Peripheral monocytes and soluble biomarkers in autoimmune encephalitis.

BACKGROUND AND OBJECTIVES: Autoimmune encephalitis (AE) is an inflammatory disease of the central nervous system which can result in long-term seizures and cognitive dysfunction despite treatment with immunotherapy. The role of the innate immune system in AE is not well established. To investigate the contribution of innate immunity to AE and its long-term outcomes we evaluated peripheral monocytes and serum cytokines in the periphery of patients with AE. METHODS AND RESULTS: We recruited 40 patients with previously diagnosed AE and 28 healthy volunteers to our cross-sectional observation study and evaluated their peripheral blood monocytes via flow cytometry and serum cytokines (CCL-2, CCL-17, G-CSF, GM-CSF, IFNγ, IL-1α, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, TNFα) via ELISA.Compared with controls the AE cohort had expansion of the 'pro-inflammatory' CD14+CD16+ monocyte sub-population (7.13% vs 5.46%, p < 0.01) with higher levels of serum IL-6 (2.34 pg/mL vs 0.54 pg/mL, p < 0.001). These changes were most significant in anti-LGI-1 antibody mediated AE, an AE subtype with poor long-term cognitive outcomes. CONCLUSION: Expansion of the peripheral CD14+CD16+ monocyte population and increased serum IL-6 in AE is reflective of changes seen in other systemic inflammatory and neurodegenerative conditions. These changes may indicate a persistent pro-inflammatory state in AE and may contribute to poor long-term outcomes.

Neuroimaging characteristics may aid in diagnosis, subtyping, and prognosis in autoimmune encephalitis.

OBJECTIVE: To examine the utility of neuroimaging characteristics as biomarkers of prognosis in seropositive autoimmune encephalitis (AE). METHODS: In this multi-center study, we retrospectively analyzed 66 cases of seropositive AE. The MRI and PET imaging was assessed by independent visual inspection. Whole brain and regional volumes were imputed by IcoMetrix, an automated volumetric assessment package. The modified Rankin Scale (mRS) was utilized to assess the patients' follow-up disability. Other outcomes were mortality, first line treatment failure, medial temporal lobe (MTL) atrophy, and clinical relapse. Univariate and multivariable regression analysis was performed. RESULTS: Abnormalities on MRI were detected in 35.1% of patients, while PET was abnormal in 46.4%. Initial median whole brain and hippocampal volumes were below the 5th and 20th percentile respectively compared to an age-matched healthy database. After a median follow-up of 715 days, 85.2% had good functional outcome (mRS ≤ 2). Nine patients developed MTL atrophy during follow-up. On multivariable analysis, inflammatory MTL changes were associated with development of MTL atrophy (HR 19.6, p = 0.007) and initial hippocampal volume had an inverse relationship with mortality (HR 0.04, p = 0.011). Patients who developed MTL atrophy had a reduced chance of good final mRS (HR 0.16, p = 0.015). CONCLUSIONS: Neuroimaging on initial hospital admission may be provide important diagnostic and prognostic information. This study demonstrates that structural and inflammatory changes of the MTL may have importance in clinical and radiological prognosis in seropositive AE.

Prevalence, risk factors, and prognosis of drug-resistant epilepsy in autoimmune encephalitis.

OBJECTIVE: To evaluate the prevalence and biomarkers of drug-resistant epilepsy (DRE) in patients with autoimmune encephalitis (AIE). METHODS: Sixty-nine patients with AIE were recruited retrospectively and electroencephalographies (EEGs) were reviewed using a standard reporting proforma. Associations between EEG biomarkers and DRE development at 12 months were examined using logistic regression modeling and were utilized to create a DRE risk score. RESULTS: Sixteen percent of patients with AIE developed DRE at 12-month follow-up. The presence of status epilepticus (SE) (OR 11.50, 95% CI [2.81, 51.86], p-value <0.001), temporal lobe focality (OR 9.90, 95% CI [2.60, 50.71], p-value 0.001) and periodic discharges (OR 19.12, 95% CI [3.79, 191.10], p-value 0.001) on the admission EEG were associated with the development of DRE at 12 months. These variables were utilized to create a clinically applicable risk score for the prediction of DRE development. CONCLUSIONS: Drug-resistant epilepsy is an infrequent complication of AIE. Electroencephalography changes during the acute illness can predict the risk of DRE at 12 months post-acute AIE. SIGNIFICANCE: The identified EEG biomarkers provide the basis to generate a clinically applicable prediction tool which could be used to inform treatment, prognosis, and select patients for acute treatment trials.

