization with ARIA-E compared with chronic age-related white matter change imaging abnormalities. The severity of ARIA-E and the magnitude of the associated microglial activation were greater in patients having AD and severe CAA concomitant disease compared with patients having CAA only. CSF anti-Aβ autoantibodies at presentation were high in all patients and markedly decreased at posttreatment follow-up, in parallel with clinical resolution of acute symptoms, reduced ARIA-E severity, and reduced microglial activation.DiscussionOur findings extend the current notion of ARIA-E by providing the first in vivo 11C-PK11195 PET evidence for an association between microglial activation and the magnitude and severity of ARIA-E in patients with increased CSF concentration of anti-Aβ autoantibodies and comorbid AD and CAA disease. Our results highlight CSF testing for anti-Aβ autoantibodies as a promising diagnostic, prognostic, and therapy response biomarker to help guide future treatment and management decisions in real clinical practice and clinical trials.

Abstract #1176275: A Rare Case of Hashimoto Encephalopathy

Hashimoto’s encephalopathy (HE) is a rare disorder characterized by an autoimmune encephalopathy associated with elevated Thyroid Peroxidase (TPO) antibodies. Clinical features include neurocognitive dysfunction, psychiatric manifestations (paranoia, hallucinations, depression), sleep disturbance, seizures, and transient neurological deficits. The heterogeneity of it’s symptoms, and the broad differential of neuropsychiatric conditions make it a challenging diagnosis. Diagnosis is made in patients with an appropriate clinical picture, elevated TPO antibodies and response to treatment.

Effect of antioxidants in temporal lobe epilepsy

Epilepsy is a common neurological disorder that affects around 70 million people in the world, which represents approximately 1%of the world population. Seizures are transitory episodes produced by excessive neuronal discharges. They are characterized bytransient behavioral changes that are caused by abnormal and excessive neuronal synchronization in the brain. These episodes canbe triggered by genetic or acquired factors that alter normal brain function such as autoimmune diseases, genetic mutations,encephalopathies, head trauma, cerebrovascular accidents, febrile seizures or statusepilepticus. Temporal lobe epilepsy is a seriousneurological disorder, which represents 60% to 70% of drug-resistant epilepsy, and is an important form of epilepsy acquired byany of the factors mentioned. Seizures can generate recurrent cycles of excitotoxicity and oxidative stress that cause neuronaldamage and cell death. Oxidative stress is an imbalance between the endogenous antioxidant system and the overproduction ofreactive oxygen species (ROS), consequently, oxidation of proteins, lipids and nucleic acids occurs in the brain, resulting inapoptosis, proteopathies, mitochondrial dysfunction, glial cell activation and neuroinflammation. ROS are responsible for thegeneration of oxidative stress and could be involved in neuronal damage that contributes to the establishment of epileptogenesis andspontaneous seizures in patients and experimental models. The administration of agents with antioxidant and anti-inflammatoryproperties could represent a therapeutic alternative aimed at reducing oxidative stress during epileptogenesis or seizures to reducethe severity of the pathological processes involved, and thus attenuate the neurobiological consequences that occur in temporal lobeepilepsy.

Inpatient Management of Encephalopathy.

Unexplained encephalopathy is a common occurrence in tertiary care centers and neurologic disorders should be considered after ruling out the infectious, toxic and metabolic etiologies. Neuroimaging combined with a thorough history and examination is often helpful in ruling out stroke and fulminant demyelinating encephalopathies. Autoimmune encephalopathy should be suspected in any patient with unexplained acute or subacute onset encephalopathy or rapidly progressing dementia. Anti-N-methyl-D-aspartate receptor (NMDA-R) encephalitis is the most studied form and Hashimoto encephalitis is the most controversial form of autoimmune encephalopathies. Obtaining a combined serum and Cerebrospinal fluid (CSF) autoantibody testing will increase the diagnostic yield of autoimmune and paraneoplastic encephalitis. When diagnosing NMDA receptor antibodies CSF is always more sensitive than serum and in contrast, voltage-gated potassium channel (VGKC) complex antibodies are more readily detectable in serum than in CSF. Neural-specific antibody tests frequently result after several weeks and treatment should be administered without a significant delay to prevent brain damage. Autoimmune encephalitis is often treatment responsive when immunotherapy (glucocorticoids, intravenous immune globulin, plasma exchange) is used in various combinations. The absence of inflammatory markers and autoantibodies in the serum or CSF may not rule out the possibility of paraneoplastic encephalopathies.

