Rasmussen encephalitis and comorbid autoimmune diseases: A window into disease mechanism?
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ABSTRACT: Objective
To describe a potential association between comorbid autoimmune disease and Rasmussen encephalitis (RE) and discuss potential insights into underlying RE pathogenesis.Methods
We report a case series of 4 patients with RE in whom a comorbid autoimmune disease was subsequently diagnosed and review the literature on possible common susceptibility factors.Results
In 4 patients who presented with typical clinical features of RE, a comorbid autoimmune disease was subsequently diagnosed: Hashimoto thyroiditis, ulcerative colitis, Crohn disease, and systemic lupus erythematosus. We discuss the possible common predisposing factors.Conclusions
The association of RE, a rare entity, with a comorbid autoimmune disease raises the possibility of shared mechanisms of susceptibility, including common immunogenetic and/or environmental risk factors.
SUBMITTER: Amrom D
PROVIDER: S-EPMC4166360 | biostudies-literature | 2014 Sep
REPOSITORIES: biostudies-literature
Publications
Rasmussen encephalitis and comorbid autoimmune diseases: A window into disease mechanism?
Amrom Dina D Kinay Demet D Hart Yvonne Y Berkovic Samuel F SF Laxer Ken K Andermann Frederick F Andermann Eva E Bar-Or Amit A
Neurology 20140820 12
<h4>Objective</h4>To describe a potential association between comorbid autoimmune disease and Rasmussen encephalitis (RE) and discuss potential insights into underlying RE pathogenesis.<h4>Methods</h4>We report a case series of 4 patients with RE in whom a comorbid autoimmune disease was subsequently diagnosed and review the literature on possible common susceptibility factors.<h4>Results</h4>In 4 patients who presented with typical clinical features of RE, a comorbid autoimmune disease was subs ...[more]
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Project description:BACKGROUND:Immune-mediated mechanisms substantially contribute to the Rasmussen encephalitis (RE) pathology, but for unknown reasons, immunotherapy is generally ineffective in patients who have already developed intractable epilepsy; overall laboratory data regarding the effect of immunotherapy on patients with RE are limited. We analyzed multiple samples from seven differently treated children with RE and evaluated the effects of immunotherapies on neuroinflammation. Immunotherapy was introduced to all patients at the time of intractable epilepsy and they all had to undergo hemispherothomy. METHODS:Immunohistochemistry, flow cytometry, Luminex multiplex bead and enzyme-linked immunosorbent assay techniques were combined to determine: 1) inflammatory changes and lymphocyte subpopulations in 45 brain tissues; 2) lymphocyte subpopulations and the levels of 12 chemokines/cytokines in 24 cerebrospinal fluid (CSF) samples and 30 blood samples; and 3) the dynamics of these parameters in four RE patients from whom multiple samples were collected. RESULTS:Sustained T cell-targeted therapy with cyclophosphamide, natalizumab, alemtuzumab, and intrathecal methotrexate (ITMTX), but not with azathioprine, substantially reduced inflammation in brain tissues. Despite the therapy, the distributions of CD8+ T cells and the levels of C-X-C motif ligand (CXCL) 10, CXCL13, and B cell activating factor (BAFF) in patients' CSF remained increased compared to controls. A therapeutic approach combining alemtuzumab and ITMTX was the most effective in producing simultaneous reductions in histopathological inflammatory findings and in the numbers of activated CD8+ T cells in the brain tissue, as well as in the overall CD8+ T cell population and chemokine/cytokine production in the CSF. CONCLUSIONS:We provide evidence that various T cell-targeted immunotherapies reduced inflammation in the brains of RE patients. The observation that intractable epilepsy persisted in all of the patients suggests a relative independence of seizure activity on the presence of T cells in the brain later in the disease course. Thus, new therapeutic targets must be identified. CXCL10, CXCL13 and BAFF levels were substantially increased in CSF from all patients and their significance in RE pathology remains to be addressed.