Psychometric deficits in autoimmune encephalitis: A retrospective study from the Australian Autoimmune Encephalitis Consortium.

BACKGROUND AND PURPOSE: Despite the rapid increase in research examining outcomes in autoimmune encephalitis (AE) patients, there are few cohort studies examining cognitive outcomes in this population. The current study aimed to characterise psychometric outcomes in this population, and explore variables that may predict psychometric outcomes. METHODS: This retrospective observational study collected psychometric data from 59 patients across six secondary and tertiary referral centres in metropolitan hospitals in Victoria, Australia between January 2008 and July 2019. Frequency and pattern analysis were employed to define and characterize psychometric outcomes. Univariable logistic regression was performed to examine predictors of intact and pathological psychometric outcomes. RESULTS: Deficits in psychometric markers of executive dysfunction were the most common finding in this cohort, followed by deficits on tasks sensitive to memory. A total of 54.2% of patients were classified as having psychometric impairments across at least two cognitive domains. Twenty-nine patterns were observed, suggesting outcomes in AE are complex. None of the demographic data, clinical features or auxiliary examination variables were predictors of psychometric outcome. CONCLUSIONS: Cognitive outcomes in AE are complex. Further detailed and standardized cognitive testing, in combination with magnetic resonance imaging volumetrics and serum/cerebrospinal fluid biomarkers, is required to provide rigorous assessments of disease outcomes.

Electroclinical biomarkers of autoimmune encephalitis.

OBJECTIVE: To evaluate the utility of electroencephalography (EEG) changes as diagnostic and prognostic biomarkers in acute autoimmune encephalitis (AIE). METHODS: One hundred and thirty-one patients with AIE were recruited retrospectively across 7 hospitals. Clinical data were collected during admission and at 12 months. EEGs were reviewed using a standard reporting proforma. Associations between EEG biomarkers, AIE subtypes, and clinical outcomes were assessed using logistic regression modeling. RESULTS: Presence of superimposed fast activity (OR 34.33; 95% CI 3.90, 4527.27; p < 0.001), fluctuating EEG abnormality (OR 6.60; 95% CI 1.60, 37.59; p = 0.008), and hemispheric focality (OR 28.48; 95% CI 3.14, 3773.14; p < 0.001) were significantly more common in N-methyl-d-aspartate receptor (NMDAR) antibody-associated patients with AIE compared to other AIE subtypes. Abnormal background rhythm was associated with a poor mRS (modified Rankin score) at discharge (OR 0.29; 95% CI 0.10, 0.75; p = 0.01) and improvement in mRS at 12 months compared with admission mRS (3.72; 95% CI 1.14, 15.23; p = 0.04). 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.

Prognostic value of acute cerebrospinal fluid abnormalities in antibody-positive autoimmune encephalitis.

OBJECTIVE: To examine the prognostic value of CSF abnormalities in seropositive autoimmune encephalitis (AE). METHODS: We retrospectively studied 57 cases of seropositive AE. Primary outcomes were mortality and modified Rankin Scale, while secondary outcomes were first line treatment failure, ICU admission and relapse. Regression analysis was performed. RESULTS: CSF white cell count (WCC) was higher in the NMDAR group, while elevated protein was more common amongst other subtypes. We found an association between WCC >5 cells/mm3 and treatment failure (OR 16.0, p = 0.006)), and between WCC >20 cells/mm3 and ICU admission (OR 19.3, p = 0.026). CONCLUSIONS: Different subsets of AE have characteristic CSF abnormalities, which may aid recognition during early evaluation. CSF WCC had prognostic significance in our study.