Putative autoimmune mechanisms for Acute Disseminated Encephalomyelitis (ADEM) and Guillain-Barré Syndrome (GBS) associated with SARS-CoV-2 infection

The novel coronavirus severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, responsible for the ongoing COVID-19 pandemic, is associated with a broad manifestation of neurological disease, including Acute Disseminated Encephalomyelitis (ADEM) and Guillain-Barré Syndrome (GBS), amongst other forms of autoimmune encephalitis, stroke, encephalopathy, delirium, and cranial neuropathies. These phenomena are not limited to human coronaviruses but are also seen in a minority of patients in response to other viral infection. There is good evidence that an autoimmune mechanism hypothesis is likely. The final pathology is probably the culmination of mixed mechanisms such as vascular and immune dysregulation as well as direct viral invasion of neurons – though there is little if any evidence of viral invasion in the literature to date. The aim of this review is to elucidate the emerging evidence about this subset of COVID-19-associated neurological disease. This unique opportunity to study the interactions between virus and host immune and central nervous system (CNS) to gain novel insights applicable to other probable autoimmune neurological disease. I have conducted a literature search as well as drawn on my own observations from the COVID-19 and encephalitis multidisciplinary meetings at Queen Square National Hospital for Neurology and Neurosurgery, London, UK.

Retrospective Evaluation of the Antibody Prevalence in Epilepsy and Encephalopathy (APE2) Score.

Autoimmune encephalitis (AE) is a rare collection of disorders that present with a diverse and often nebulous set of clinical symptoms. Indiscriminate use of multi-antibody panels decreases their overall utility and predictive value. Application of a standardized scoring system may help reduce the number of specimens that generate misleading or uninformative results. The results of autoimmune encephalopathy, epilepsy, or dementia autoantibody panels performed on serum (n = 251) or cerebrospinal fluid (CSF) (n = 235) specimens from October 9th, 2016 to October 11th, 2019 were collected. Retrospective chart review was performed to calculate the Antibody Prevalence in Epilepsy and Encephalopathy (APE2) score for patients with an antibody above the assay-specific reference interval and to classify results as true or false positive. Of the 486 specimens, 60 (12.3%) generated positive results for any AE antibody (6 CSF and 54 serum). After removing 2 duplicate specimens collected from a single patient, 10 of the remaining 58 were determined to be true positives and 8 contained neural-specific antibodies. Application of the APE2 score revealed that 89% of all true positives and 86% of specimens with neural-specific antibodies had a score ≥4. In contrast, 76% of false positives, 74% of clinically nonspecific antibodies, and 85% of the negative specimens had an APE2 score <4. The APE2 score can improve the diagnostic utility of autoimmune encephalopathy evaluation panels.

Anti-NMDAR Encephalitis: Multidisciplinary Development of a Clinical Practice Guideline.

Anti-NMDAR Encephalitis: Multidisciplinary Development of a Clinical Practice Guideline.

Autoimmune Encephalitis After SARS-CoV-2 Infection: Case Frequency, Findings, and Outcomes.