| S-EPMC7517818 | biostudies-literature
Project description:Rasmussen encephalitis (RE) is a rare childhood neurological disease characterized by progressive unilateral loss of function, hemispheric atrophy and drug-resistant epilepsy. Affected brain tissue shows signs of infiltrating cytotoxic T-cells, microglial activation, and neuronal death, implicating an inflammatory disease process. Recent studies have identified molecular correlates of inflammation in RE, but cell-type-specific mechanisms remain unclear. We used single-nucleus RNA-sequencing (snRNA-seq) to assess gene expression across multiple cell types in brain tissue resected from two children with RE. We found transcriptionally distinct microglial populations enriched in RE compared to two age-matched individuals with unaffected brain tissue and two individuals with Type I focal cortical dysplasia (FCD). Specifically, microglia in RE tissues demonstrated increased expression of genes associated with cytokine signaling, interferon-mediated pathways, and T-cell activation. We extended these findings using spatial proteomic analysis of tissue from four surgical resections to examine expression profiles of microglia within their pathological context. Microglia that were spatially aggregated into nodules had increased expression of dynamic immune regulatory markers (PD-L1, CD14, CD11c), T-cell activation markers (CD40, CD80) and were physically located near distinct CD4+ and CD8+ lymphocyte populations. These findings help elucidate the complex immune microenvironment of RE.
| S-EPMC9677917 | biostudies-literature
Project description:Rasmussen encephalitis (RE) is a rare pediatric neuroinflammatory disease of unknown etiology characterized by intractable seizures, and progressive atrophy usually confined to one cerebral hemisphere. Surgical removal or disconnection of the affected cerebral hemisphere is currently the only intervention that effectively stops the seizures. Histopathological evaluation of resected brain tissue has shown that activated brain resident macrophages (microglia) and infiltrating T cells are involved in the inflammatory reaction. Here, we report that T cells isolated from seven RE brain surgery specimens express the resident memory T cell (TRM) marker CD103. CD103 was expressed by >50% of CD8(+) ?? T cells and ?? T cells irrespective of the length of time from seizure onset to surgery, which ranged from 0.3 to 8.4?years. Only ~10% of CD4(+) ?? were CD103(+), which was consistent with the observation that few CD4(+) T cells are found in RE brain parenchyma. Clusters of T cells in brain parenchyma, which are a characteristic of RE histopathology, stained for CD103. Less than 10% of T cells isolated from brain specimens from eight surgical cases of focal cortical dysplasia (FCD), a condition that is also characterized by intractable seizures, were CD103(+). In contrast to the RE cases, the percent of CD103(+) T cells increased with the length of time from seizure onset to surgery. In sections of brain tissue from the FCD cases, T cells were predominantly found around blood vessels, and did not stain for CD103. The presence of significant numbers of TRM cells in RE brain irrespective of the length of time between clinical presentation and surgical intervention supports the conclusion that a cellular immune response to an as yet unidentified antigen(s) occurs at an early stage of the disease. Reactivated TRM cells may contribute to disease progression.
| S-EPMC4763066 | biostudies-other
Project description:Rasmussen encephalitis (RE) is a rare childhood neurological disease characterized by progressive unilateral loss of function, hemispheric atrophy and drug-resistant epilepsy. Affected brain tissue shows signs of infiltrating cytotoxic T-cells, microglial activation, and neuronal death, implicating an inflammatory disease process. Recent studies have identified molecular correlates of inflammation in RE, but cell-type-specific mechanisms remain unclear. We used single-nucleus RNA-sequencing (snRNA-seq) to assess gene expression across multiple cell types in brain tissue resected from two children with RE. We found transcriptionally distinct microglial populations enriched in RE compared to two age-matched individuals with unaffected brain tissue and two individuals with Type I focal cortical dysplasia (FCD). Specifically, microglia in RE tissues demonstrated upregulation of genes associated with cytokine signaling, interferon-mediated pathways, and T-cell activation. We extended these findings using spatial proteomic analysis of tissue from four surgical resections to examine expression profiles of microglia within their pathological context. Microglia that were spatially aggregated into nodules had increased expression of dynamic immune regulatory markers (PD-L1, CD14, CD11c), T-cell activation markers (CD40, CD80) and were physically located near distinct CD4+ and CD8+ lymphocyte populations. These findings help elucidate the complex immune microenvironment of RE.