Generalized and orofacial choreoathetosis: a case report of anti-CV2 paraneoplastic syndrome after cardiac arrest.

CV2/CRMP5 is the most common antibody accompaniment of paraneoplastic choreoathetosis. We present a case of paraneoplastic choreothetosis with associated cerebellar dysfunction, peripheral neuropathy, and likely dysautonomia. Our patient developed a movement disorder after a cardiopulmonary arrest, which unfortunately masked the true etiology of his symptoms. He was later found to have extensive stage small cell lung cancer, with further evaluation revealing seropositivity for anti-CV2 antibodies. Choreoathetosis is a known sequelae of hypoxic-ischemic brain injury, but clinicians should continue to keep an open mind. The utility of immunotherapy is unclear in these circumstances and many physicians adopt a symptom-based approach.

Peripheral Immune Cell Ratios and Clinical Outcomes in Seropositive Autoimmune Encephalitis: A Study by the Australian Autoimmune Encephalitis Consortium.

Objective: To examine the utility of the peripheral blood neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR) as biomarkers of prognosis in seropositive autoimmune encephalitis (AE). Methods: In this multicenter study, we retrospectively analyzed 57 cases of seropositive AE with hospital admissions between January 2008 and June 2019. The initial full blood examination was used to determine each patients' NLR and MLR. The modified Rankin Scale (mRS) was utilized to assess the patients' follow-up disability at 12 months and then at final follow-up. Primary outcomes were mortality and mRS, while secondary outcomes were failure of first line treatment, ICU admission, and clinical relapse. Univariate and multivariable regression analysis was performed. Results: During initial hospital admission 44.7% of patients had unsuccessful first line treatment. After a median follow-up of 700 days, 82.7% had good functional outcome (mRS ≤2) while five patients had died. On multivariable analysis, high NLR was associated with higher odds of first line treatment failure (OR 1.32, 95% CI 1.03-1.69, p = 0.029). Increased MLR was not associated with any short or long-term outcome. Conclusions: NLR on initial hospital admission blood tests may be provide important prognostic information for cases of seropositive AE. This study demonstrates the potential use of NLR as a prognostic marker in the clinical evaluation of patients with seropositive AE.

Prognosticating autoimmune encephalitis: A systematic review.

OBJECTIVE: To perform a systematic review of the current scientific literature in order to identify variables associated with patient prognosis in autoimmune encephalitis. METHODS: We performed a systematic literature search using MEDLINE, Embase, PubMed and PsychInfo databases. We selected studies that explored the correlation between early clinical and paraclinical findings, and patient outcomes. Data was extracted, analyzed and recorded in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Forty four publications detailing 2823 subjects matched our inclusion criteria. There was considerable heterogeneity in methodology, patient profile, investigation results and clinical outcome measures. Findings were often discrepant for cases of anti-NMDAR encephalitis when compared with other causes of autoimmune encephalitis. Delay in immunotherapy contributed to a variety of worse outcomes for patients with different subsets of autoimmune encephalitis. Altered consciousness, ICU admission and no use of immunotherapy were variables associated with poor prognosis in anti-NMDAR encephalitis. Older age, sex, the presence of status epilepticus, CSF abnormalities and MRI changes were unlikely to have significant prognostic value. The influence of antibody titers, autonomic dysfunction and underlying malignancy was unclear. CONCLUSIONS: A number of variables were identified to have potential predictive value for outcomes in autoimmune encephalitis. Heterogeneous study design, size and quality were major limiting factors in this review.

Prognosis in autoimmune encephalitis: Database.

Autoimmune encephalitis is a rare and debilitating disease. An important question in clinical neurology is what factors may be correlated with outcomes in autoimmune encephalitis. There is observational data describing statistical analyses on such variables, but there are no review articles that collaborate and interpret this information. This data in brief article represents the data collection for such a review (Broadley et al., 2018). Herein we summarize clinical information from 44 research articles, in particular pertaining to outcomes and prognostic variables.