Background and ObjectivesAutoimmune encephalitis (AE) cases after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been reported, but the frequency is unknown. We aimed to determine the frequency and diagnostic features of coronavirus disease 2019 (COVID-19)–related AE.MethodsResidual sera from 556 consecutive Mayo Clinic Rochester patients (laboratory cohort) who underwent autoimmune encephalopathy neural immunoglobulin G (IgG) evaluation were tested for total antibodies against the SARS-CoV-2 spike glycoprotein using a Food and Drug Administration–authorized chemiluminescence assay (October 2019–December 2020). Clinical records from patients with a positive SARS-CoV-2 antibody result and available research consent were reviewed. This laboratory cohort was cross-referenced with the Department of Neurology's COVID-19–related consultative experience (encephalopathy cohort, n = 31).ResultsEighteen of the laboratory cohort (3%) were SARS-CoV-2 antibody positive (April–December 2020). Diagnoses were as follows: AE, 2; postacute sequelae of SARS CoV-2 infection (PASC), 3; toxic-metabolic encephalopathy during COVID-19 pneumonia, 2; diverse non–COVID-19 relatable neurologic diagnoses, 9; unavailable, 2. Five of the encephalopathy cohort had AE (16%, including the 2 laboratory cohort cases that overlapped), representing 0.05% of 10,384 patients diagnosed and cared for with any COVID-19 illness at Mayo Clinic Rochester in 2020. The 5 patients met definite (n = 1), probable (n = 1), or possible (n = 3) AE diagnostic criteria; median symptom onset age was 61 years (range, 46–63); 3 were women. All 5 were neural IgG negative and 4 tested were SARS-CoV-2 PCR/IgG index negative in CSF. Phenotypes (and accompanying MRI and EEG findings) were diverse (delirium [n = 5], seizures [n = 2], rhombencephalitis [n = 1], aphasia [n = 1], and ataxia [n = 1]). No acute disseminated encephalomyelitis cases were encountered. The 3 patients with possible AE had spontaneously resolving syndromes. One with definite limbic encephalitis was immune therapy responsive but had residual mood and memory problems. One patient with probable autoimmune rhombencephalitis died despite immune therapy. The remaining 26 encephalopathy cohort patients had toxic-metabolic diagnoses.DiscussionWe encountered occasional cases of AE in our 2020 COVID-19 experience. Consistent with sporadic reports and small case series during the COVID-19 pandemic, and prior experience of postinfectious AE, our cases had diverse clinical presentations and were neural IgG and CSF viral particle negative. Application of diagnostic criteria assists in differentiation of AE from toxic-metabolic causes arising in the setting of systemic infection.

Evolving Causes of Rapidly Progressive Dementia: A 5-Year Comparative Study.

Rapidly progressive dementia (RPD) is a clinical syndrome developing in <1 to 2 years. Recent progress in RPD evaluation is significant, so RPD's prevalence may change over time. The aim of our new case series was to estimate the relative frequency of RPDs' causative entities, considering the recent advances in RPDs' diagnosis, and compare the results with those of our previous report. We retrospectively reviewed the medical records of 47 patients who were referred to Attikon University Hospital during a 5-year period for a suspected RPD. Neurodegenerative diseases were the most frequent causes (38%), followed by prion disease (19%) and autoimmune encephalopathy (AE, 17%). AE cases were by far more common than in our previous report, while other than AE secondary causes were significantly decreased. Mean time to dementia was 9 months in neurodegenerative diseases and 5 months in non-neurodegenerative. Main clinical findings across all patients were memory impairment (66%) and behavioral-emotional disturbances (48%). Neurodegenerative diseases are common causes of RPD and have a slower evolution than non-neurodegenerative. Diagnostic novelties enabled the recognition of AE, whereas more common secondary causes are probably now diagnosed in primary settings since the recognition of RPD as distinct clinical entity is continually increasing.

WS1.12. EEG Coma Patterns and Prognosis

Identify the EEG coma patterns is just one of the steps in clinical management of those with coma. This lecture will discuss on the importance of EEG in diagnosis, prognosis, management and monitoring of disease progress, but also the limitations of EEG. There are various EEG patterns in coma including both focal and generalised EEG patterns. It is essential to correlate the EEG with clinical findings, in order to determine the aetiology, although in certain cases the EEG patterns will guide the diagnosis e.g. triphasic waves in metabolic encephalopathy and periodic discharges in someone suspected to have Creutzfeldt- Jakob disease. A clinical-based approach to differentiate epileptiform and non-epileptiform patterns will be presented based on clinical history, EEG patterns, neuroimaging and response to antiepileptic drugs. An attempt to determine the severity and prognosis based on EEG patterns will be made, in correlation with the underlying aetiology and other clinical findings. Lastly, EEG patterns in coma secondary to autoimmune encephalopathy will be discussed.