2022-12-21 | GSE213364 | GEO
Project description:Rasmussen encephalitis (RE) is a rare but devastating condition, mainly in children, characterized by sustained brain inflammation, atrophy of one cerebral hemisphere, epilepsy, and progressive cognitive deterioration. The etiology of RE-induced seizures associated with the inflammatory process remains unknown.Cortical tissue samples from children undergoing surgical resections for the treatment of RE (n = 16) and non-RE (n = 12) were compared using electrophysiological, morphological, and immunohistochemical techniques to examine neuronal properties and the relationship with microglial activation using the specific microglia/macrophage calcium-binding protein, IBA1 in conjunction with connexins and pannexin expression.Compared with non-RE cases, pyramidal neurons from RE cases displayed increased cell capacitance and reduced input resistance. However, neuronal somatic areas were not increased in size. Instead, intracellular injection of biocytin led to increased dye coupling between neurons from RE cases. By Western blot, expression of IBA1 and pannexin was increased while connexin 32 was decreased in RE cases compared with non-RE cases. IBA1 immunostaining overlapped with pannexin and connexin 36 in RE cases.In RE, these results support the notion that a possible mechanism for cellular hyperexcitability may be related to increased intercellular coupling from pannexin linked to increased microglial activation. Such findings suggest that a possible antiseizure treatment for RE may involve the use of gap junction blockers.
| S-EPMC4303544 | biostudies-literature
Project description:Rasmussen encephalitis is a unilateral encephalitis characterized by treatment-resistant epilepsy and progressive cognitive and motor decline. MRI reveals inflammation and neuropathology reveals reactive astrocytes, microglial activation, microglial nodules, T cell infiltration, and neuronal loss.
Despite the abundant evidence of altered signaling pathways in Rasmussen brain tissue and associated genetic variants, the mechanisms remain poorly understood, and it is uncertain which are a part or result of the underlying cause
In Rasmussen brain tissue, we identified by RNAseq altered immune signaling pathways, immune cell type annotation enrichment, and by whole exome sequencing HLA variants more common to Rasmussen. These findings demonstrate immune cell infiltration associated with innate and adaptive immune responses, as well as HLA variants that may increase vulnerability to RE.
2022-04-05 | MSV000089203 | MassIVE
Project description:ObjectiveTo determine the clinical features and presence in CSF of antineuronal antibodies in patients with pathologically proven autoimmune encephalitis derived from a cohort of patients with suspected Creutzfeldt-Jakob disease (CJD).MethodsThe Dutch Surveillance Centre for Prion Diseases performed 384 autopsies on patients with suspected CJD over a 14-year period (1998-2011). Clinical information was collected from treating physicians. Antineuronal antibodies were tested in CSF obtained postmortem by immunohistochemistry on fresh frozen rat brain sections, by Luminex assay for the presence of well-characterized onconeural antibodies, and by cell-based assays for antibodies against NMDAR, GABABR1/2, GABAAR GLUR1/2, LGI1, Caspr2, and DPPX.ResultsIn 203 patients, a diagnosis of definite CJD was made, while in 181 a variety of other conditions were diagnosed, mainly neurodegenerative. In 22 of these 181, the neuropathologist diagnosed autoimmune encephalitis. One patient was excluded because of lack of clinical information. Inflammatory infiltrates were predominantly perivascular and consisted mainly of T cells. The predominant locations were basal ganglia and thalamus (90%) and temporal lobes and hippocampus (81%). In 6 patients (29%), antineuronal antibodies were detected in postmortem CSF, directed against Hu, NMDAR, GABABR1/2, Caspr2, and an unidentified synaptic antigen in 2. The most frequent symptoms were dementia (90%), gait disturbance (86%), cerebellar signs (67%), and neuropsychiatric symptoms (67%). Immunopathologic and clinical findings did not differ between autoantibody-negative patients and patients with antineuronal antibodies.ConclusionsIt is important to consider immune-mediated disorders in the differential diagnosis of rapidly progressive neurologic deficits.