In Utero Injections of Nanoparticle Encapsulated Myelin Oligodendrocyte Glycoprotein Peptides Prevent Experimental Autoimmune Encephalopathy Via Central Tolerance

IntroductionIn utero hematopoietic cell transplantation (IUHCT) of allogenic bone marrow mononuclear cells (MNC) results in successful engraftment across immune barriers. This is secondary to immune tolerance that is acquired due to the presence of donor cells in the thymus prior to E17. We have demonstrated that immune tolerance to specific proteins is possible by injecting nanoparticle encapsulated peptides which are taken up by dendritic cells and presented in the thymus.The aim of this study is to show that in utero injections of nanoparticle encapsulated antigen can produce tolerance to that antigen. We demonstrate this by preventing the autoimmune disease Experimental Autoimmune Encephalopathy (EAE, the mouse equivalent of multiple sclerosis) by injecting NPs loaded with the peptide Myelin Oligodendrocyte Glycoprotein (35-55) (MOG35-55.)MethodsIn utero injections of nanoparticles were performed in C57BL/6 mice at E14 intravenously through the vitelline vein. Post-natal boosters were injected subcutaneously at 2, 4, 6, and 8 weeks of age. Disease inducing injections of MOG with Complete Freud's Adjuvant (CFA) was given at 8 1/7 weeks. Intraperitoneal pertussis toxin (PT) was given on the same day as the MOG/CFA and again 48 hours later. Positive controls got MOG/CFA and PT injections. Negative controls got CFA without MOG as well as the PT injections.Mice were monitored for paralysis using the 5-point EAE scoring system for 4 weeks after the MOG/CFA injection. Spines and brains were harvested 2 weeks after the disease inducing MOG/CFA injection. Spines and brains were filtered and then MNCs were isolated using a Percoll gradient. MNCs were stained for CD45, CD19, CD11b, CD3, CD4, CD8, and I-A(b) MOG35-55 tetramer. Cells were then analyzed on the FACSAria™.Results are expressed as mean±SEM, and statistical analysis was performed using 1-way ANOVA with Bonferroni post-hoc tests. Experimental protocols were approved by the Institutional Animal Care and Use Committee at The Children's Hospital of Philadelphia.ResultsMice that received MOG nanoparticles prenatally along with boosters (Group A) developed disease with less frequency than mice that received MOG nanoparticles postnatally along with boosters (Group B) or positive controls (Group D) (52.0% vs 87.5% vs 90.0% p<0.005) supporting the theory that antigen needs to be expressed prior to E17 in the thymus to develop tolerance. Mice that were injected prenatally with MOG nanoparticles and did not receive booster injections (Group C) also did as poorly as positive controls (85.72% vs 90.0%) suggesting that continued antigen expression is necessary to maintain tolerance. Group A also had significantly lower EAE scores on days 15 to 28 compared to Group B, Group C, and the positive control group (p<0.005).Spinal cord and brain analysis of the Group A mice showed significantly fewer CD45 cells compared to the positive control but not the negative control (133.2±52.0 vs 6062.5±1166.9 vs 79.8±15.0 p<0.0001.) The same is seen with CD3 cells (45.6±17.0 vs 4727.3±1283.0 vs 21.3±2.8 p<0.0001) and CD4 cells (12.6±5.7 vs 3339.6912.1 vs 11.8±0.8 p<0.0001.) Finally, the same is seen with CD4+ Tetramer+ cells (0.7±0.3 vs 379.1±156.6 vs 2.9±1.0 p<0.0001) showing that there is central tolerance to the MOG peptide.ConclusionBy decreasing the frequency and average severity of EAE and demonstrating the lack of CD4+ Tetramer+ cells in the spine, we have shown that autoimmune disease can be prevented by central tolerance to the target antigen. We have demonstrated that this central tolerance is possible with prenatal injections of nanoparticle encapsulated peptide. We have also shown that continued antigen presentation is necessary to maintain central tolerance. We hope that nanoparticle encapsulated peptides could provide a possible pharmacological benefit for numerous autoimmune diseases in the future. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Autoimmune Antibody in Encephalopathic Patients: A Pilot Study