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Project description:BackgroundSleep disorders (SDs) in autoimmune encephalitis (AE) have received little attention and are poorly understood. We investigated the clinical characteristics, risk factors, and cerebral metabolic mechanism of SD in AE.MethodsClinical, laboratory, and imaging data were retrospectively reviewed in 121 consecutively patients with definite AE. The risk factors for SD in AE were estimated by logistic regression analysis. Group comparisons based on 18F-fluorodeoxy-glucose positron emission tomography (18F-FDG-PET) data were made between patients with and without SD, to further analyze potential brain metabolic mechanism of SD in AE.ResultsA total of 52.9% patients (64/121) with SD were identified. The multivariate logistic model analysis showed that smoking [odds ratio (OR), 6.774 (95% CI, 1.238-37.082); p = 0.027], increased Hamilton Depression scale (HAMD) score [OR, 1.074 (95% CI, 1.002-1.152); p = 0.045], hyperhomocysteinemia [OR, 2.815 (95% CI, 1.057-7.496); p = 0.038], elevated neuron-specific enolase (NSE) level [OR, 1.069 (95% CI, 1.007-1.135); p = 0.03] were independently correlated with higher risk of SD in AE patients. Contrastingly, high MoCA score [OR, 0.821 (95% CI, 0.752-0.896); p < 0.001] was associated with lower risk of SD in AE subjects. Compared to controls, AE patients had less total sleep time, less sleep efficiency, longer sleep latency, more wake, higher percent of stage N1, lower percent of stage N3 and rapid eye movement, and more arousal index in non-rapid eye movement sleep (p < 0.05 for all). Voxel-based group comparison analysis showed that, compared to patients without SD, patients with SD had increased metabolism in the basal ganglia, cerebellum, brainstem, median temporal lobe, thalamus, and hypothalamus [p < 0.05, false discovery rate (FDR) corrected]; decreased metabolism in superior frontal gyrus, medial frontal gyrus, and posterior cingulate cortex (p < 0.001, uncorrected). These results were confirmed by region of interest-based analysis between PET and sleep quality.ConclusionSmoking, increased HAMD score, hyperhomocysteinemia, and elevated NSE level were correlated with higher risk of SD. High MoCA score was associated with lower risk of SD in AE subjects. Moreover, a widespread metabolic network dysfunction may be involved in the pathological mechanism of SD in AE.
| S-EPMC8652207 | biostudies-literature
Project description:Interaction between genetic and epigenetic mechanisms may lead to autoimmune diseases. The features of these diseases show familial aggregation. The generality and specificity are keys to studying pathogenesis and etiology of them. This research integrated data of genetics and epigenetics, to find disease-related genes based on the levels of expression and regulation, and explored then to the shared and specific mechanism of them by analyzing shared and specific pathways of common four autoimmune diseases, including Type 1 Diabetes Mellitus (T1D), Multiple Sclerosis (MS), Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE). The results showed that Lysosome and Fc gamma R-mediated phagocytosis are shared pathways of the four diseases. It means that the occurrence and development of them may associate with lysosomes and phagocytosis. And there were 2 pathways are shared pathways of three diseases, ribosome pathway associated with susceptibility to MS, RA and SLE, and Pathogenic Escherichia coli infection associated with susceptibility to T1D, MS and RA; 9 pathways are shared pathways of two diseases. The corporate underlying causes of these diseases may be these shared pathways activated. Furthermore, we found that T1D-related specific pathways (Insulin signaling,etc.) were 9, MS (Proteasome,etc.) is also 9, RA and SLE is 10 and 6 respectively. These pathways could help us to reveal shared and specific mechanisms of the four diseases.
| S-EPMC5752449 | biostudies-literature
Project description: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.
| S-EPMC7563270 | biostudies-literature