Objective: To investigate the specificity of the antibodies related to autoimmune encephalitis and to identify possible associated factors with the false-positive result. Materials and Methods: The present study was a prospective observational study, conducted at the Ramathibodi Hospital between June and December 2019. All patients, who had acute to subacute encephalopathy from any causes, were recruited to the study. Their serum or cerebrospinal fluid (CSF) were taken to analyze for autoimmune encephalitis assays and anti-thyroid antibodies. The authors did not interfere with the primary physicians on any management of the patients. Clinical and laboratory data were systematically reviewed and collected from medical records. The clinical outcome was evaluated one month after the onset. Results: Fifty-one patients were recruited. Only one patient had autoimmune encephalitis related to anti-CV2/CRMP5 antibody. Seventeen out of the remaining fifty patients had positive tests for anti-thyroid antibodies of which five had Hashimoto’s thyroiditis and one of them did not have the document of thyroid status. Eleven remaining patients appeared to have false-positive test since their medical conditions were all clearly explained by other causes. Comparison of clinical and laboratory data between patients with false-positive test and patients with true negative test did not show any significant difference except the duration of the symptoms, which was significantly shorter in the false-positive group. Conclusion: False-positive anti-thyroid antibodies appear to be common in patients with acute encephalopathy. The occurrence of serum/CSF antibody in acute encephalopathy may be a true association, but it may not be the cause of encephalopathy. Therefore, the diagnosis of autoimmune encephalopathy based on anti-thyroid antibodies should be carefully made and excluded from all other possible causes. Keywords: Autoimmune encephalitis; Metabolic encephalopathy; Hashimoto’s encephalopathy; False positive

An AGS associated mutation causes cellular RNA editing deficiency in mouse brain which lead to IFN pathway activation, mimicking the interferonopathy of patient brains

Abstract Objective: To determine whether and how a gene mutation found in Aicardi-Goutières syndrome (AGS), a severe autoimmune encephalopathy, is sufficient to activate the interferon signaling pathway in the brain. Background: Genetic mutations in six coding genes were found associated with AGS patients, however, none of them was demonstrated able to cause IFN pathway activation in the brain tissue, the most critical pathogenetic change of AGS. How an AGS-associated mutation activates the IFN pathway in the brain that leads to brain injury remains to be revealed. Methods: A knock-In mouse model was established through CRISPR/Cas9 gene editing approach, in which a single G&amp;gt;T nucleotide replacement was introduced into mouse genome, that encodes the change for p.K948N in mouse ADAR1 at its catalytic domain, equivalent to the p.K999N mutation found in AGS patients. We analyzed the enzyme activity of ADAR1 on the neuron specific mRNA substrates in the KI mice through RNA sequencing, the activities of IFN signaling pathway by measuring expressions of IFN stimulated inflammatory cytokines. Brain injury was observed by pathology studies. Results: The genetic mutation was confirmed. RNA transcription and protein translation were tested not affected by the mutation. The cellular RNA process in neurons was altered due to decreased enzyme activity of mutant ADAR1 on certain mRNA substrates. ISG expression were significantly increased at RNA and protein levels. Cell death in the brain was observed in the KI mice. Conclusion: A mouse model was successfully established recapitulating the genetic and innate immunologic features of AGS. An ADAR1 gene mutation is sufficient to cause IFN pathway activation in the brain through altering cellular RNA process.

Hashimoto’s Encephalopathy: A Remediable Cause of Unexplained Encephalopathy

Hashimoto’s encephalopathy is non-vasculitic autoimmune steroid responsive encephalopathy. It is an uncommon syndrome characterized by altered level of consciousness, confusion, seizures and myoclonus. Exact pathogenesis is yet to be determined though humoral hyper-immune response is favored mechanism rather than dysthyroidism. We present a case of Hashimoto’s encephalopathy in an eighty years old lady who presented with unexplained drowsiness. Extensive workup for the cause of drowsiness was carried outto find structural, metabolic, autoimmune or para-neoplastic etiology only to reveal high titers of anti-TPO antibodies. Patient responded remarkably to high dose steroids.

Leucine-rich glioma-inactivated protein 1 antibody-mediated autoimmune encephalitis in a 4-year-old girl: a case report

BackgroundLeucine-rich glioma-inactivated protein 1 (LGI1) antibody-mediated encephalitis is a rare subtype of autoimmune encephalopathy, which is associated with autoimmunity against the neuronal plasma membrane proteins. The characteristic symptoms of this disease are memory dysfunction, seizures, faciobrachial dystonic seizures, cognitive deficits, neuropsychiatric disturbances, and intractable hyponatremia. The diagnosis of this disease mainly depends on the presence of anti-LGI1 antibody in serum or cerebrospinal fluid of patients. LGI1 antibody encephalitis has been reported mostly in adults, with rare occurrences in children.Case presentationIn this report, we described a 4-year-old girl with typical seizures. Seizure types included focal seizures and generalized tonic-clonic seizures. The electroencephalogram findings showed focal discharges. Brain magnetic resonance imaging (MRI) showed normal. The cerebrospinal fluid (CSF) levels of cells, glucose, and chloride were within the normal range, and the culture did not reveal growth of any pathogen. Test of serum LGI1-Ab was positive, while the tests for autoimmune encephalitis antibody series in CSF were negative. The seizures of the patient were completely controlled after the therapy of immunoglobulin, methylprednisolone and antiepileptic drugs (AEDs), and the mental state almost returned to normal.ConclusionTo our knowledge, the patient described here may be the youngest case of LGI1 antibody encephalitis reported to date. Children with the LGI1 antibody-associated encephalitis may present only with single symptoms such as epileptic seizures and have good response to the therapy of immunoglobulin, methylprednisolone and antiepileptic drugs. Our case report will provide hints for pediatricians in the diagnosis and treatment of LGI1-antibody encephalitis.

Neurological Disorders Associated With COVID-19 Hospital Admissions: Experience of a Single Tertiary Healthcare Center.

Background: Early reports have detailed a range of neurological symptoms in patients with the SARS-CoV-2 infection. However, there is a lack of detailed description and incidence of the neurological disorders amongst hospitalized COVID-19 patients. We describe a range of neurological disorders (other than non-specific neurological symptoms), including their clinical, radiological, and laboratory findings, encountered in our cohort of COVID-19 patients admitted to a large tertiary institution.Methods: We reviewed our prospectively collated database of all adult Neurology referrals, Neurology and Stroke admissions and Neurological multi-disciplinary team meetings for all hospitalized patients with suspected or proven COVID-19 from 17 March 2020 to 31 August 2020.Results: Twenty-nine of 1,243 COVID-19 inpatients (2.3%) presented with COVID-19-related neurological disorders. The mean age was 68.9 ± 13.5(SD) years, age range of 34–97 years, and there were 16 males. Twenty two patients had confirmed, five were probable and two had suspected COVID-19 infection according to the WHO case classification. Eight patients (27%) required critical care admission. Neurological symptoms at presentation included acute confusion and delirium, seizures, and new focal neurological deficits. Based on the pre-defined neurological phenotype, COVID-19 patients were grouped into four main categories. Sixteen patients had cerebrovascular events (13 with acute ischemic stroke and three had hemorrhagic features), seven patients were found to have inflammatory, non-inflammatory and autoimmune encephalopathy (including two with known Multiple Sclerosis), whilst disorders of movement and peripheral nervous system were diagnosed in three patients each.Conclusion: Although the exact prevalence and etiology remain unclear, new onset of neurological disorders, in addition to anosmia, is non-sporadic during the acute COVID-19-infection. Longitudinal follow-up of these patients is required to determine the clinical and functional outcome, treatment response and long-term effects of the SARS-CoV-2 infection.